Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:33][C:34]1([OH:38])[CH2:37][NH:36][CH2:35]1>>[OH:38][C:34]1([CH3:33])[CH2:37][N:36]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC1(O)CNC1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1) and 3-methylazetidin-3-ol to afford an off-white powder. HPLC (Condition 4) tR=4.52 min, UPLC-MS (Condition 3) tR=0.88 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.30 (s, 3H) 3.61 (s, 4H) 5.40 (s, 1H) 6.41 (s, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.74-7.89 (m, 3H) 8.04 (d, J=2.35 Hz, 1H) 8.70 (s, 1H) 10.20 (s, 1H) 12.90-13.15 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:15])[CH:11]=[C:12](C)[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.CC(C)(C=CC)CC(=[O:21])C>>[CH3:1][C:2]12[O:21][C:3]1([C:10](=[O:15])/[CH:11]=[CH:12]\[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7]2
Reactant: CC=CC(C)(C)CC(C)=O
Reactant: CC(C)=CC(=O)C1C(C)=CCCC1(C)C
Product: C/C=C\C(=O)C12OC1(C)CCCC2(C)C

Procedure:
MS: M+ = 208 (0.1); m/e: 193 (1); 175 (0.1); 165 (0.1); 151 (15); 135 (2); 123 (9); 111 (6); 95 (4); 81 (2); 69 (100); 55 (18); 41 (26) 29 (3).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)#[N:20]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCC(O)CC1
Yield: 40.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (4 g) and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (4 g), the title compound (2.8 g) was obtained. melting point: 224-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=[O:10])[CH:5]=[CH:4][N:3]=1>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc(Cl)c1
Agent: Cl
Product: O=C(O)Cc1ccnc(Cl)c1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A solution of diethyl 2-(2-chloropyridin-4-yl)malonate (1.30 g, 4.79 mmol) in conc. HCl (15 ml) was refluxed for 18 h. The reaction mixture was cooled to room temperature, concentrated and co-distilled with toluene (2×20 ml) to afford the crude product. Purification by triturating with diethyl ether afforded 500 mg (57%) of 2-(2-chloropyridin-4-yl)acetic acid as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[C:10]2[N:11]=[CH:12][N:13]([OH:16])[C:14](=[O:15])[C:9]=2[S:8][CH:7]=1.O>O1CCCC1.N1C=CC=CC=1.CN1CCCC1=O>[C:1]([O:16][N:13]1[C:14](=[O:15])[C:9]2[S:8][CH:7]=[C:6]([Br:5])[C:10]=2[N:11]=[CH:12]1)(=[O:3])[CH3:2]
Reactant: O=c1c2scc(Br)c2ncn1O
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)On1cnc2c(Br)csc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of acetyl chloride (0.234 g) in dry tetrahydrofuran (3 ml) was added a solution of the product from Example 4 (0.741 g) in pyridine (0.237 g) and N-methylpyrrolidone (5 ml) at room temperature. The solution was stirred at room temperature for 3 days and then poured into water (15 ml). The resulting precipitate was filtered, washed with water and dried to give title product, m.p. 159-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1I.[C:13]([Si](C)(C)C)#[CH:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:13]#[CH:14]
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: C#Cc1ccc(C(F)(F)F)cc1Cl
Yield: 80.2 %

Procedure:
The title compound was prepared according to the procedure described in step-5 and step-6 of Intermediate-2 by using 2-chloro-1-iodo-4-(trifluoromethyl)benzene (1.0 g, 3.2 mmol), ethynyl(trimethyl)silane (0.541 g, 5.5 mmol), copper iodide (0.027 g, 0.14 mmol), bis(triphenylphosphine) palladium(II) chloride (0.050 g, 0.072 mmol), TBAF (catalytic) and DCM to afford 0.525 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 4.88 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 8.01 (s, 1H).
Reaction SMILES: Br.[OH:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[C:17]2[C:26]3[CH:25]=[CH:24][S:23][C:22]=3[C:21](=[O:27])[CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:13][CH2:12]1.[OH-].[Na+].[Na]>C(O)C>[OH:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][C:14](=[C:17]2[C:26]3[CH:25]=[CH:24][S:23][C:22]=3[CH:21]([OH:27])[CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:15][CH2:16]1
Reactant: O=C1Cc2ccccc2C(=C2CCN(CCOCCOCCO)CC2)c2ccsc21
Agent: Br
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: OCCOCCOCCN1CCC(=C2c3ccccc3CC(O)c3sccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.8 g 4-{1-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]piperidin-4-ylidene}-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-10(9H)one hydrobromide are added with stirring to a solution of 0.5 g sodium hydroxide in 100 ml ethanol. After 15 minutes, 0.45 g sodium borhydride are added in small portions and the mixture is agitated for 20 hours at room temperature. The solvent is then distilled off, the residue is taken up with water and with sodium hydroxide solution and extracted several times with chloroform. The combined extracts are then dried and evaporated, to give the title compound as a light yellow oil. The hydrogenofumarate of the title compound melts at 110°-113°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:33](=[O:37])[CH:32]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(Cl)cc2Cl)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5Cl)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 19.5 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.548 mmol) and 4-(2,4-dichlorophenyl)pyridine-2(1H)-one (132 mg, 0.548 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) provided the title compound (56 mg, 20%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.56-7.52 (m, 2H), 7.47 (d, J=7.0 Hz, 1H), 7.39-7.32 (m, 3H), 7.10 (br s, 1H), 6.69 (s, 1H), 6.35 (d, J=5.7 Hz, 1H), 4.66 (s, 2H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.84 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:34])=[C:4]([C:8]2[N:9]=[C:10]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:35]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36]1>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:40]([C:37]3[CH:38]=[CH:39][O:35][CH:36]=3)(=[O:42])=[O:41])[C:3]=2[F:34])[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: O=S(=O)(Cl)c1ccoc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (280 mg, 0.556 mmol) in pyridine (3 mL) was added 3-furansulfonyl chloride (139 mg, 0.833 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extract was dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to the title compound (310 mg). MS (ESI): 634.1 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (225 mg, 0.835 mmol), 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 18 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (199 mg, 68.5%) as a solid.
Reaction SMILES: [Fe:1].[NH:2]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[S:3]([C:6]([F:9])([F:8])[F:7])(=[O:5])=[O:4]>O>[NH:2]([S:3]([C:6]([F:9])([F:7])[F:8])(=[O:5])=[O:4])[S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11].[NH:2]([S:3]([C:6]([F:9])([F:7])[F:8])(=[O:5])=[O:4])[S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11].[Fe+2:1]
Reactant: [Fe]
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: [Fe+2]
Temperature: 150 °C

Procedure:
Iron metal (5.0 g, 99.95% purity) lumps were suspended in water (50 mL) and hydrogen bis-triflimide (HNTf2) (10 g) was added. This mixture was heated under reflux for 72 hours. The resultant slurry was cooled, filtered and concentrated on a rotary evaporator to give a pale yellow solution that crystalised on standing. The pale yellow crystals were heated at 150° C. at 1 mmHg to remove the residual water and hydrogen bis-triflimide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[H-].[Na+].I[CH:15]([CH3:17])[CH3:16]>CN(C)C=O>[CH:15]([O:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[OH:11])([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
A solution of 15.5 g of 4-nitrocatechol (100 mmol) in 200 ml of N,N-dimethylformamide is added dropwise at 0° C. to a 60% suspension of sodium hydride in oil (4.2 g, 105 mmol). At the end of the addition (1 hour), the dark red solution is stirred at 0° C. for 1.5 hours and 10.5 mnl of 2-iodopropane (105 mmol) are then added dropwise. The mixture is then brought to 80° C. and stirred for 16 hours. It is then cooled to room temperature, the solvent is evaporated off and the dark red oil is dissolved in dichloromethane (300 ml). The solution is washed with water and then with saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off. The expected product is isolated by chromatography on a column of silica (eluent: 80/20 cyclohexane/ethyl acetate). 10.5 g of a yellow oil which solidifies are recovered:
Reaction SMILES: [N:1]1[C:2]([CH2:10][NH2:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]=O>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1[CH:16]1[N:11]([CH2:10][C:2]2[N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]3[CH:3]=2)[C:14](=[O:13])[CH2:15][CH2:18][CH2:19]1
Reactant: NCc1cn2ccccc2n1
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cn2ccccc2n1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available imidazo[1,2-a]pyridin-2-ylmethanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.50 min.; [M+H]+: 366.12 g/mol.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[CH2:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Cl:4][C:10]([CH2:9][C:8]1[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=1[CH3:6])([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(Cc1ccccc1C)C(C)=O
Product: CCOC(=O)C(Cl)(Cc1ccccc1C)C(C)=O

Procedure:
325 g (2.4 moles) of sulfuryl chloride were added dropwise to 511.0 g (2.2 moles) of ethyl 2-(o-methylbenzyl)-acetoacetate in the course of 2 hours, while stirring. Thereafter, the mixture was heated at 50° to 55° C. for 4 hours. The crude product was purified by vacuum distillation without a column. 547 g (92% of the theoretical yield) of ethyl 2-chloro-2-(o-methylbenzyl)-acetoacetate of boiling point 120° C. at 0.01 mm Hg were obtained.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([C@@H:27]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:28]([O:58][CH3:59])[CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C@H:37]([O:56][CH3:57])[C@@H:38]([CH3:55])[C:39](=[O:54])[NH:40][C@H:41]([C:49]3[S:50][CH:51]=[CH:52][N:53]=3)[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:31])[CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1>O1CCCC1.C(NCC)C>[CH3:59][O:58][C@@H:28]([C@@H:27]([N:25]([CH3:26])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH2:18])[C@@H:60]([CH3:63])[CH2:61][CH3:62])[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C@H:37]([O:56][CH3:57])[C@@H:38]([CH3:55])[C:39](=[O:54])[NH:40][C@H:41]([C:49]1[S:50][CH:51]=[CH:52][N:53]=1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:31]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Yield: 79 %

Procedure:
According to general procedure A, from #85 (5.00 g, 5.68 mmol, 1 eq.) in tetrahydrofuran (10 mL, 0.56 M) and diethylamine (3 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #86 (2.952 g, 79%) as a solid. LC-MS: m/z 658.5 [M+H+], 680.5 [M+Na+] retention time=0.66 minute; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8.4 Hz) and 8.90 (br d, J=8.8 Hz), total 1H], [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.3 Hz), total 1H], [7.63 (d, J=3.3 Hz) and 7.66 (d, J=3.3 Hz), total 1H], 7.12-7.31 (m, 5H), [5.39 (ddd, J=11.2, 8.4, 4.2 Hz) and 5.54 (ddd, J=11.9, 8.9, 4.0 Hz), total 1H], 3.15, 3.19, 3.20 and 3.26 (4 s, total 6H), 2.86 and 2.98 (2 br s, total 3H), [1.06 (d, J=6.6 Hz) and 1.11 (d, J=6.6 Hz), total 3H].
Reaction SMILES: C([NH:8][CH2:9][CH:10]([C:15]#[N:16])[CH:11]([OH:14])[CH2:12][CH3:13])C1C=CC=CC=1.[H][H]>N.CO.[Ni]>[NH2:8][CH2:9][CH:10]([CH2:15][NH2:16])[CH:11]([OH:14])[CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCC(O)C(C#N)CNCc1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCC(O)C(CN)CN
Reaction time: 1 h
Yield: 150.3 %

Procedure:
To a solution of 1-benzylamino-2-cyano-3-hydroxypentane (1.0 g) in 5% ammonia-methanol solution (20 ml) was added Raney Nickel (W2, 5g). After stirring under atmospheric pressure of hydrogen at room temperature for 4 hours, the catalyst was filtered off and to the filtrate were added ammonium formate (1.4 g) and 10% palladium on carbon (1 g, 50% wet). After stirring for 1 hour under reflux, the catalyst was filtered off and the filtrate was evaporated to give 1-amino-2-aminomethyl-3-hydroxypentane (0.91 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH:12][S:13]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])(=[O:15])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[C:7](=[N:12][S:13]([C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])(=[O:15])=[O:14])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CC(C)(C)C1=CC(=NS(=O)(=O)c2c(Cl)cc(Cl)cc2Cl)C(=O)C=C1

Procedure:
In 500 ml of ethyl acetate were dispersed 60.0 g of 4-t-butyl-2-(2,4,6-trichlorobenzenesulfonylamino)phenol and 63.8 g of manganese dioxide. The mixture was refluxed upon heating for 1 hour. After cooling the mixture, inorganic substances were filtered out with Celite. The solvent was then evaporated to obtain orange crystals. The crystals were used in the next reaction without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.O.[NH2:18][NH2:19]>CCO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([NH:18][NH2:19])=[O:12])[N:10]=2)[CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1nc2ccc(I)cn2c1C
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)NN)nc2ccc(I)cn12
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (250 mg) in EtOH (5 ml) was added hydrazine hydrate (0.14 ml) at room temperature. The reaction vessel was sealed and heated at 80° C. for 16 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was washed with EtOAc to give the title compound (200 mg) as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](O)[CH2:13][CH2:14][OH:15].C(OC)(OC)OC.C(N(CC)CC)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:2]1([CH2:9][CH2:10][CH3:11])[O:15][CH2:14][CH2:13][CH2:12][O:1]1)[CH3:8]
Reactant: OCCCO
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: COC(OC)OC
Product: CCCC1(CC(=O)OCC)OCCCO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.5 %

Procedure:
A mixture of ethyl 3-oxohexanoate (5 g, 31.6 mmol), 1,3-propanediol (3.61 g, 47.4 mmol), trimethyl orthoformate (5.78 ml, 34.8 mmol), and p-toluenesulfonic acid monohydrate (272 mg, 1.58 mmol) was stirred at room temperature for 22 hours. After completion of the reaction, triethylamine (881 μl, 6.32 mmol) was added to the reaction mixture which was then concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (5.5 g, yield: 80.5%) as a light yellow oil.
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:23][CH2:24][C:25]1([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.O>[OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH:23][CH2:24][C:25]1([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:4]
Reactant: COC(=O)C1(CN)CCCC1
Reactant: CC(C)[C@H](O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C1(CNC(=O)[C@@H](O)C(C)C)CCCC1
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
To a solution of (S)-2-hydroxy-3-methyl-butyric acid (300 mg, 2.5 mmol) in CH2Cl2/DMF (5:1, 20 mL) at 0° C. was added HOBT (382 mg, 2.5 mmol) and EDC (477 mg, 2.5 mmol). The mixture was stirred for 10 min then methyl 1-(aminomethyl)cyclopentanecarboxylate (321 mg, 2.25 mmol) and iPr2NEt (0.5 mL, 2.5 mmol) were added and stirring was continued for 3 h. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, 1N HCl, sat'd NaHCO3, dried over magnesium sulfate, concentrated, and purified using flash chromatography to give a white solid (420 mg, 72%). MS [M+H]+258.
Reaction SMILES: [Cl:1]C1C=[C:4]([N:12]2CCN(CCCC(O)=O)[C:14](=[O:24])[C@@H:13]2C)[CH:5]=[CH:6][C:7]=1[C:8](F)(F)F.C1C2(CCNC[C@H]2O)C1>>[ClH:1].[CH2:7]1[C:6]2([CH2:5][CH2:4][NH:12][CH2:13][C@H:14]2[OH:24])[CH2:8]1
Reactant: C[C@H]1C(=O)N(CCCC(=O)O)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Agent: O[C@@H]1CNCCC12CC2
Product: Cl

Procedure:
In analogy to the procedure described in Example 15, 4-[(S)-4-(3-chloro-4-trifluoromethyl-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-butyric acid (26% ee) and 1.1 eq. of (S)-6-aza-spiro[2.5]octan-4-ol; hydrochloride (intermediate 2) gave after precipitation (Et2O/n-pentane) the titled compound in 95% yield as light yellow foam. MS: 488.19 (MH+, Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccncc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(4-pyridyl)acetate hydrochloride (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp=175-181° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(C(C)=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(O)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(OCCO)cc1

Procedure:
4-(2-Methyl-1H-imidazol-1-yl)phenol (10.0g, 0.057 mole), 2-chloroethanol (13.88 g, 0.172 mole) and potassium carbonate (23.74 g, 0.172 mole) were combined in methyl ethyl ketone (200 ml) and heated at reflux temperature for four days. The solution was cooled and the solid filtered and rinsed with acetone. The filtrate was concentrated to a residue and the residue triturated with hot acetone (2×50 ml). The remaining solid (1.5 g) was dissolved in methylene chloride. Insoluble materials were removed by filtrateion, and the filtrate concentraed to obtain 0.50 g (4%), mp 125°-127° C. Proton NMR indicates that methylene chloride is present in the sample.