Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([NH:8][OH:9])=[O:7].N1C=CC=CC=1.[CH2:21]([C:23]([CH2:30][CH3:31])([C:27](Cl)=[O:28])[C:24](Cl)=[O:25])[CH3:22]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([N:8]1[C:24](=[O:25])[C:23]([CH2:30][CH3:31])([CH2:21][CH3:22])[C:27](=[O:28])[O:9]1)=[O:7]
Reactant: COc1ccc(C(=O)NO)cc1OC
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(OC)c(OC)c2)C1=O
Yield: 73.4 %

Procedure:
A mixture consisting of 1.97 g (0.0100 mol) of 3,4-dimethoxybenzohydroxamic acid, mp 170-173° C. (dec.) (lit, mp 167-168° C., F. Aljundi, E. Hannig, and K. Bohm, Pharmazie, 28, 362 (1973)), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 1.977 g (0.0100 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 1 hour at room temperature after which time all the hydroxamic acid has dissolved. The solution was extracted three times with 50 ml portions of water, four times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 2.36 g (73.5%) of crude 2-(3,4-dimethoxybenzoyl)-4,4-diethylisoxazolidine-3,5dione as a solid residue. Recrystallization of the solid from absolute ethanol gave pure 2-(3,4-dimethoxybenzoyl)-4,4-diethylisoxazolidine-3 5dione as a white solid: mp 108-109° C. IR (Nujol) 1805 (s, C=0), 1752 (s, C=0), 1693 cm-1 (s, C=0); 1H NMR (400 MHz, CDCl3) δ7.40-7.54 (m, 2H), 6.94-6.96 (d, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 1.97 (q, 4H), 1.02 (t, 6H); High resolution MS, calc'd for: C16H19NO6 : 321.1212. Found: 321.1208. Anal. Calc'd for: C16H19NO6 : C, 59.80; H, 5.96; N, 4.36. Found: C, 60.04; H, 6.05; N, 4.44.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:6])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (13.4 g: 50 mmole) in dichloromethane (50 ml), p-chlorobenzenesulfonyl chloride (12.66 g: 60 mmole) is added in a nitrogen atmosphere at room temperature and a solution of triethylamine (8.69 ml: 62.5 mmole) in dichloromethane (10 ml) is further added dropwise. The mixture is stirred at room temperature overnight. The reaction mixture is successively washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (toluene-ethyl acetate) to give crude (2S,4R)-1-allyloxycarbonyl-2-p-chlorobenzenesulfonyloxy methyl-4-methanesulfonyloxypyrrolidine (23.73 g) as oil. Yield: 105%. NMR δ(CDCl3) ppm: 2.2 to 2.6(m, 2H), 3.04(s, 3H), 3.58(dd, J=5.0 Hz, J=11.4 Hz, 1H), 3.8 to 4.0(m, 1H), 4.1 to 4.3(m, 3H), 4.5(m, 3H), 5.1 to 5.4(m, 3H), 5.7 to 6.0(m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:21][CH2:22][C:23](Cl)=O>C(O)(=O)C>[Cl:21][CH2:22][C:23]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=2)[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1c2ccc([N+](=O)[O-])cc2nc(CCl)n1-c1ccccc1Cl
Yield: 56.4 %

Procedure:
Prepared according to Procedure B with 1o (500 mg, 1.71 mmol) and chloroacetyl chloride (0.41 mL, 5.14 mmol) in acetic acid (10 mL). Purified by extraction from aqueous K2CO3, followed by two chromatographies in CH2Cl2 to afford 338 mg of a yellow oil (56%). 1H NMR (CDCl3) δ: 8.64 (d, J=2.2 Hz, 1H); 8.48 (d, J=8.8 Hz, 1H); 8.32 (dd, J=2.2, 8.7 Hz, 1H); 7.66 (dd, J=2.5, 6.0 Hz, 1H); 7.52-7.59 (m, 3H); 4.41 (d, J=12 Hz, 1H), 4.10 (d, J=12 Hz, 1H). MS (ES): m/z 350.0 (M+)
Reaction SMILES: [C:1]([O:13]CC)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[K+]>C(O)C>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:12])[CH3:11]
Reactant: CCOC(=O)CCCCCC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCCCCC(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 67.3 %

Procedure:
To a solution of diethyl heptanedioate (65 g, 0.30 mol) in Ethanol (400 mL) was added KOH (16.8 g, 0.30 mmol). The mixture was stirred at 80° C. for 24 hours, and concentrated under reduced pressure. The resulting mixture was poured into water and the pH value of the solution was adjusted to 1 by concentrated H2SO4. After removal of the solvent, the crude product was purified by flash chromatography SiO2(EtOH:EtOAc=1:10) to give the desired compound (38 g, yield 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](O)=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].B.C1COCC1.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCCO)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(5-nitropyridin-2-yloxy)phenyl]propionic acid (2.64 g, 9.2 mmol) in THF (50 mL) was added dropwise a 1 M borane-THF complex THF solution (38.4 mL, 38.4 mmol) under ice cooling. The reaction solution was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and then brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 1.17 g of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([Cl:18])[N:12]=1>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:15]3[N:14]=[C:13]([Cl:18])[N:12]=[C:11]([Cl:10])[N:16]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of 5-Cyclopropyl-2H-pyrazol-3-ylamine(334 mg, 2.71 mmol) in 2 ml of THF was added dropwise to a solution of 2,4,6-Trichloro-[1,3,5]triazine (500 mg, 2.71 mmol) in 5 ml of THF at room temperature. After 1 hour, the precipitate was collected to afford 370 mg (50.4% yield) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Na].[CH3:11][SH:12]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[CH3:11][S:12][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: CS
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na]
Solvent: Clc1ccccc1
Product: CSc1ccccc1C#N

Procedure:
2-Chlorobenzonitrile (27.5 g, 0.2 mol), monochlorobenzene (30.0 g), and a 50% by weight aqueous solution (1.0 g) of tetra-n-butyl ammonium bromide were placed in a 500-ml four-necked flask equipped with a stirrer, a thermometer, a dropping funnel, and a condenser under a nitrogen atmosphere to obtain a mixture. A 30% by weight aqueous solution (51.4 g) of sodium salt of methanethiol (0.22 mol) was added dropwise to the mixture at 60 to 65° C. over a period of 5 hours under stirring. After completion of the dropwise addition, the mixture was further allowed to react at the same temperature for 12 hours. By this operation, 2-(methylthio)benzonitrile was obtained.
Reaction SMILES: [CH:1]1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:1][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccccc1
Solvent: c1ccncc1
Product: Cc1cccnc1
Yield: 99.5 %

Procedure:
The condensate 13 led to the working up after addition of 1800 ml of benzene per hour separated into 2 phases. The aqueous phase was extracted with 1800 ml of benzene hourly. In the distillation of the benzene phases there resulted per hour 851 grams of pyridine and 862 grams of 3-methylpyridine corresponding to a yield of 98.4% of pyridine and 99.5% yield of 3-methylpyridine based on the content of reaction gases supplied.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[CH:38]1([N:41]=[C:42]=[O:43])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:42](=[O:43])[NH:41][CH:38]3[CH2:40][CH2:39]3)(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: NS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: O=C=NC1CC1
Product: O=C(NC1CC1)NS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 48.5 %

Procedure:
Using 7-(2-chloro-4-fluorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.10 g, 0.18 mmol) obtained in step 5 and cyclopropylisocyanate (0.046 g, 0.549 mmol) instead of ethylisocyanate, and in the same manner as in Example 7, the title compound (0.055 g, 47%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]1[O:13][CH:5]1[CH2:6][O:7]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:4]2[C:3]3[C:8](=[C:9]([F:12])[CH:10]=[CH:11][C:2]=3[F:1])[O:7][CH2:6][CH:5]2[OH:13])=[CH:17][CH:16]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Fc1ccc(F)c2c1OCC1OC21
Solvent: O
Solvent: ClCCl
Product: OC1COc2c(F)ccc(F)c2C1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,8-Difluoro-2H-chromene oxide (23 g, 0.125 mole) and 4-Chloro-benzenethiol (18.1 g, 0.125 mmole) were dissolved in 500 ml DCM and InCl3 (2.9 g, 0.013 mole) was added. The reaction was stirred at room temperature overnight. 200 ml DCM and 200 ml water were added. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/hexane from 0/100 to 50/50 in 55 minute). Yield: 23.2 g, 57%. 1H NMR (CDCl3 400 MHz δ 7.48 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 7.01 (m, 1H), 6.64 (m, 1H), 4.63 (d, J=11.7 Hz, 1H), 4.32-4.41 (m, 2H), 4.12 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccccc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and phenylboronic acid (Aldrich, Buchs, Switzerland, 16.5 mg, 0.135 mmol) to give the title compound as a white solid. (HPLC: tR 2.70 min (Method A); M+H=370 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.16 (s, 1H), 8.11-8.06 (m, 1H), 7.93-7.88 (m, 1H), 7.56-7.53 (m, 1H), 7.50-7.44 (m, 4H), 7.42-7.34 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[NH3:14]>>[CH3:1][O:2][C:3]1[C:4]([C:10]([NH2:14])=[O:12])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COC(=O)c1ncc(C)nc1OC
Reactant: N
Product: COc1nc(C)cnc1C(N)=O
Temperature: 50 °C
Yield: 87 %

Procedure:
1 g (5.5 mmol) of methyl 3-methoxy-5-methylpyrazine-carboxylate was initially charged in 15 ml (198 mmol) of NH3 (25%) and the mixture was stirred at 50° C. After concentration, 0.8 g of 3-methoxy-5-methylpyrazine-2-carboxamide was obtained. The yield was 86 percent. Other data concerning the title product was:
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[NH2:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31]([S:35]S(C2C=CC(C)=CC=2)(=O)=O)=[C:30]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31]([S:35][C:3]2[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[CH2:7][C:2]=2[OH:1])=[C:30]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1N
Reaction time: 18 h

Procedure:
The compound was synthesized following General Method 9 using 118 mg (0.33 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 150 mg (0.33 mmol) of toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl) ester (prepared in Example HHHH), 184 mg (1.32 mmol) of K2CO3 and 2 mL of DMF. The reaction was worked up by partitioning between EtOAc and H2O. The organic layer was separated and concentrated, then triturated with Et2O. The resultant solid was placed in chilled HCI-saturated CH2Cl2 and stirred for 18 hours. After concentration, the residue was triturated with Et2O to yield the title compound, m.p. 140-145° C. 1H NMR (DMSO-d6) δ 1.5 (s, 9 H), 1.9 (s, 3 H), 2.05 (m, 4 H), 2.5 (m, 6 H), 6.68 (d, 4 H), 6.75 (s, 1 H), 7.0 (d, 4 H), 7.35 (s, 1 H), 7.95 (s 2 H), 9.25 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:22][CH:23]=1)[NH:24][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[C:9]2[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CCCC(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12

Procedure:
Prepared from 4-chloro-δ-oxobenzenepentanoic acid and (4-chlorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (250 MHz, DMSO-d6) δ2.55-2.61 (2H, m), 3.07-3.13 (2H, m), 7.16 (2H, d, J 12.6 Hz), 7.41 (2H, d, J 12.6 Hz), 7.62-7.71 (3H, m), 11.52 (1H, br s), and 12.19 (1H, br s). m/z (ES+) 331, 333 (M+1).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: CC(C)(C)CCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2321, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.1 min, 96.8% purity.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39](S(C)(=O)=O)[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([O:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:9]3[CH:8]=[C:7]([CH:21]4[CH2:23][CH2:22]4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:10]=3)[CH2:16][CH2:15]2)[N:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCO)CC2)n1
Reactant: CS(=O)(=O)c1nccc(OCc2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCOc3nccc(OCc4ccccc4)n3)CC2)n1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
0.5 g of 3-[4-(2-tert-Butyl-6-cyclopropyl-pyrimidin-4-yl)-piperazin-1-yl]-propan-1-ol (1.57 mmol) were dissolved in 5 ml of tetrahydrofuran. 1.5 ml of n-butyllithium (15% in hexane) were added to the mixture at 0° C. Stirring was continued for 30 min and then 0.45 g of 4-benzyloxy-2-methanesulfonyl-pyrimidine (1.7 mmol) dissolved in 5 ml of tetrahydrofuran were added. The reaction was stirred overnight at room temperature and for an additional 2 h at 40° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (0-3%) as eluent to yield 0.6 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.[CH:13]([Mg]Cl)([CH3:15])[CH3:14].[Cl-].[NH4+]>CCOCC>[Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]([OH:12])[CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1cc(Br)c2c(c1)OCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)C(O)c1cc(Br)c2c(c1)OCO2
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 7-bromo-benzo[1,3]dioxole-5-carbaldehyde (437 mg, 1.91 mmol) in dry ether (6 mL) was added slowly under argon at −30° C. isopropylmagnesium chloride (1.15 mL, 2.0 M in ether, 2.29 mmol) and the solution stirred for 30 minute. A solution of aqueous ammonium chloride was added and the layers separated. The aqueous layer was extrated with ethyl acetate and the organic combined and washed with water, brine, dried (MgSO4), filtered and evaporated to give 503 mg of 1-(7-bromo-benzo[1,3]dioxol-5-yl)-2-methyl-propan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][CH3:32])=[CH:26][CH:27]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CO)cc3)c2CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (133 mg, 0.306 mmol) in anhydrous DMF (2 mL) under nitrogen, add sodium hydride (60% dispersion, 13-15 mg, 0.375 mmol) at ambient temperature and continue stirring for 30 min. Add methyl iodide (80 □L, 1.28 mmol). After 15 min, dilute with water, extract three times with EtOAc, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (15:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-methoxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil, which crystallizes on standing to a white solid (87 mg, 63%), along with recovered starting material (22 mg, 17%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 348 (M+H-Boc)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7].[OH-].[NH4+:13]>C1COCC1>[NH2:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7]
Reactant: [NH4+]
Reactant: N#Cc1cc(F)cc(CBr)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(CN)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 14, step 1, 10 g, 0.47 mol) in THF (50 mL) was added ammonium hydroxide solution 25% (2.0 L). The resulting mixture was stirred for 2 h at 85° C. It was then cooled down to RT and extracted with dichloromethane. The organic layer was washed with water, brine, dried and concentrated, affording the title compound as a slight yellow liquid (5 g, 71%). 1H NMR (DMSO-d6, 400 MHz): δ 7.6 (d, J=6.6 Hz, 1H), 7.57 (t, J=0.6 Hz, 1H), 7.55 (s, 1H), 3.74 (d, 2H), 1.97 (s, 2H). LC/MS (Method A) 151.0 (M+H)+. HPLC (Method A) Rt: 0.88 min (Purity 98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:15]#[N:16])[N:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH2:1]([O:3][C:4](=[O:17])[C:5]([N:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[C:15]([NH2:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(C#N)N(C)Cc1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(=C(N)c1ccccc1)N(C)Cc1ccccc1

Procedure:
Ethyl-2-[methyl(phenylmethyl)amino]-cyanoacetate (0.049 mol, 11.3 g) was dissolved in 300 mL of ether and added to 32 mL of 3M PhMgBr, and the resulting mixture was refluxed for 18 h. The reaction was cooled, quenched with sat. NH4Cl solution and extracted with ether. The organics were dried, concentrated, and chromatographed using 1:1 hexanes:ethyl acetate to give 5 g of product. 1H NMR (300 MHz) CDCl3: 7.6-7.2 (m, 10H), 5.01 (s, 1H), 4.27 (t, 2H), 3.59 (s, 2H), 2.73 (t, 2H), 2.31 (s, 3H).