Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1ncccc1CO)C1CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
To a flame-dried flask containing 1-benzyl-4-(N-methyl-N-(3-methoxycarbonyl-2-pyridyl)amino)piperidine (XXIX, EXAMPLE 34, 750 mg) in dry tetrahydrofuran (22 ml) at 0° under nitrogen is added lithium aluminum hydride (84 mg) in two portions. The mixture is stirred at 0° for 1.5 hrs, quenched carefully with aqueous sodium hydroxide (5%, 5 ml), diluted with water (10 ml) and filtered through a pad of diatomaceous earth. The filtrate is then extracted with methylene chloride (2×30 ml) and the combined organic phases are washed with saline (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 8.28, 7.53, 7.31, 7.24, 6.99, 4.90, 4.71, 3.48, 3.16, 2.91, 2.74, 1.99 and 1.74δ.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10][N:11]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH:12]=1)=[O:5])[CH3:2].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C)C=O>[C:23]1([C:9]2[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][N:11]([CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:36][CH2:35][C:34]4[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=4)=[O:19])=[CH:16][CH:15]=3)[N:10]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2)nc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.7 %

Procedure:
A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazol-1-ylmethyl]benzoic acid (500 mg), 4-trifluoromethylbenzylamine (250 mg), 1-hydroxybenzotriazole monohydrate (210 mg), WSC (270 mg), and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-phenyl-1-[4-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (550 mg, yield: 77%) was obtained as a colorless amorphous substance from the fraction eluted with ethyl acetate-hexane (3:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[NH2:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: Nc1nn(-c2ccccc2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Nc1nn(-c2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
A mixture of (3-amino-1-phenyl-1H-pyrazol-4-yl)methanol (12.29 g), activated manganese dioxide (35 g) and tetrahydrofuran (200 mL) was stirred at room temperature for 16 hrs. The reaction mixture was filtered, and the filtrate was concentrated. Recrystallization of the residue from tetrahydrofuran-hexane gave 3-amino-1-phenyl-1H-pyrazole-4-carbaldehyde as pale-yellow crystals (10.02 g, yield 82%). melting point: 129-130° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C:48](=O)[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2].[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([NH:65][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-20-fluoro-1, 14-dihydroxy-12-[2'-(3"-methoxy-4"-oxocyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ] octacos-18-ene-2,3,10,16-tetraone from Example 24 (79.7 mg) in dry isopropyl alcohol (3 ml) is added benzylamine (86.5 mg). The mixture is stirred at r.t. for 30 min., and cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][CH:10]([CH3:26])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1)=[O:12]>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:24][CH2:25][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH:10]([CH3:9])[CH3:26])[CH:19]=[CH:18][CH:17]=2)[CH2:21][CH2:22]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCCCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 6-chloro-1-hexanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 347.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15]>O1CCCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[CH3:1])[N:16]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
2-Methylbenzimidazole (5.0 g) was dissolved in tetrahydrofuran (50 ml), and sodium hydride (60% purity, oily) (1.6 g) was added thereto at room temperature. After stirring for 1 hour, cyanuric chloride (7.0 g) was added at room temperature, followed by stirring for 3 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 2.6 g of the desired product as a white powder (m.p. at least 300° C.).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([OH:9])[CH2:5][CH2:4]1)=O.[ClH:10]>>[ClH:10].[ClH:10].[OH:9][N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=CN1CCN(O)CC1
Agent: Cl
Product: ON1CCNCC1
Reaction time: 0.33 h

Procedure:
3N Hydrochloric acid (50 ml) was added to 1-formyl-4-hydroxypiperazine (5.0 g) and the mixture was stirred at 77° to 87° C. for 20 minutes. After stirring, water was distilled off under reduced pressure to give a pale yellow residue, which was washed with ethanol and recrystallized from a mixed solvent of water-ethanol to give 1-hydroxypiperazine dihydrochloride (5.0 g) as light brown prisms, m.p. 164°-175° C. (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:18])[C:11](=[O:12])[N:10]([CH3:13])[C@@H:9]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:8]2[O:7]1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:18][C:6]1([C:4]([OH:5])=[O:3])[C:11](=[O:12])[N:10]([CH3:13])[C@@H:9]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:8]2[O:7]1
Reactant: CCOC(=O)C1(C)O[C@@H]2CCCC[C@H]2N(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1C(=O)C(C)(C(=O)O)O[C@@H]2CCCC[C@H]21
Yield: 70.7 %

Procedure:
trans-Ethyl-2,4-dimethyl-3-oxo-octahydro-2H-1,4-benzoxazine-2-carboxylate (180 mg, 0.71 mmoles) and 1N NaOH (1.1 ml, 1.1 mmoles) in dioxan (5 ml) were stirred for 20 hours. The solvent was evaporated, 1N HCl (11 ml, 11 mmoles) was added to the residue and the mixture was extracted with ethyl acetate (3×20 ml). The organic phase was dried over MgSO4 and the solvent was evaporated. Thus there were obtained 114 mg (71%) of the title product in the form of a viscous yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:32]#[C:31][C:29]([OH:33])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=5)[CH3:30])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: C#CC(C)(O)c1ccccn1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C1CC1)c1ccccn1
Yield: 16 %

Procedure:
10-bromo-3-cyclopropyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol via General Procedure E to yield 9.5 mg (16%) of (±)-3-cyclopropyl-9-fluoro-10-[3-hydroxy-3-(2-pyridyl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.Cl.CN.C[CH2:25][N:26](CC)CC>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([NH:26][CH3:25])=[O:20])[N:9]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2I)n1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.7 %

Procedure:
To a mixture of 1-(2-iodophenyl)-3-isoquinolinecarboxylic acid (0.1868 g, 0.5 mmol), benzotriazol-1-yloxy-tris (demethylamino) phosphonium hexafluorophosphate (BOP) (0.2219 g, 0.5 mmol), Methylamine hydrochloride (0.1019 g, 1.5 mmol) in DMF (8 mL) was added Et3N (0.42 mL, 4.5 mmol). The resulting mixture was stirred under Ar at room temperature for 7 h and quenched by adding H2O (10 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was purified on column (SiO2, 50% ethyl acetate/hexane, 0.1% Et3N), thereby giving a white foam (0.1237 g, 65%). mp: 167-168° C. 1H NMR (CDCl3) d 3.03, 3.05 (two s, 3 H, N-methyl), 7.25 (t, J=10.5 Hz, 1 H, aromatic), 7.39 (d, J=7.5 Hz, 1 H), 7.48-7.68 (m, 3 H, aromatic), 7.75 (t, J=9 Hz, 1 H, aromatic), 8.02-8.06 (m, 2 H, aromatic), 8.18 (br s, 1 H, NH), 8.65 (s, aromatic). 13C NMR (CDCl3) d 26.13 (q, N-methyl), 97.79 (s, C--I), 120.02 (d, aromatic), 127.29 (d, aromatic), 127.75 (d, aromatic), 127.98 (d, aromatic), 128.53 (d, aromatic), 128.76 (d, aromatic), 130 13 (d, aromatic), 130.31 (d, aromatic), 130.81 (d, aromatic), 136.81 (s, aromatic), 139.42 (d, aromatic), 142.59 (s, aromatic), 143.30 (s, aromatic), 160.79 (s, aromatic), 165.32 (s, --CO--). HRMS calcd. for C17H13IN3IN2O: 388.0073. Found: 388.0070.
Reaction SMILES: C[N:2]([CH3:16])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.N[C:18]1[C:22]([C:23]#[N:24])=C[NH:20][N:19]=1>C(O)(=O)C>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[N:20]3[N:19]=[CH:18][C:22]([C:23]#[N:24])=[C:16]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: N#Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccc([N+](=O)[O-])c3)ccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 24.4 g of 3-dimethylamino-3'-nitroacrylophenone, 13.0 g of 3-aminopyrazole-4-carbonitrile and 120 ml of glacial acetic acid was heated at reflux for 7 hours, then was stirred at room temperature for 16 hours. The precipitate was collected, triturated with saturated aqueous sodium bicarbonate, filtered and washed with water. The solid was then triturated with acetonitrile, filtered and dried and gave the desired product, mp 244°-246° C.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3](OC)=[O:4].[CH3:11][NH:12][NH2:13]>CCOCC>[OH:4][C:3]1[N:12]([CH3:11])[N:13]=[C:1]([C:7]([O:9][CH3:10])=[O:8])[CH:2]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: CNN
Solvent: CCOCC
Product: COC(=O)c1cc(O)n(C)n1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
102.3 g (0.72 mol) Dimethyl acetylenedicarboxylate was added to 1000 ml ether and the mixture cooled to -5° C. in an ice-methanol bath. 33 g (0.72 mol) methylhydrazine in 100 ml ether was added dropwise at a rate that the inner temperature did not rise above 0° C. The mixture was stirred for one hour at 0° C., the precipitate suction filtered off, washed with ether and dried at 40° C. in vacuo. The intermediate was immersed in an oil-bath heated to 120° C. The reaction product was recrystallised from methanol.
Reaction SMILES: [CH:1]1([NH:7][CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]1([CH2:15][N:16]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19](=[O:26])OC2=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:1]1([N:7]([CH3:8])[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:16][CH2:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1oc(=O)n(CC2CCCCC2)c2ccccc12
Reactant: CNC1CCCCC1
Product: CN(C(=O)c1ccccc1NCC1CCCCC1)C1CCCCC1
Yield: 67 %

Procedure:
The title compound (0.3 g, 67%) was obtained as a orange solid from N-cyclohexyl-N-methylamine and 1-Cyclohexylmethyl-1H-benzo[d][1,3]oxazine-2,4-dione following the same procedure as described in Preparation 7.
Reaction SMILES: [CH2:1]([C:6]1[CH2:7][CH:8]([CH2:17]O)[S:9][CH2:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>C(Cl)Cl>[Br:39][CH2:17][CH:8]1[CH2:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][S:9]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCC1=C(CCCCC)CC(CO)SC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC1=C(CCCCC)CC(CBr)SC1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Part B. The alcohol from Part A above is dissolved in methylene chloride along with carbon tetrabromide, and cooled to 0° C. A methylene chloride solution of triphenylphosphine is added dropwise. The mixture is stirred for 14 hours, then evaporated and rapidly eluted through a plug ofsilica gel with an appropriate solvent system to afford 2-bromomethyl-3,6-dihydro-4,5-dipentyl-2H-thiopyran. This compound is useddirectly, and treated with potassium cyanide in dimethylsulfoxide at 80° C. until thin-layer chromatography shows the reaction is complete. At this point, the solution is cooled, and poured into 4 volumesof water. This mixture is extracted with ethyl acetate, and the extract is washed with more water (3× an equal volume), then brine, then dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography will then purify the product, (3,6-dihydro-4,5-dipentyl-2H-thiopyran-2-yl)acetonitrile.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:25])=[C:22]([OH:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:25])=[C:22]([CH:23]=1)[O:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Nc1ccc(Br)c(O)c1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Br)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 30.4 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.2 g, 6.7 mmol) in N,N-dimethylformamide (60 mL) were added 5-amino-2-bromophenol (1.9 g, 10 mmol) and potassium carbonate (1.8 g, 13 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0). The solvent was evaporated under reduced pressure and the obtained solid was washed with diisopropyl ether to give the title compound (0.79 g, 31%) as a yellow powder.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:39])[C:36]([OH:38])=O)=[CH:31][CH:30]=1>>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]([N:13]3[CH2:14][CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH:16]([N:18]([CH3:19])[C:36](=[O:38])[CH:35]([C:32]4[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=4)[CH3:39])[CH2:17]3)=[O:12])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Product: CC(C(=O)N(C)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-propionamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-fluoro-alpha-methylphenyl acetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless oil. MS m/e: 560.2 [M]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[C:37]([F:40])([F:39])[F:38])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH:28]([O:27][C:21]2[CH:20]=[C:19]([N:18]3[C:12]4[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=4[N:16]=[CH:17]3)[S:23][C:22]=2[C:24]([NH2:26])=[O:25])[CH3:29])=[C:31]([C:37]([F:40])([F:38])[F:39])[CH:32]=1
Reactant: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.48 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{-1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide in 25 ml THF is cooled to 0° C. At 0° C. 0.91 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11]([O:13][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H]1c1ccc(O)cc1
Temperature: 40 °C
Yield: 58.6 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 50 mL of acetone. To the stirred solvent was added (1R,2S)-2-(4-hydroxyphenyl)cyclopropanecarboxylic acid (0.51 g, 2.86 mmol). The reaction mixture was brought to 0° C., potassium bicarbonate (0.28 g, 2.8 mmol), stirred for 10 minutes, benzyl bromide (0.3 mL, 2.8 mmol) was added drop wise. The reaction mixture was heated at 40° C. for 2 h. The reaction mixture was concentrated to distill off the solvent; water (25 mL) was added and extracted with ethyl acetate (25 mL). The organic layer was washed with brine solution (25 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow liquid (0.44 g, yield: 57.2%). 1H NMR (300 MHz, CDCl3): δ 7.30 (s, 4H), 7.19 (s, 1H), 6.89-6.92 (d, 2H), 6.66-6.68 (d, 2H), 5.08 (s, 2H), 4.89 (s, 1H), 2.41-2.48 (m, 1H), 1.78-1.84 (m, 1H), 1.49-1.56 (m, 1H), 1.17-1.24 (m, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]2[C:9]=1[CH2:10][CH2:11][C:12]2=[O:18].S(OC)(OC)(=O)=O>CC(C)=O>[F:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:1])=[C:13]2[C:9]=1[CH2:10][CH2:11][C:12]2=[O:18]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2c(F)ccc(O)c21
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(F)c2c1C(=O)CC2

Procedure:
In a nitrogen atmosphere, to 300 g powdered potassium carbonate in 1.5 1 of acetone is added 121 g II under stirring, followed by 83 ml of dimethyl sulphate. After heating to reflux for 2 hrs, the solvent is distilled off, water is added and the mixture refluxed for a further hour. Extraction with methylene chloride and evaporation gives 125 g of crude III, which is purified by crystallization from EtOAc, m.p. 118°-120°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(=O)OC(C)(C)C)=[C:6]([CH:16]=O)[CH:5]=[CH:4][N:3]=1.[C:18]1([CH2:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[N:8]=[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]3([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:43])[CH3:41])[CH2:34][CH2:35][CH2:36]3)=[CH:29][CH:28]=1)[C:24]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:16]2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Reactant: CC(C)(C)OC(=O)Nc1c(C=O)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Cl)nccc4cc3-c3ccccc3)cc2)CCC1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl (2-chloro-4-formylpyridin-3-yl)carbamate (7-3) (300 mg, 1.17 mmol), tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (4-1) (427 mg, 1.17 mmol) and potassium carbonate (485 mg, 3.51 mmol) in DMF (10 mL) was stirred at 120° C. for 15 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane-EtOAc) to give tert-butyl {1-[4-(8-chloro-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-4) as a pale yellow solid.