Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[OH:24].C[O:26][C:27](=[O:34])[CH:28](Br)[CH2:29][CH:30]([CH3:32])[CH3:31]>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[O:24][C:7]1[CH:6]=[N:5][N:4]([CH:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27]([OH:26])=[O:34])[C:3](=[O:15])[CH:2]=1
Reactant: Oc1c(F)cccc1F
Reactant: COC(=O)C(Br)CC(C)C
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: CC(C)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-4-methyl-pentanoic acid methyl ester (Intermediate 11) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid as a white solid (1.48 g, 89% for the final step); ES+-HRMS m/e calcd for C16H16N2O4F2 [M+H+] 361.0970, found 361.0969. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.0 Hz, 6H), 1.24-1.45 (m, 1H), 1.84 (ddd, J=14.0, 9.5, 4.3 Hz, 1H), 2.04-2.18 (m, 1H), 5.39 (dd, J=11.1, 4.3 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H), 7.30-7.44 (m, 2H), 7.44-7.57 (m, 1H), 8.28 (d, J=2.7 Hz, 1H), 13.09 (br s, 1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[C:21](=O)[NH:22][C:23]3[CH2:29][CH2:28][CH:27]=[CH:26][C:24]=3[S:25][C:19]=2[CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[C:21](=[S:2])[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[S:25][C:19]=2[CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NC2=C(C=CCC2)Sc2cc(C(F)(F)F)ccc21
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc2c(c1)Sc1ccccc1NC2=S
Yield: 106.6 %

Procedure:
Phosphorus pentasulphide (2.25 g) was added to a solution of 3-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one (2 g, 6.8 mmol) in pyridine (30 ml) and the mixture heated under reflux for 6.5 hr. The mixture was allowed to cool and then poured into warm water (100 ml) with stirring. Filtration of the cooled mixture and recrystallisation from ethanol gave the title compound as yellow needles (1.68 g, m.p. 236°-239° C., Rf 0.58, hexane/EtOAc 2:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:38])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2SC)=[CH:25][C:24]=1[F:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:40]1C=C(C=CC=1)C(OO)=O.[O-:50][S:51]([O-:54])(=S)=O.[Na+].[Na+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:38])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:51]([CH3:40])(=[O:54])=[O:50])=[CH:25][C:24]=1[F:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1ccccc1-c1ccc(NC(=O)[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c(F)c1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.1 g, 7.3 mmol) was dissolved in 20 mL EtOAc, added added m-chloroperoxybenzoic acid (7.2 g, 29 mmol) in one portion and stirred at ambient temperature for 3 hours. A 10% aqueous solution (50 mL) of Na2S2O3 was added to the vigorously stirring reaction in order to quench peroxide. After 20 minutes the solution was diluted with 100 mL EtOAc, separated layers, washed organics with sat. NaHCO3 (3×100 mL), water (2×100 mL), brine, dried with MgSO4, filtered and concentrated to yield title compound. (4.3 g, 99%) APCI (AP−): 591.3 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[C:17]1([C:23]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)(O)[C:24]#C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:38]1(C)C=CC=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]2[O:12][CH2:38][C:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:29][CH:28]=3)[CH:24]=[C:4]2[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(O)c2ccccc2c1O
Reactant: C#CC(O)(c1ccccc1)c1ccc(N2CCCC2)cc1
Reactant: Cc1ccccc1
Product: COC(=O)C1=C(O)c2ccccc2C2OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C12
Yield: 62 %

Procedure:
A mixture of methyl 1,4-dihydroxynaphthalene-2-carboxylate (3.93 g, 18 mmol), 1-phenyl-1-(4-pyrrolidinophenyl)prop-2-yn-1-ol (5 g, 18 mmol) and Al2O3 (4 g) in PhMe (100 mL) was heated at reflux for 1.5 h, cooled, filtered, the residue washed with DCM and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (40% in hexanes) as eluent. The solvent was removed under reduced pressure and the residue was crystallized from Et2O-hexanes to give the title compound (5.47 g, 62%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:36]Br>C(Cl)Cl.O>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[Br:36])[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: BrBr
Reactant: C[C@@H](O[C@H]1CN(C2=CC(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](O[C@H]1CN(C2=C(Br)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a round bottomed flask, 150 mg (0.299 mmol) 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one (Example 3, step F) was dissolved in methylene chloride (5 mL) under nitrogen atmosphere and cooled to 0° C. To this solution was added a solution of 300 mg (1.877 mmol) bromine in methylene chloride (5 mL). The resulting solution was stirred for 0.25 hr at 0° C. then was quenched by the addition of sat. aq. Na2SO3 until a clear solution resulted. The mixture was diluted with 5 mL water then extracted with methylene chloride (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The resulting oil was purified by prep TLC on silica gel eluting with methylene chloride/methanol (95/5) to afford the title compound and a small amount of the less polar 2,2-dibromo compound. Monobromide, 1H-NMR (CD3OD): δ: 1.44 (d, 3H), 2.48 (br. s, 2H), 2.87 (m, 2H), 3.43 (m, 1H), 3.66 (m, 1H), 4.0-4.22 (m, 2H), 4.70-4.83 (m, 2H), 6.98 (t, 2H), 7.18 (dd, 2H), 7.70 (s, 2H), 7.83 (s, 1H)ppm. MS: 580.0 and 582 (MH+) observed. Dibromide, 1H-NMR (CD3OD): δ: 1.46 (d, 3H), 2.82 (d, 1H), 3.24 (dd, 1H), 3.38-4.85 (m, 7H), 5.35, 5.36 (2s, 1H), 7.00 (m, 2H), 7.20 (m, 2H), 7.67-7.87 (m, 3H)ppm. MS: 657.9, 659.9 and 661.9 (MH+) observed.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH:18]([CH3:21])[CH:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19](=[O:20])[CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: O=Nc1ccccc1
Reactant: CC(C=O)c1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C(=O)N(O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (30 mg, 0.2 mmol) was added under argon to a solution of 2-phenylpropanal (134 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (72.8 mg, 0.2 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl.O1CCOCC1>COCCO>[C:13]([N:10]1[CH2:11][C:12]2[C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[NH:7][CH2:8][CH2:9]1)(=[O:15])[CH3:14]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCNc2cccc(N)c2C1
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2CN(C(C)=O)CCN3)ncc1Cl
Yield: 3.8 %

Procedure:
1-(6-Amino-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-ethanone (35 mg, 0.17 mmol) was dissolved in 2-methoxyethanol (3 mL) and the mixture was treated with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (25 mg, 0.084 mmol) and 4N HCl/dioxane (0.05 mL, 0.17 mmol). The reaction was then irradiated at 140° C. for 20 minutes. The mixture was then reduced en vacuo and the crude mixture was purified by prep HPLC to afford 1.47 mg of 2-[2-(4-Acetyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide as a light brown foam. LC/MS (ESI)=466.37 (M+H). 1H NMR (400 MHz, MeOD, d4) δ 8.80 (m, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.79 (m, 3H), 7.64 (m, 3H), 7.35 (m, 1H), 6.97 (m, 1H), 6.49 (m, 1H), 3.64 (m, 2H), 3.35 (m, 2H), 3.21 (m, 2H), 2.98 (s, 3H), 1.94 (d, 3H, J=7.07 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[NH:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1)#[N:2].C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C.CO>CN(C=O)C>[CH2:14]([C:13]1[N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[C:1]#[N:2])=[CH:6][CH:7]=2)[C:26](=[O:25])[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][N:18]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=N)NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
The title compound is prepared by stirring one equivalent of N-[(2'-cyanobiphen-4-yl)-methyl]valeramidine with diethyl ethoxymethylenemalonate (Aldrich) in a suitable solvent such as methanol or DMF. After the initial adduct is formed, one equivalent of base such as sodium methoxide is added then the material is stirred for an additional period of time, possibly with heating. Standard workup procedures appropriate to the chosen reaction solvent should be followed.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=S)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:25](O)(=O)[CH2:26]C(CC(O)=O)(C(O)=O)O>C(O)CCC>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:23][N:24]=[C:8]1[C:9]([O:11][CH2:12][CH2:13][CH2:25][CH3:26])=[O:10]
Reactant: CCOC(=O)C(=S)NCCCCOC
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)c1nnc(-c2ccccc2)n1CCCCOC
Temperature: 140 °C
Reaction time: 15 h

Procedure:
Ethyl [(4-methoxybutyl)amino](thioxo)acetate (1.2 g) and benzohydrazide (745 mg) were dissolved in 1-butanol (10 ml), and the mixture was stirred at 140° C. for 15 hr. The reaction mixture was cooled to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (8:2) was concentrated under reduced pressure to give the object product (80 mg).
Reaction SMILES: ClC1[CH:7]=[C:6](NC2N=CN=C(NC(C3CC3)=O)C=2)[C:5](=O)[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29](F)[CH:28]=3)(C)NC(=O)C=12.N1C=CN=C1.[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].[OH2:47]>ClCCl>[CH2:22]([NH:4][CH2:5][CH2:6][CH2:7][O:47][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-(benzylamino)propan-1-ol (1, 2.0 g, 12.1 mmol) in dichloromethane (20 mL), imidazole (2.47 g, 36.0 mmol) and tert-butyldimethylsilyl chloride (1.1 g, 13 mmol) were added at room temperature. The reaction mass was stirred at room temperature for 16 h. Water was added to the reaction mixture and layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated to afford N-benzyl-3-((tert-butyldimethylsilyl) oxy) propan-1-amine (2) as brown solid. Yield: 3.2 g, 94%; MS (ESI) m/z 280.29 [M−1]−.
Reaction SMILES: CO.[C:3]([CH:7]([CH2:13][CH:14]=[CH2:15])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])(OC)=[O:4].[BH4-].[Na+].COCCOC>O>[OH:4][CH2:3][CH:7]([CH2:13][CH:14]=[CH2:15])[CH2:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: C=CCC(CCCC#N)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: C=CCC(CO)CCCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (4136 mL) is added dropwise over about 3 hours to a mixture of 2054 g of 5-carbomethoxy-oct-7-enenitrile, 1286 g of sodium borohydride and 20.5 L of 1,2-dimethoxyethane heated at 75°. The reaction mixture is heated at 95° for 31/2 hours, stirred at room temperature overnight, and cooled to 8° C. in an ice bath. Water (21.0 L) is added slowly, the mixture is again stirred for 11/2 hours at room temperature, and then extracted with ethyl acetate (2×20 L). The combined extract is washed with brine, dried over sodium sulfate and evaporated to dryness at 65-70°/3 mm Hg. The residue is distilled to yield 6-hydroxy-5-(2-propenyl)-hexanenitrile, b.p. 113-116°/0.8 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH3:17])=[CH:6][CH2:5][CH2:4][CH2:3]1.[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12>>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:12]([C:11]3[CH:15]=[CH:16][C:8]([C:7]4[C:2]([CH3:1])([CH3:18])[CH2:3][CH2:4][CH2:5][CH:6]=4)=[C:9]([CH3:17])[CH:10]=3)=[O:14])[CH2:24][C:23]=12
Reactant: Cc1cc(C(=O)O)ccc1C1=CCCCC1(C)C
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCCC1(C)C
Yield: 51.2 %

Procedure:
4-(6,6-Dimethyl-cyclohex-1-en-1-yl)-3-methyl-benzoic acid of Step B (0.078 g, 0.319 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.065 g, 0.351 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.0670 g) as white crystals, m.p. 131° C.
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl.CN(C)[C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]>O1CCCC1.C(OCC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]
Reactant: COc1cccc(CCl)c1
Reactant: CN(C)C(=O)C1CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(CC(=O)C2CC2)c1
Reaction time: 1 h

Procedure:
A 250 ml round-bottomed flask is filled with magnesium (4.9 g, 0.20 mol) and iodine (0.1 g) is sublimated to the magnesium, then diethyl ether (100 ml) is added and under boiling a solution of 3-methoxybenzyl chloride (11.9 ml, 0.1 mol) and diethyl ether (40 ml) are added to the reaction mixture. The mixture is boiled for one hour and at this temperature a solution of cyclopropanecarboxylic acid dimethylamide (16.6 g, 0.15 mol) and tetrahydrofuran (70 ml) are added. The reaction mixture is stirred for half an hour and under cooling aqueous hydrogen chloride (80 ml, 1:1) is added dropwise to the mixture. The organic layer is dried and the residue (32 g) is fractionated in vacuo.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)c(C(=O)O)nn(C)c1=O
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
To a suspension of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (200 mg, 0.99 mmol) and 2-fluoro-4-iodoaniline (478 mg, 1.97 mmol) in THF (6.5 mL) at −78° C. was slowly added a solution of LiHMDS (3.00 mL, 3.00 mmol, 1 M solution in THF). After complete addition, the resulting mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with 6 N aqueous HCl (8 mL) at 0° C., warmed to room temperature, and stirred for 1.5 hours. The precipitates were filtered, washed with water and ether, and triturated with ether to afford 158 mg (38%) of the desired product.
Reaction SMILES: CNCCC(OC1C=CC(C(F)(F)F)=CC=1)C1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27].[F:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)C>[F:34][C:35]1[CH:40]=[C:39]([CH:38]=[CH:37][CH:36]=1)[O:27][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][Cl:23]
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Oc1cccc(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cccc(O[C@H](CCCl)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 15.7 %

Procedure:
Following a similar procedure for the chiral synthesis of fluoxetine [Srebnik, M. et al., J. Org. Chem. 25 53(13), 2916–20 (1988), hereby incorporated by reference herein], a solution of (S)-(−)3-chloro-1-phenyl-1-propanol (4.00 g, 23.4 mmol), 3-fluorophenol (2.63 g, 23.4 mmol), and diethyl azodicarboxylate (4.00 g, 23.4 mmol) were dissolved in THF (200 mL). The mixture was cooled to 0° C. and triphenylphosphine (6.77 g, 25.8 mmol, 1.1 equiv) was added slowly over 10 min. The reaction mixture was then stirred at room temperature for 18 h. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL). The pentane washings were filtered and the filtrate was evaporated under vacuum to give a clear oil. This oil was dissolved in diethyl ether (150 mL) and washed with 1% HCl-satd. NaCl (25 mL), 0.1N NaOH-satd. NaCl (2×25 mL), and finally H2O (2×25 mL). The organic layer was then dried (anh. Na2SO4), filtered, and evaporated to dryness under vacuum to give an orange oil. The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc, to provide 971 mg (15.7%) of product as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[ClH:20].F[C:22]1(F)[CH2:25][NH:24][CH2:23]1.[CH2:27](N(CC)CC)[CH3:28]>>[ClH:20].[ClH:20].[N:24]1[CH:23]=[CH:28][C:27]([O:1][CH:2]2[CH2:3][CH2:4][C:5]3([CH2:6][CH2:7][NH:8][CH2:9][CH2:10]3)[CH2:18][CH2:19]2)=[CH:22][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: FC1(F)CNC1
Reactant: CCN(CC)CC
Agent: Cl
Product: c1cc(OC2CCC3(CCNCC3)CC2)ccn1

Procedure:
The preparation was carried out in two stages, analogously to the synthesis of amine F-39, from tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate and 3,3-difluoroazetidine hydrochloride with the addition of triethylamine (1 equiv.), or as follows:
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:29][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncc3c(C)c(Br)c(=O)n(C4CCCC4)c3n2)cc1
Yield: 86.9 %

Procedure:
A suspension of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.70 mmol) and 4-methoxybenzylamine (0.39 mL, 4.0 mmol) in toluene (15 mL) was heated under reflux for 2 hours. The solution was cooled, and the resulting solid was collected by filtration to give 6-bromo-8-cyclopentyl-2-(4-methoxy-benzylamino)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.04 g, 86.4%). 1H NMR δ (400 MHz, CDCl3) 1.6 (m, 2H), 1.8 (m, 2H), 2.0 (m, 2H), 2.2 (m, 2H), 2.53 (s, 3H), 3.79 (s, 3H), 4.59 (m, 2H), 5.96 (m, 1H), 6.1 (m, 1H), 6.86 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 8.5 (br s, 1H). MS (APCI) (C21H23Br1N4O2): Calc for M+H, 443.1; Found, 443.1
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:16]=[C:17]([S:22]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]([NH2:38])=O)(=[O:24])=[O:23])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:19]1[CH:18]=[C:17]([S:22]([NH:25][C:26]2[C:27]3[C:32](=[C:31]([C:36]#[N:38])[CH:30]=[CH:29][CH:28]=3)[CH:33]=[CH:34][CH:35]=2)(=[O:24])=[O:23])[CH:16]=[C:15]([Cl:14])[CH:20]=1
Reactant: NC(=O)c1cccc2c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cccc12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc2c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.49 ml trifluoroacetic anhydride are added dropwise to a mixture of 1.13 g 5-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid amide and 1.07 ml triethylamine in 50 ml methylene chloride while cooling with an ice bath. Then the ice bath is removed and the reaction mixture is stirred for one hour at ambient temperature. In all, another 1.00 ml triethylamine and 0.70 ml trifluoroacetic anhydride are added successively and the reaction mixture is stirred overnight at ambient temperature. For working up the mixture is combined with 50 ml of water. The organic phase is washed with 2 N citric acid solution and saturated sodium hydrogen carbonate solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (85:15 to 65:35).