Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[F:11])[CH3:2].C1C(=O)N([Br:19])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[Br:19][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([F:11])=[CH:5][C:6]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(OC)cc1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(Br)c(OC)cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
1-ethyl-2-fluoro-4-methoxybenzene (MET) (7.70 g, 50 mmol) was dissolved in acetonitrile (100 mL), and NBS (9.80 g, 55 mmol) was added in a single solid addition. The reaction was stirred at rt and was completed in 3-4 hours. The reaction mixture was quenched with 2M Na2SO3 (40 mL, 0.08 mol) and concentrated to ¼ of the total volume, then diluted with water (80 mL) and petroleum ether (50 mL). The organic layer was cut and washed with water (3×50 mL), 1M NaOH (50 mL), water (50 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to yield 1-bromo-5-ethyl-4-fluoro-2-methoxybenzene (BrMET) as a colorless oil (11.16 g, 96%): 1H NMR (CDCl3) δ 1.19 (t, J=7.6, 3H), 2.58 (q, J=7.6, 2H), 3.85 (s, 3H), 6.61 (d, J=11.4, 1H), 7.35 (d, J=8.1, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O1CCCC1.CO>C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([OH:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)c2ccccc21
Temperature: 25 °C
Yield: 95.4 %

Procedure:
To a flask were charged 25.04 g of 1-benzyloxycarbonyl-2,3-dihydro-4-quinolone, 6.72 g of sodium borohydride and 200 mL of tetrahydrofuran, and the flask was incubated in a water bath wherein the temperature was maintained constant at 25° C. To the flasks was added dropwise 50 mL of methanol over about 30 minutes with watching out heat generation/foam formation. After confirming the reaction termination by TLC, to the flask was added dropwise 400 mL of water with watching out foam formation, and to the solution was added 800 mL of ethyl acetate and the objective product was extracted. Further, the organic layer was washed with 2.5% saline, and then to the organic layer was added MgSO4, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure to give 24.05 g of 1-benzyloxycarbonyl-4-hydroxy-1,2,3,4-tetrahydroquinoline as white solid (86% yield).
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)(=O)C>[S:13]([C:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])([OH:3])(=[O:2])=[O:1]
Reactant: O
Reactant: CCOC(=O)C1=C(S)CCCCC1
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCCCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
Sodium peroxyborate tetrahydrate (6.8 g) was admixed with acetic acid (37 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-1-cycloheptene-1-carboxylate (3.0 g, synthesized in accordance with Tetrahedron, Vol.30, p.3753 (1974)) in acetic acid (15 ml) was added dropwise over 1 hour. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (100 ml) and stirred at room temperature for 3 hours and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (10 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (70 ml) and stirred at room temperature for 1 hour. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (100 ml) and the pellet which precipitated was isolated by a filtration to obtain ethyl 2-sulfo-1-cycloheptene-1-carboxylate as a white powder (3.4 g) containing inorganic substances. This (1.5 g) was dissolved in thionyl chloride (4 ml) and then stirred at 80 to 90° C. for 15 hours. The mixture was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (30 ml). The solution obtained was washed with saturated brine (30 ml×2) and then dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by flash chromatography on silica gel column (eluent: ethyl acetate/hexane=1/8) to yield ethyl 2-chlorosulfonyl-1-cycloheptene-1-carboxylate (590 mg) as a brown oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1>C(O)(=O)C>[N+:1]([C:16]1[CH:17]=[C:12]([CH2:11][CH:8]2[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]2)[CH:13]=[CH:14][C:15]=1[OH:18])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(CC2CCNCC2)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CC2CCNCC2)ccc1O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Concentrated nitric acid in acetic acid (8 mL 70% HNO3 aq in 16 mL acetic acid) was added slowly to a stirred solution of 4-(piperidin-4-ylmethyl)phenol (Guzikowski et al, J. Med Chem., 2000, 43, 984–994) (100 mmol) in acetic acid (300 mL) and the resultant slurry stirred at 80° C. for 1 h. The reaction mixture was then filtered and evaporated in vacuo to give the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[C:5]2([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=1)O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)CCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[CH:5]2[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=1
Reactant: COc1cc(F)cc(C2(O)c3cc(Br)ccc3C(=O)N2C)c1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CCOCC
Product: COc1cc(F)cc(C2c3cc(Br)ccc3C(=O)N2C)c1

Procedure:
To a well stirred suspension of 5-Bromo-3-(3-fluoro-5-methoxy-phenyl)-3-hydroxy-2-methyl-2,3-dihydro-isoindol-1-one (106 mg; 0.29 mmol) in ethylene dichloride (1 ml) at 0° C. is added Triethylsilane (84 mg; 0.72 mmol) and Boron Trifluorid etherate (54 μl; 0.43 mmol). It is let to come to ambient temperature and stirred for 1 hour. The reaction mixture is then purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)=[O:18])=[CH:13][CH:12]=2)[CH:2]=1
Reactant: O=C(NCc1ccc(Br)cc1)c1ccc(-c2ccccc2)cc1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(-c2cccnc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a sealed tube was added pyridin-3-ylboronic acid 10-4 (25 mg, 0.21 mmol), N-(4-bromobenzyl)biphenyl-4-carboxamide 10−3 (50 mg, 0.14 mmol), Pd(PPh3)4 (16 mg, 0.014 mmol), saturated Na2CO3 (2.1 mL), ethanol (0.7 mL) and toluene (0.7 mL). The reaction was heated to 110° C. and stirred for 2 hours. After cooling to room temperature, the reaction was diluted into ethyl acetate, washed with brine. The organic phase was taken to dryness by rotary evaporation. The residue was purified by HPLC to give N-(4-(pyridin-3-yl)benzyl)biphenyl-4-carboxamide 10 as off-white solid. MS m/z 385.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.18 (t, 1H), 8.89 (s, 1H), 8.57 (d, 1H), 8.08 (m, 3H), 7.81 (d, 2H), 7.75-7.70 (m, 4H), 7.52-7.42 (m, 6H), 4.57 (d, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([Cl:28])=[C:7]([NH:13][C:14]3[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]4=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:16]4[N:15]=3)[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=2)[CH2:2]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].Cl.CN(C)CCCN=C=NCC.C1C=C2N=NN(O)C2=CC=1.O.C([O-])(=O)C.[NH4+]>CN1C(=O)CCC1.CO.O>[Cl:28][C:6]1[C:5]([CH:3]2[CH2:2][N:1]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:4]2)=[CH:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:16]2[N:15]=1
Reactant: N#CCC(=O)O
Reactant: CCNc1nc(Nc2cc(C#N)cc(C3CNC3)c2Cl)nn2c(C#N)cnc12
Agent: CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCNc1nc(Nc2cc(C#N)cc(C3CN(C(=O)CC#N)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.6 %

Procedure:
A mixture of 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (15 mg, 0.038 mmol), 2-cyanoacetic acid (4.9 mg, 0.057 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.4 mg, 0.065 mmol), and HOBT monohydrate (9.9 mg, 0.065 mmol) in NMP (1 mL) was stirred at room temperature for 4 hr. Preparative HPLC (Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water; Mobile Phase B: methanol; Buffer: 20-mM ammonium acetate; Gradient: 30-95% B over 19.5 minutes, then a 14.0 minute hold at 95% B; Flow: 20 mL/min) afforded the title compound (3.6 mg). This was converted to the mono HCl salt.
Reaction SMILES: I[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:3][CH2:4][OH:5].[O:12]1CCC[CH2:13]1>>[C:6]1([C:2]2[C:13](=[O:12])[O:5][CH2:4][CH:3]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCC=C(I)c1ccccc1
Reactant: C1CCOC1
Product: O=C1OCC=C1c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
3-Iodo-3-phenyl-prop-2-en-1-ol (Description 1; 1 g, 3.8 mM) was dissolved in tetrahydrofuran (20 ml) and Hunig's base (2.67 ml, 15.4 mM) and degassed using a Firestone valve (×3). Carbon monoxide was bubbled through the solution for 10 minutes after which tris(dibenzylideneacetone)dipalladium (141 mg; 4 mol %) and 1,4 bis(diphenylphosphino) butane (65 mg; 4 mol %) were added. The reaction was heated at 50° C. under an atmosphere of carbon monoxide. After 2 hours, when the reaction was 50% complete, an extra addition of the palladium source and phosphine ligand were made. After a further 2 hours the reaction was cooled, filtered, the solvent removed in vacuo and the residue was dispersed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×40 ml), the combined organic layers were washed with brine, dried over MgSO4 and the solvent removed in vacuo. Purification was carried out by silica chromatography eluting in increasing concentrations of ethyl acetate in hexane (0-15%) to afford the title compound as a tan-coloured solid (0.56 g, yield 91%).
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:12][CH2:13][N:14]1[C:22]2[C:21]([O:23][CH3:24])=[N:20][CH:19]=[N:18][C:17]=2[C:16]([CH:25]=O)=[CH:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:27][C:28]([CH2:33][OH:34])([CH2:31][OH:32])[CH2:29][OH:30]>CO>[CH2:5]([O:12][CH2:13][N:14]1[C:22]2[C:21]([O:23][CH3:24])=[N:20][CH:19]=[N:18][C:17]=2[C:16]([CH2:25][NH:27][C:28]([CH2:33][OH:34])([CH2:31][OH:32])[CH2:29][OH:30])=[CH:15]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Reactant: NC(CO)(CO)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ncnc2c(CNC(CO)(CO)CO)cn(COCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
Sodium cyanoborohydride was added to a suspension of 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (50 mg, 168 μmol) and 2-amino-2-(hydroxymethyl)propane-1,3-diol (20.37 mg, 168 μmol) in methanol (5 mL) and stirred overnight at r.t. The crude reaction was absorbed onto silica and eluted with 20% MeOH/EtOAc to afford 2-((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(hydroxymethyl)propane-1,3-diol (24 mg, 59.6 μmol, 35.5% yield) as a syrup. 1H NMR (d4-MeOH) 8.42 (s, 1H), 7.65 (s, 1H), 7.23 (m, 5H), 5.74 (s, 2H), 4.51 (s, 2H), 4.11 (s, 3H), 4.04 (s, 2H), 3.68 (s, 6H). 13C NMR (d4-MeOH) 158.4, 151.2, 150.9, 139.1, 134.4, 129.7, 129.2, 129.0, 117.5, 116.4, 78.9, 71.9, 62.9, 62.6, 54.8, 36.6.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([NH:22][C@@H:23]([CH2:26][CH3:27])[CH2:24]O)(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:22][C@@H:23]([CH2:26][CH3:27])[CH2:24][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (1.06 g, 4.40 mmol), N-Boc-(S)-(−)-2-amino-1-butanol (1.0 g, 5.28 mmol) and triphenylphosphine (1.73 g, 6.61 mmol) were dissolved in 15 ml of dry THF under nitrogen atmosphere. DIAD (1.73 ml; 8.81 mmol) was added slowly by syringe to cooled (0° C.) reaction mixture. After being stirred overnight at RT, the reaction mixture was evaporated to dryness. The evaporation residue was dissolved in 20 ml of 10% HCl (g)/EtOH-solution and stirred at RT overnight to induce Boc-deprotection. Solvents were evaporated and the evaporation residue was taken up in water and brine. Thus obtained solution was washed twice with DCM, made alkaline (pH˜12) by adding 2 M NaOH-solution, and extracted twice with DCM. The latter organic extracts were combined, dried over Na2SO4, filtered and evaporated to give 568 mg (47%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ0.87-0.94 (m, 3H), 1.10-1.45 (m, 2H), 2.97-3.05 (m. 1H), 4.01 (dd, 1H), 4.13 (dd, 1H), 4.68-4.86 (m, 1H), 6.97 (d, 1H), 7.86 (d, 1H), 7.95 (dd, 1H), 7.97 (dd, 1H), 8.10-8.12 (m, 1H). MS [M+1]: m/z [274.8+1].
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=O)(C)(C)C.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:35][C:34]=1[C:45]1[CH:46]=[C:47]([CH:61]=[CH:62][N:63]=1)[C:48]([NH:50][C@@H:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH2:53][CH2:52]1)=[O:49].CCN=C=NCCCN(C)C.Cl.CO>ClCCl.CN(C)C1C=CN=CC=1>[C@@H:51]1([NH:50][C:48]([C:47]2[CH:61]=[CH:62][N:63]=[C:45]([C:34]3[CH:35]=[C:36]([N:39]4[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]4)[CH:37]=[CH:38][C:33]=3[NH:32][C:25]([C:24]3[CH:23]=[C:22]([CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:6]([OH:5])=[O:31])[CH:30]=[CH:29][CH:28]=3)=[O:27])[CH:46]=2)=[O:49])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH2:53][CH2:52]1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 251 substituting 126e in place of 25b. Into a 50-mL round-bottom flask, was placed a solution of 3-(3-(2-(2-(2-(3-tert-butoxy-3-oxopropoxy)ethoxy)ethoxy)ethoxy)propyl)benzoic acid (1.308 g, 2.97 mmol, 1.00 equiv) in dichloromethane (15 mL), 2-(2-amino-5-(piperidin-1-yl)phenyl)-N—((S)-1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide (1.26 g, 2.96 mmol, 0.99 equiv), EDC.HCl (854.8 mg, 4.46 mmol, 1.50 equiv), 4-dimethylaminopyridine (544 mg, 4.46 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS/TLC (DCM:MeOH=10:1). The resulting mixture was washed with 2×20 mL of NH4Cl aq. The resulting mixture was washed with 2×20 mL of Brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10˜1:1). This resulted in 2.0 g (79%) of tert-butyl 3-(2-(2-(2-(3-(3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)phenyl)propoxy)ethoxy)ethoxy)ethoxy)propanoate as yellow oil.
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4CCOCC4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.CN[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>>[OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH2:24][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Reactant: CNc1cccnc1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCc4cccnc4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing oxan-4-amine hydrochloride with 3-(methylamino)pyridine. off-white solid (26.4 mg, 9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[S:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[S:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1sc(Nc2cccc(Br)c2)nc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
A solution of 8.6 g (0.05 mol) of 3-bromoaniline in 100 ml of dimethylformamide is added dropwise to a solution of 12.0 g (0.06 mol) of 2,4-dichloro-5-nitrothiazole in 100 ml of dimethylformamide at 0° C. to 5° C. in the course of about 2 hours and the mixture is subsequently stirred at the same temperature for a further 4 hours. It is then stirred into 1,000 ml of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred in 80 ml of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 16.0 g (95.7% of theory) of 2-(3bromophenylamino)-4-chloro-5-nitrothiazole of melting point 191° C. to 192° C. (decomposition) are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(O)C.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Solvent: Clc1ccccc1Cl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.8 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), IPA (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml IPA. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.80 to 0.82%].
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCNc1ccccn1
Yield: 23.6 %

Procedure:
Crude 2-[[4-(tert-butoxycarbonyl)amino-1-butyl]amino]pyridine (3.13 mmole) was treated with TFA (10 mL) in CH2Cl2 (10 mL). After 2 hr the mixture was concentrated under reduced pressure. The residue was taken up in 1.0 N NaOH (20 mL) and extracted with CHCl3 (4×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (122 mg, 24%) as a yellow oil: MS (ES) m/e 166 (M+H)+.
Reaction SMILES: [CH3:1][O:2][P:3]([CH:5]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH3:6])[OH:4].C[O-].[Na+].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO.Cl>[CH3:1][O:2][P:3]([CH:5]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH3:6])([CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])=[O:4]
Reactant: COP(O)C(C)NC(=O)OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCP(=O)(OC)C(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
To a stirred solution of 0.36 gm (0.0014 mol) of 1-benzyloxycarbonylaminoethylphosphonous acid methyl ester in 3 ml of methanol at 0° C. was added a solution of sodium methoxide in methanol (0.77 ml of a 2N solution) dropwise over 10 minutes whereupon was then added methyl acrylate 0.126 ml (0.0014 mol). The reaction mixture was stirred 30 minutes at 0° C. and 4 hours at room temperature whereupon it was diluted with 1N HCl. The mixture was extracted twice with ethyl acetate. The organic fractions were dried over sodium sulfate, filtered through magnesium sulfate and evaporated in vacuo. The product mixture was purified by chromatography (silica, 9:1, ethylacetate:acetonitrile) to give 0.34 gm of methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-1-ethyl]-phosphinate.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[SH:10][C:11]1N[N:14]=[N:13][CH:12]=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N.OS(O)(=O)=O>ClCCl.C(OCC)(=O)C>[CH3:7][Si:4]([CH3:5])([CH3:6])[N:3]1[C:11]([S:10][Si:4]([CH3:7])([CH3:6])[CH3:5])=[CH:12][N:13]=[N:14]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Sc1cnn[nH]1
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)Sc1cnnn1[Si](C)(C)C
Yield: 96 %

Procedure:
1.52 ml of hexamethyldisilazane (7.3 mmoles) were added to a refluxing mixture of 0.49 (4.86 mmoles) of 5-mercapto-1,2,3-(1H)-triazole, 5 mg (0.207 mmole) of saccharin, 10 ml of ethyl acetate and 15 ml of dichloromethane and the ammonia evolved was titrated with 1 N H2SO4 by the method described in Example 1A. It was found that 2 equivalents (4.9 mmoles) were evolved after refluxing for 30 minutes. Volatile materials were evaporated in vacuo to obtain 1.19 g (96%) of 1-trimethylsilyl-5-trimethylsilylthio-1,2,3-triazole NMR Spectrum was taken in carbon tetrachloride solution: Δ0.31 (9H); 0.48 (9H); 7.46 (1H).