Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:25][CH2:26][CH3:27])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][C:17](=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)[CH3:2].C(O)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:25][CH2:26][CH3:27])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCC(=O)NCCOc1ccc(CC(OCC)C(=O)OCC)cc1
Solvent: C1CCOC1
Solvent: CCCCO
Product: CCCCCCCNCCOc1ccc(CC(OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
A solution of the compound obtained in Step d (46 mg) in THF (2 ml) was added with borane/dimethyl sulfide complex (55 μl, Tokyo Kasei Kogyo). The reaction mixture was stirred at room temperature for 24 hours, added with butanol (2 ml) and stirred for 2 hours. The reaction mixture was concentrated, and the resulting residue was applied on a silica gel column and eluted with chloroform/methanol (100:5, then 100:10) to obtain the title compound (31.7 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)[CH3:2].[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:18]=1[NH2:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:19][C:18]1[C:17]([Cl:16])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:24])[CH3:2]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CCN(CC)C(=O)Cc1ccccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCN(CC)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Yield: 81.8 %

Procedure:
A mixture of 6.0 g (0.019 mole) of N,N-diethyl(o-iodophenyl)acetamide, 3.38 g (0.021 mole) of 2,6-dichloroaniline, 2.93 g (0.021 mole) of anhydrous potassium carbonate, 1.0 g of copper powder and 1.0 g of cuprous iodide was reacted in 85 ml of xylene for 24 hours to obtain 5.46 g of a colorless needle having a melting point of 99° to 101° C. The yield was 81.4%.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][Cl:18]>CC(C)=O>[Cl:18][CH2:17][CH2:16][N:5]1[CH2:6][CH2:7][C:2]([F:8])([F:1])[CH2:3][CH2:4]1
Reactant: FC1(F)CCNCC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC1(F)CCN(CCCl)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
To a solution of 4,4-difluoropiperidine (1.00 g, 6.35 mmol) in acetone (15 mL), were added potassium carbonate (2.19 g, 15.9 mmol) and 1-bromo-2-chloroethane (635 μL, 7.62 mmol) and the mixture was stirred for 8 h at 50° C. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=0/100→30/70) to obtain title compound (188 mg, 16%) as a pale yellow oil.
Reaction SMILES: C([O:3][P:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:35])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:17]=2[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:10][CH:9]=1)([CH3:6])=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1.CCOC(C)=O>[C:31]([O:30][C:28]([NH:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:21][C:16]=1[NH:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][P:4]([CH3:6])(=[O:3])[OH:5])=[CH:13][CH:12]=1)=[O:35])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOP(C)(=O)Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CP(C)(=O)O)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution [4-(2-tert-butoxycarbonylamino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-methyl-phosphinic acid ethyl ester (377 mg, 0.733 mmol) in dioxane (2 mL) was added NaOH (1 mL, 5.00 mmol, 5M) and the solution was heated to 60° C. After 18 h, the reaction was diluted with EtOAc, acidified with 1N HCl. The organic layer was dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The material was used without further purification. 1H NMR (DMSO-d6) δ 9.94 (s, 1H), 8.74 (br s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.79 (d, J=2.0 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.50 (dd, J=5.0, 1.2 Hz, 1H), 7.48 (dd, J=8.5, 2.0 Hz, 1H), 7.44-7.39 (m, 3H), 7.10 (dd, J=5.3, 3.5 Hz, 1H), 3.13 (d, J=17.9 Hz, 2H), 1.43 (s, 9H), 1.21 (d, J=13.8 Hz, 3H). MS: cal'd 387 (MH+; -Boc), exp 387 (MH+; -Boc).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cnc(NC(=O)c3cccc(OC)c3)c(Cc3ccccc3)n2)cc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 82.5 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (800 mg, 2.75 mmol) in pyridine (10 mL) were successively added 4-(dimethylamino)pyridine (33.6 mg, 275 μmol) and m-anisoyl chloride (18) (773 μL, 5.50 mmol) at room temperature, and the mixture was heated with stirring at 50° C. for 22 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residual pyridine was azeotropically removed with toluene (×3). The residue was purified by column chromatography (silica gel 100 g, dichloromethane/ethyl acetate=9/1). The residue was recrystallized from ethyl acetate to give Compound 11y (967 mg, 2.27 mmol, 82.5%) as a colorless solid. Rf=0.63 (dichloromethane/ethyl acetate=9/1), 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 6H), 4.19 (s, 2H), 7.05-7.12 (AA′BB′, 2H), 7.14-7.28 (m, 6H), 7.42-7.49 (m, 2H), 7.53 (d, 1H, J=7.5 Hz), 8.06-8.12 (AA′BB′, 2H), 8.98 (s, 1H), 10.77 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 41.5, 55.3, 55.4, 112.5, 114.3 (2C), 118.6, 119.3, 126.7 (2C), 128.1, 128.55, 128.61 (2C), 128.5 (2C), 129.6, 135.0, 136.8, 137.7, 143.3, 149.2, 149.9, 159.8, 160.9, 165.7; IR (KBr, cm−1) 700, 746, 833, 1022, 1040, 1117, 1179, 1254, 1300, 1325, 1373, 1416, 1441, 1501, 1607, 1655, 2936, 3265; Anal. Calcd. For C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.55; H, 5.36; N, 9.86.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(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>[CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2CC1CC1
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: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2CC1CC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (94.0 mg, 0.299 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (104 mg, 0.314 mmol), Na2CO3 (79.0 mg, 0.745 mmol) and Pd(PPh3)4 (21 mg, 0.018 mmol) in DMF (7.5 mL)/water (1.5 mL). The crude material was purified by an SCX column (2 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→1% MeOH in CH2Cl2 (15-34)→2% MeOH in CH2Cl2 (35-56)], yielding the title compound as an off-white yellow solid. 1H NMR (CDCl3, 400 MHz): δ=0.44-0.50 (m, 2H), 0.63-0.71 (m, 2H), 1.29-1.39 (m, 1H), 4.15 (d, J=7.2 Hz, 2H), 5.20 (brs, 2H), 7.29 (s, 1H), 7.46-7.52 (m, 11H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.8, 8.2 Hz, 11H), 7.91 (d, J=8.8 Hz, 11H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.8 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=4.05 (2C, −), 11.31 (+), 48.99 (−), 100.98 (Cquart), 115.67 (Cquart), 118.96 (+), 123.30 (+), 125.94 (Cquart), 127.46 (+), 127.55 (2C, +), 128.23 (+), 128.47 (+), 128.87 (2C, +), 129.50 (+), 136.50 (Cquart), 136.55 (+), 139.45 (Cquart), 148.52 (Cquart), 150.97 (Cquart), 152.04 (+), 156.99 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (100) [MH+], 338.2 (22) [MH+—C4H6]. HPLC: tR=2.9 min (OpenLynx, polar—5 min).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])[CH:5](O)[C:6]1[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[CH:9][C:10]=1[N+:11]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[O:23][C:4]1[C:3](=[O:2])[NH:11][C:10]2[CH:9]=[N:8][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:5]=1
Reactant: COC(=O)C(Oc1ccc(F)cc1F)C(O)c1c([N+](=O)[O-])cnn1COCC[Si](C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ncc2[nH]c(=O)c(Oc3ccc(F)cc3F)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
To a solution of 2-(2,4-difluorophenoxy)-3-hydroxy-3-[4-nitro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]propionic acid methyl ester (125 mg, 0.264 mmol) in ethanol (2 mL) and water (1 mL) was added ammonium chloride (74 mg, 5.2 eq) followed by iron powder (Fisher Brand, Electrolytic). The resulting mixture was stirred at room temperature for 45 minutes, refluxed overnight, cooled to room temperature, diluted with ethanol, and filtered through a 3 cm bed of celite with additional ethanol. The filtrate was concentrated, and the residue was diluted with ethyl acetate (80 mL) and water (40 mL). The organic layer was separated, washed with water (2×40 mL) and brine (1×40 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound as a thick tan oil (98 mg, (M+H)+=394).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.[H-].[Na+].O>CN(C=O)C>[CH:19]1([O:1][C:2]2[CH:3]=[C:4]([N:10]3[C:18]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=4[N:12]=[CH:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(-n2cnc3cnccc32)cc1O
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2cnc3cnccc32)cc1OC1CCCC1
Yield: 21.8 %

Procedure:
A solution of 2.05 g of 1-(3hydroxy-4-methoxyphenyl)-1H-imidazo[4,5-c]pyridine, 2.5 g of cyclopentylbromide and 665 mg of NaH in 20 ml of DMF was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate, dried to give 1.4 g of crude product. Recrystallization from CH2Cl2 gave 574 mg product. M.P.: 66°-88° C.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[CH2:12]([C:16]([NH2:18])=[O:17])[C:13]([NH2:15])=[NH:14].Cl.[O-]CC.[Na+]>CCO>[OH:9][C:1]1[CH:2]=[C:3]([OH:5])[N:15]=[C:13]([CH2:12][C:16]([NH2:18])=[O:17])[N:14]=1
Reactant: N=C(N)CC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)Cc1nc(O)cc(O)n1

Procedure:
Diethyl malonate and malonamamidine hydrochloride were combined in EtOH (50 mL) with stirring. Sodium ethoxide was added dropwise via addition funnel over 10 minutes. The reaction was stirred overnight at room temperature to give 2-(4,6-dihydroxy-pyrimidin-2-yl)-acetamide.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>N1C=CC=CC=1.Cl>[CH:1]1([C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)C1CCCCC1
Yield: 64.4 %

Procedure:
Cyclohexanoyl chloride (1.05 g, 7.14 mmol) was added dropwise to a stirred suspension of 2-amino-5-nitropyrimidine (1.0 g, 7.14 mmol) in pyridine (10 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere. The reaction mixture was cooled then stirred in 2N hydrochloric acid (100 ml) and extracted with ethyl acetate. Crystallisation from ethyl acetate/hexane, yielded 2-(N-cyclohexanoyl)amino-5-nitropyrimidine (1.15 g, 64% yield) as a beige solid:
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[Cl:22][C:23]1[C:24]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:25][CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[C:23]=3[Cl:22])=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2Cl)OC1(C)C
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(N5CCOCC5)c4Cl)cc32)c1Cl
Yield: 49 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 4-[3-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholine as in General Procedure 4A to give the title compound as a tan foam (49% yield). M.p. (foam), LCMS: m/z=493.59 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (t, J=5.3 Hz, 2H), 3.38 (t, J=4.8 Hz, 4H), 3.52-3.58 (m, 2H), 3.89 (t, J=4.3 Hz, 4H), 4.47 (d, J=1.3 Hz, 2H), 5.16 (bs, 1H), 6.89 (d, J=5.0 Hz, 1H), 6.97-7.06 (m, 2H), 7.08-7.15 (m, 1H), 7.56 (d, J=1.8 Hz, 1H), 8.17 (d, J=5.0 Hz, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)([F:7])[F:6]>O.[Cl-].C([N+](CC)(CC)CC)C>[F:4][C:5]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:1]#[N:2])=[CH:11][CH:10]=1)([F:7])[F:6]
Reactant: [C-]#N
Reactant: FC(F)(F)Sc1ccc(CCl)cc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(SC(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 123.3 %

Procedure:
75 g of sodium cyanide were dissolved in 200 ml of water, and 15 g of tetraethylammonium chloride after 450 g of 4-trifluoromethylmercapto-benzyl chloride were added. The reaction mixture was stirred at 110° C. for 1 hour and then cooled. The cold mixture was diluted with 200 ml of water and then extracted twice with methylene chloride. After drying the organic phase, the solvent was distilled off and the crude product was purified by distillation. 410 g of 4-trifluoromethylmercapto-benzyl cyanide were obtained. Boiling point=95°-97° C./1.5 mm Hg; nD20 =1.5025.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1>C(O)C>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:12][CH2:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[CH:18][CH:17]=1
Reactant: SCCc1ccc2c(c1)OCO2
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc(CSCCc2ccc3c(c2)OCO3)ccn1
Temperature: 70 °C
Yield: 59.8 %

Procedure:
3.30 g of 2-(1,3-benzodioxol-5-yl)ethanethiol was dissolved in 30 ml of ethanol. 1.65 g of sodium hydroxide and then 2.70 g of 4-picolyl chloride hydrochloride were added to the solution and the mixture was heated under reflux at 70° C. for 30 min. The solvent was distilled off and water was added to the residue. After extraction with ethyl acetate, 1N hydrochloric acid was added to the extract. The aqueous layer was acidified, taken up and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 8 with potassium carbonate. After extraction with ethyl acetate, the extract was washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified according to silica gel column chromatography (ethyl acetate/hexane=1:4) to obtain 2.69 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:8][C:9]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>C1COCC1>[C:9]([Si:12]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:8]
Reactant: C=CCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
To a solution of 5-hexen-1-ol (5 g, 50 mmol) in THF (80 mL) were sequentially added TBDMSCl (8.4 g, 55 mmol) and imidazole (4.01 g, 60 mmol). The mixture was stirred at rt overnight. Water was added and the two phases separated. The aq. phase was extracted with ether and the combined org. layers were dried over MgSO4 and concentrated to give the title intermediate as a colourless liquid (11.2 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C([Li])CCC.Br[CH2:23][C:24]1[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=1.O>O1CCCC1>[F:1][C:2]1[C:3]([CH2:16][CH2:23][C:24]2[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[N:6][CH:7]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ncc1F
Reactant: CC(C)c1csc(CBr)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1csc(CCc2cc(NC(=O)OC(C)(C)C)ncc2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
The tert-butyl N-(5-fluoro-4-methyl-2-pyridyl)carbamate (75.6 mg, 0.334 mmol) obtained in (F) was dissolved in tetrahydrofuran (2 ml) and added dropwise with n-butyl lithium (1.5 M solution in hexane, 0.468 ml, 0.702 mmol) at −78° C. under argon atmosphere. The reaction mixture was warmed to room temperature, stirred for 1 hour, cooled to −78° C. again, added dropwise with a solution of 2-(bromomethyl)-4-isopropyl-1,3-thiazole (84.6 mg, 0.384 mmol) in tetrahydrofuran (2 ml), and then warmed to room temperature. The reaction mixture was added with water and extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:ethyl acetate=100:1) to obtain the title compound (40.0 mg, 33%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:3]1[CH:2]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:4]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1ccc(F)cc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 13, substituting 4-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.93 (s, 2H), 7.88 (dd, J=8.7, 5.9 Hz, 1H), 7.56 (dd, J=9.2, 2.5 Hz, 1H), 7.38-7.30 (m, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([CH2:10][C@:11]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([OH:13])[CH3:12])=[N+]=[N-]>C1COCC1>[NH2:7][CH2:10][C@:11]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([OH:13])[CH3:12]
Reactant: C[C@@](O)(CN=[N+]=[N-])c1cc(Br)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@](O)(CN)c1cc(Br)ccc1F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of LiAlH4 (4.65 g, 122 mmol) in THF (250 ml) was added under argon at 0-5° C. a solution of (S)-1-azido-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (33.4 g, 122 mmol) dissolved in THF (150 ml) over a period of 30 min. After stirring for 1 h at 0-5° C., the reaction was quenched by careful addition of water (4.7 ml), 4 N NaOH (4.7 ml) and water (14.1 ml) and stirred again for 3 h at 25° C. The white suspension was dried with MgSO4, filtered and concentrated. The solidified product was re-crystallized from TBME-hexane to provide the title compound as beige crystals: 98% ee (Chiralpak AD-H hexane-EtOH 75-25+0.05% NEt3); TLC (CH2Cl2-MeOH 10:1) Rf=0.10; HPLC RtH5=0.558 min; ESIMS: 248, 250 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 7.76 (dd, 1H), 7.25 (m, 1H), 6.82 (dd, 1H), 4.16 (br s, 1H), 3.19 (d, 1H), 2.72 (d, 1H), 1.44 (s, 3H), 0.95 (br s, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH2:22]CC)=[O:21])[CH2:4][CH:5](O)[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].P1(O)(OC2C=CC=CC=2C2C=CC=CC=2O1)=[O:26]>>[OH:26][CH2:2][CH2:1][N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH3:22])=[O:21])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: O=P1(O)Oc2ccccc2-c2ccccc2O1
Reactant: CCCS(=O)CCCN(CC)CC(O)COc1ccc(C#N)cc1
Product: CS(=O)CCCN(CCO)CCCOc1ccc(C#N)cc1

Procedure:
4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2-hydroxypropoxy]-benzonitrile, addition salt with biphenyl-2,2'-diyl hydrogen phosphate
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][NH2:19])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][NH:19][S:32]([CH2:31][CH2:30][CH2:29][F:28])(=[O:34])=[O:33])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Reactant: O=S(=O)(Cl)CCCF
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CCCF)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
Tert-butyl[7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (32 mg, 0.87 mmol) was dissolved in dichloromethane (15 mL) and 4-dimethylaminopyridine (12 mg, 0.096 mmol) and 3-fluoropropane-1-sulfonyl chloride (14 mg, 0.087 mmol) were added. The reaction mixture was stirred at room temperature over night. The dichloromethane solution of the crude product was washed successively with 1N aqueous hydrochloric acid and aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane, methanol, silica gel). Yield: 9.3 mg (0.019 mmol, 22%).