Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Cl[C:19]1[N:20]=[CH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[CH3:17])[NH2:1])[N:20]=1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc2ccccc2cn1
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(N)cc1-c1cc2ccccc2cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask containing 5-amino-2-methyl-phenylboronic acid pinacol ester (233 mg, 1 mmol), 3-chloro-isoquinoline (2-(5 mg, 1.5 mmol), Pd(PPh3)4 (128 mg, 0.1 mmol) is added toluene (4 ml), EtOH (1 ml) and aqueous 2M Na2CO3 solution (2 ml). The flask is purged with argon and sealed. The mixture is stirred at 90° C. for 18 hours, cooled to room temperature and extracted using water and ethyl acetate. The organic layer is separated, washed with brine, dried over MgSO4 and concentrated. The residue is subjected to silica gel flash chromatography, eluted with ethyl acetate in hexanes from 30% to 50% to afford 3-(isoquinolin-3-yl)-4-methylaniline as a brown oil. LC-MS m/z: 235.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH2:27]1[C@@H:30]([C:31]([OH:33])=[O:32])[NH:29][CH2:28]1>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([N:29]5[CH2:28][CH2:27][C@H:30]5[C:31]([OH:33])=[O:32])[CH:26]=[CH:25][C:5]=43)[CH:9]=2)[N:15]([CH2:20][C:21]([F:22])([F:24])[F:23])[N:16]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(CC(F)(F)F)n1
Reactant: O=C(O)[C@@H]1CCN1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CC[C@H]4C(=O)O)cc2OCC3)n(CC(F)(F)F)n1

Procedure:
Following the procedure in Example 551, 8-bromo-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene and (L)-azetidine-2-carboxylic acid were reacted to give (S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-azetidine-2-carboxylic acid. LCMS: RT=2.93 min, [M+H]+=449
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH2:18]Br.[H-].[Na+]>CN(C)C=O>[C:1]1([S:7]([N:10]2[CH2:18][C:17]3[S:16][CH:15]=[N:14][C:13]=3[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ncsc1CBr
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N1Cc2ncsc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzenesulfonamide (638 mg) and 4,5-bis(bromomethyl)thiazole (M. Al. Hariri, O. Galley, F. Pautet, H. Fillion, Eur. J. Org. Chem., pp. 593-594 (1998)) (1.10 g) were dissolved in N,N-dimethylformamide (10 mL) under ice cooling, and sodium hydride (60% in oil, 357 mg) was added thereto at a time, followed by stirring at room temperature for 3 hours. The resultant mixture was partitioned between water and methylene chloride, and the organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=9:1), to thereby give the title compound (137 mg).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.Cl[C:22]1[N:30]=[C:29]([NH2:31])[N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH:20][C:22]3[N:30]=[C:29]([NH2:31])[N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 44.4 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (500 mg, 1.71 mmol), 6-chloro-9H-purin-2-amine (436 mg, 2.57 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.895 mL, 5.14 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was diluted with MeOH/DMSO and purified by preparative HPLC (basic mode) eluting with 20-30% ACN in water. The fractions containing the desired compound were collected and concentrated in vacuo. The residue was re-crystallized in an EtOAc/MeOH/hexane mixture to give the title compound (295 mg, 44.4%). 1H NMR (500 MHz, CD3OD) δ ppm 1.50 (d, J=6.83 Hz, 3 H), 3.59-3.66 (m, 3 H), 3.89 (br s, 3 H), 5.56 (br s, 1 H), 6.45 (d, J=1.95 Hz, 1 H), 6.68-6.73 (m, 1 H), 7.58-7.65 (m, 2 H), 7.77-7.89 (m, 2 H); ESI-MS m/z [M+H]+ calc'd for C19H20N10, 389; found 389.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:22](=[O:23])[CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]=2[CH2:10]1)=O)(C)(C)C.[ClH:24]>C(OCC)C>[ClH:24].[NH2:8][CH:9]1[C:22](=[O:23])[CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]=2[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc3ccccc3c2CC1=O
Agent: Cl
Solvent: CCOCC
Product: NC1Cc2ccc3ccccc3c2CC1=O
Reaction time: 6 h

Procedure:
Under argon to a solution of 2-tertbutoxycarbonylamino-1,2-dihydro-3(4H) -phenanthrenone (74 mg) in anhydrous diethyl ether (5 ml) was added a saturated solution of hydrochloric acid in diethyl ether (5 ml). The mixture was stirred for 6 hours and the formed precipitate was filtered and dried under vacuum to afford the title compound as a white solid (42 mg)
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]Br)=[CH:13][CH:12]=1.[NH4+].[Cl-]>C(OCC)C.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:8])=[CH:13][CH:12]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: OC(CCc1ccc(F)cc1)c1cccnc1

Procedure:
A solution of 10.7 g (0.10 mole) of nicotinaldehyde in 100 ml of diethyl ether is added dropwise, while stirring, to a solution prepared from 2.92 g (0.12 mole) of magnesium and 24.4 g (0.12 mole) of 2-(4-fluorophenyl)-ethyl bromide in 250 ml of diethyl ether, and the mixture is then refluxed for 2 hours. Cooling is followed by hydrolysis with water, and the pH is brought to 8 with saturated aqueous NH4Cl solution. The phases are separated, the aqueous phase is extracted twice more with ether, and the combined organic phases are washed with water and dried over NgSO4. The solvent is evaporated off and the residue is distilled under reduced pressure to give 10.2 g (44% of theory) of compound No. 4 of boiling point 190° C. (2 mbar).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=O)[NH:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[S:35][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=[CH:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NCC(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)s1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
The mixture of 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.44 mmol) and Lawesson's reagent (1.23 g, 3.0 mmol) in THF (16 ml) was heated at 80° C. for 4 hours. The solvent was removed under reduced pressure and the mixture was diluted with EtOAc. The organic phase was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 2-[5-(4-Bromo-phenyl)-thiazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (655 mg). m/z: 410.7 (M+H)+.
Reaction SMILES: C(OC(Cl)=O)C.[C:7]([OH:15])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:16]([N:18](CC)[CH2:19]C)C.CNC>O1CCCC1.C(O)C>[CH3:16][N:18]([CH3:19])[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCN(CC)CC
Reactant: CCCCCCC(=O)O
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethylchloroformate (18.3 ml) was added slowly to a solution of heptanoic acid (20.0 g) and triethylamine (26.7 ml) in tetrahydrofuran (250 ml), maintained at -10°. The resulting mixture was stirred at 10° for 0.75 hour, cooled to 5° and a 33% solution of dimethylamine in ethanol (41.6 ml) added dropwise. This mixture was then allowed to warm to room temperature and stirred for 4 hours. The mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in chloroform (250 ml) and washed with 1% aqueous sodium carbonate solution (200 ml) and water, then dried and evaporated. The residual oil was chromatographed on silica gel to give N,N-dimethylheptanamide (14.1 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](OC)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CO)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
In a 500 ml round-bottomed flask at room temperature under nitrogen, methyl 6-methyl-3-pyridinecarboxylate (10 g, 66.2 mmol) was dissolved in dry tetrahydrofuran (100 ml) to give a orange solution. The mixture was then cooled down to 0° C. and lithium aluminum hydride (36.4 ml, 72.8 mmol) was added dropwise, keeping internal temperature below 0° C. At the end of addition the ice-bath was removed and the resulting solution was stirred at room temperature for 3 hours. The mixture was slowly additioned with 2.73 ml of water, 2.73 ml of NaOH 1M and 8.2 ml of water. The resulting yellow suspension was stirred at room temperature for ˜30 minutes and then filtered over a Gooch funnel. The solid was washed with Et2O (3×100 ml). The combined organics were dried over Na2SO4, filtered and concentrated to give the title product (7.48 g) as orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:12].CO.[NH4+].[Cl-]>[Zn].C1COCC1>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(O)c(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 0° C. solution of 2-chloro-3-fluoro-4-nitrophenol (25 g, 130.9 mmol) in 1:1 MeOH and THF (400 mL) was treated with NH4Cl (70 g, 1.3 mol), followed by the portion-wise addition of zinc (83.2 g, 1.3 mol), then warmed to RT and stirred for 2 h. The solids were removed via filtration, the filtrate concentrated to dryness and the residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 and concentrated to afford 4-amino-2-chloro-3-fluorophenol (16 g, 76%). 1H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1 H), 6.59-6.51 (m, 2 H), 4.65 (s, 2H); MS (ESI): m/z 162.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: CC(Oc1ccccn1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccn3)cc2)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 20.1 %

Procedure:
To a solution of 4-(1-(pyridin-2-yloxy)ethyl)benzoic acid (160 mg, 0.66 mmol), 1-hydroxybenzotriozole (135 mg, 1.0 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol), triethylamine (0.3 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyridin-2-yloxy)ethyl)benzamide as a white solid (50 mg, 40%). LRMS (M+H+) m/z: 377.17. found 377. HPLC Purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.06-8.04 (m, 1H), 7.80-7.68 (m, 3H), 7.44-7.42 (m, 2H), 6.93-6.84 (m, 2H), 6.17 (q, J=6.6 Hz, 1H), 5.84 (s, 1H), 4.27 (d, J=4.8, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.55 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:45]=[CH:44][C:34]([CH2:35][NH:36]C(=O)OC(C)(C)C)=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:36][CH2:35][C:34]1[CH:44]=[CH:45][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:32][CH:33]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CNC(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(CN)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To a solution of rac tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzylcarbamate (64 mg, example XC31) in CH2Cl2 (4 ml) was added TRIFLUOROACETIC ACID (5.92 g, 4 mL) and the reaction was stirred at 0 C for 1.5 hrs. The crude reaction mixture was concentrated in vacuo and the taken up in CH2Cl2 (80 mL) and washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and concentrated to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-aminomethyl-phenyl)-amide as a white solid (54.3 mg, 99%). HRMS (ES+) m/z Calcd for C30H31Cl2F2N4O [(M+H)+]: 571.1838. found: 571.1837.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].CON(C)[C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>C1COCC1>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCBr
Reactant: CCCCCCCCCC(=O)N(C)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)CCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Polished shaved magnesium (3.2 g, 134 mmol) was heated, and thereafter, an anhydrous THF solution (68 ml) of 1-bromononane (12.9 ml, 67.5 mmol) was slowly added dropwise thereto. After heating to reflux for 1.5 hours, the reaction solution was cooled to a room temperature, and it was then added dropwise to a THF (80 mL) solution of the N-methoxy-N-methyldecanamide (4.8 g, 22.5 mmol) obtained by the method described in Production Example D-1-1. After the obtained mixture had been stirred for 30 minutes, 1 N hydrochloric acid was added to the reaction solution, followed by extraction with diethyl ether two times. Anhydrous magnesium sulfate was added to the organic layer to dry it, and the resultant was filtrated and was then concentrated. The obtained residue was purified using column chromatography (hexane:dichloromethane=8:1), so as to obtain 10-nonadecanone (6.0 g, 95%) as a ketone body in the form of a white amorphous solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].[CH3:21]I>C1COCC1>[CH3:21][O:1][CH2:2][CH2:3][C@@H:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
(R)-tert-Butyl 3-hydroxy-1-phenylpropylcarbamate (Intermediate 60, 258 mg, 1.03 mmol) was dissolved in THF under nitrogen at 0° C. NaH was added and the reaction mixture was stirred at 0° C. for 10 min. MeI was added and the reaction mixture was stirred at room temperature for 30 min. then quenched with sat. aq. Na2SO4 and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified via column chromatography using a biotage SP1 25+M column with a gradient 50% EtOAc in heptane calculated from TLC. Product fractions were combined and concentrated to give the title compound as a white solid (78 mg, 29%). LCMS=[M+H]=266
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[F:24][C:25]([F:37])([F:36])[S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([S:26]([C:25]([F:37])([F:24])[F:36])(=[O:28])=[O:27])=[CH:30][CH:31]=4)=[O:2])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)(CC1)CC2
Yield: 13.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-trifluoromethylsulfonylaniline (77.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-trifluoromethylsulfonylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (10.8 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16].C(Cl)Cl.[C:22]([C@@H:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:24]([C:22]#[N:23])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:26]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Yield: 76.3 %

Procedure:
6.2 g of dicyclohexycarbodiimide were added to a solution of 9.5 g of the product of Step C, 30 ml of methylene chloride and 3 ml of pyridine and the reaction mixture was stirred for half and hour. 6.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added thereto and the mixture was stirred for an hour and half and filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried, and evaporated to dryness. The 15.3 g of oil residue were chromatographed over silica gel and eluted with a 97-3 mixture of benzene-ethyl acetate to obtain 12 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonylethynyl)-cyclopropane-carboxylate melting at 101° C.
Reaction SMILES: [Cl-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[C:36]1[S:40][C:39]([CH:41]=O)=[CH:38][C:37]=1[CH3:43]>>[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[C:36]1[S:40][C:39]([CH:41]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:38][C:37]=1[CH3:43]
Reactant: Cc1cc(C=O)sc1C1OCCO1
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: [Cl-]
Product: CC(=O)Nc1nc(C=Cc2cc(C)c(C3OCCO3)s2)cs1
Yield: 74.7 %

Procedure:
In a similar manner as in Production Example 16, step 1, {[2-(acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphonium chloride (12.03 g, 26.56 mmol) and 5-(1,3-dioxolan-2-yl)-4-methylthiophene-2-carbaldehyde (3.51 g, 17.7 mmol) were condensed to give N-(4-{2-[5-(1,3-dioxolan-2-yl)-4-methylthiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (4.450 g, 13.23 mmol, yield 74.7%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:14]=[N:13][S:12][N:11]=2)=[C:6]([CH:9]=1)[CH:7]=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:14]=[N:13][S:12][N:11]=2)=[C:6]([CH:9]=1)[CH2:7][NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: O=Cc1cc(Cl)ccc1-c1cnsn1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNCc2cc(Cl)ccc2-c2cnsn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-chloro-2-(1,2,5-thiadiazol-3-yl)benzaldehyde (0.155 g, 0.69 mmol), 4-methoxybenzylamine (0.09 mL, 0.69 mmol) and acetic acid (0.05 mL, 0.83 mmol) in 1,2-dichloroethane (5.2 mL) was added sodium triacetoxyborohydride (0.731 g, 3.45 mmol). The solution was stirred at ambient temperature for 16 h then partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic phase was dried (Na2SO4) and reduced in vacuo. The residue was purified by automated preparative chromatography on silica (eluting with 5% CH2Cl2/EtOAc/hexanes gradient, 5–50% EtOAc). N-[5-Chloro-2-(1,2,5-thiadiazol-3-yl)benzyl]-N-(4-methoxybenzyl)amine was isolated as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.74 (s, 2H), 3.81 (s, 3H), 3.82 (s, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 8.84 (s,1H); MS m/z=346.5.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([CH3:30])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[N:17]([CH3:29])[C:18](=[O:28])[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:20][C:10]2=1)=O.O.[NH2:33]N>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[C:18](=[O:28])[N:17]([CH3:29])[C:11]3[N:12]([CH3:16])[C:13]4[C:9]([C:10]=3[CH:20]=2)=[CH:8][C:7]([C:5]2[NH:33][N:2]=[CH:3][C:4]=2[CH3:30])=[CH:15][CH:14]=4)=[CH:26][CH:25]=1
Reactant: NN
Reactant: CC(=CN(C)C)C(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C
Solvent: O
Product: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 40 above using compound B, 6-(3-dimethylamino-2-methylacryloyl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine hydrate.