Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:28][C@H:29]2[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30]2)[CH:22]=[CH:21]3)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[C@H:29]1([NH:28][C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][CH:27]=[C:18]([NH:17][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:16])[CH:19]=3)[N:24]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCNCC1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.040 mmol) was dissolved in methylene chloride (1.0 mL). At 0° C. trifluoroacetic acid (0.030 mL, 0.40 mmol) was added and the reaction mixture was stirred at ambient temperature over night. 20% sodium carbonate solution in water was added and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried on magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography (silica gel, methylene chloride:methanol gradient=95:5→2:1) to yield the title compound (5.0 mg; 31%) as an off-white solid; MS: m/e=402.5 (M+H+).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(=O)([O-])[O-].[Na+].[Na+].C(O)CC.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:31]1([C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:11])[N:5]=[CH:4][C:3]=2[NH:20][C@@H:21]2[CH2:26][C@@H:25]3[CH2:27][C@@H:23]([C:24]3([CH3:29])[CH3:28])[C@H:22]2[CH3:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Reactant: OB(O)c1ccccc1
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: CCCO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1-c1ccccc1)C2(C)C
Yield: 121.2 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.105 mmol), phenylboronic acid (26 mg, 0.21 mmol) and tetrakistriphenylphosphinepalladium (13 mg, 0.011 mmol) in 2 M aqueous sodium carbonate-1-propanol (1:5, 2.4 mL) were stirred in a nitrogen stream at 100° C. overnight. After cooling, the reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography (chloroform/methanol=20/1) to give the desired product (60 mg, 100% yield).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[N:34][CH:35]=1>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)[CH3:28])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from boronic acid 4 (400 mg, 1.05 mmol) and 5-bromo-2-methylpyridine (181 mg, 1.05 mmol) in accordance with Method B.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#N)=[CH:16][C:15]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([Mg]Cl)[CH2:27][CH2:26][CH2:25][CH2:24]1.[OH2:30].Cl>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl[Mg]C1CCCC1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2F)CC1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C3CCCC3)cc2F)CC1
Temperature: 0 °C

Procedure:
A −78° C. solution of 4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.27 g, 0.87 mmol) in Et2O (10 mL) was treated with cyclopentylmagnesium chloride (1.5 mL, 2 M). The mixture was allowed to slowly reach rt overnight. The reaction was then cooled to 0° C. and water added (10 mL). The pH of the mixture was adjusted to ˜7 with 1 M HCl and was extracted with Et2O and the solvent removed. Purification on SiO2EtOAc/hexanes) provided 0.19 g of the title compound. MS (ESI): mass calcd. for C21H29FN2O3, 376.47. m/z found, 377.5 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].N.[CH3:45][N:46]1[CH:53]=[N:52][C:48]([CH2:49][CH2:50][NH2:51])=[CH:47]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl.CN(C=O)C>[C:17]([C:8]1([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:32]([NH:51][CH2:50][CH2:49][C:48]2[N:52]=[CH:53][N:46]([CH3:45])[CH:47]=2)=[O:33])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:6][CH2:7]1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: Cn1cnc(CCN)c1
Reactant: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)NCCc2cn(C)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
75 mg (0.18 mmol) of 1-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidin-4-yl}butan-1-one and 40 mg (0.2 mmol) of para-nitrophenyl chloroformate are dissolved in 5 ml of dichloromethane. The mixture is stirred for 1 hour at room temperature and the solution is then stopped by adding 20% aqueous ammonia and extracted with dichloromethane. The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated to dryness. The oil obtained is diluted in 5 ml of DMF, the mixture is heated to 80° C. and 39 mg (0.2 mmol) of 1-methylhistamine and 0.05 ml (0.36 mmol) of triethylamine are then added, and the solution is stirred for 5 minutes at 80° C. and for 10 minutes at room temperature. The reaction is stopped by adding aqueous 1N sodium hydroxide solution and then extracted with DCM. The organic phase is washed with water and then dried over sulfate, filtered and concentrated. The oil obtained is chromatographed on silica gel (eluent: 90/10 DCM/MeOH). 40 mg of 1-[(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1-methyl-1H-imidazol-4-yl)ethyl]urea in the form of a colourless oil are obtained in a yield of 39%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][C:12]([NH2:14])=[S:13])([CH3:3])[CH3:2].C[CH:16](C(C1C=CC(C2N=CN(C3C=CC(OC(F)(F)F)=CC=3)N=2)=CC=1)C)[C:17](N=[N+]=[N-])=[O:18].[N:46]([CH:49]([CH3:74])[CH:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[N:62]=[CH:61][N:60]([C:63]3[CH:68]=[CH:67][C:66]([O:69][C:70]([F:73])([F:72])[F:71])=[CH:65][CH:64]=3)[N:59]=2)=[CH:54][CH:53]=1)[CH3:51])=[C:47]=[O:48]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:17](=[O:18])[CH2:16][S:13]/[C:12]/1=[N:14]\[C:47]([NH:46][CH:49]([CH:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[N:62]=[CH:61][N:60]([C:63]3[CH:68]=[CH:67][C:66]([O:69][C:70]([F:72])([F:71])[F:73])=[CH:65][CH:64]=3)[N:59]=2)=[CH:54][CH:53]=1)[CH3:51])[CH3:74])=[O:48])([CH3:3])[CH3:2]
Reactant: CC(C(=O)N=[N+]=[N-])C(C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Reactant: CC(N=C=O)C(C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC(C)C(C)c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 35 using 1-(2-isopropyl-5-methylphenyl)thiourea and 2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1 H-1,2,4-triazol-3-yl)phenyl)butanoyl azide/3-(4-(3-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C35a) and isolated as an off-white powder (0.146 g, 39%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:24][F:25])[CH:13]([CH3:14])[C:12](=O)[N:11]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:24][F:25])[CH:13]([CH3:14])[CH2:12][N:11]([C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)NC(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: CC1CN([C@H](C)c2ccccc2)C[C@@]1(CF)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
To a solution of (3S)-3-(tert-butoxycarbonylamino)-3-fluoromethyl-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine (485 mg, 1.38 mmol) in tetrahydrofuran (10 mL), 1.00M solution of borane in tetrahydrofuran (4.57 mL, 4.57 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction mixture under reduced pressure, water (1 mL), ethanol (9 mL), and triethylamine (1 mL) were added in an ice bath, and the mixture was heated under reflux for 1.5 hours. After concentrating the reaction mixture under reduced pressure, water (100 mL) was added, and the mixture was extracted with chloroform (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 12:1→1:1) to obtain 350 mg (75%) of the title compound as a colorless oily substance.
Reaction SMILES: [F-].[K+].[C:3]1(=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])C1.I[CH3:15].[C:16](#N)[CH3:17]>>[CH3:15][C:16]1([CH3:17])[C:3](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12]
Reactant: CC#N
Reactant: O=C1CC(=O)c2ccccc21
Reactant: CI
Agent: [F-]
Agent: [K+]
Product: CC1(C)C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
Potassium fluoride on Celite® [loading wt: 50% purchased from Sigma-Aldrich Co.] (5.8 g, ˜50 mmol) is heated at 135° C. for 2 h under vacuum (<20 torr). The solid is then permitted to cool to room temperature and placed under a nitrogen atmosphere at which time a solution of indan-1,3-dione (CAS# 606-23-5, 1.46 g, 10.0 mmol) in acetonitrile (15 mL) is added followed by iodomethane (1.8 mL, 30 mmol). The reaction is heated in a sealed vessel at 70° C. overnight. The reaction mixture is cooled to room temperature and filtered through a pad of Celite®. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:9) to furnish 2,2-dimethyl-indan-1,3-dione; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (s, 6 H), 7.84-7.89 (m, 2 H), 7.96-8.02 (m, 2 H).
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[C:26]3[C:22](C=[CH:24][NH:25]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:27]=[C:26]3[C:22]([C:7]([CH:6]=[O:10])=[CH:24][NH:25]3)=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
To a solution of DMF (5.0 mL, 64 mmol) and CH2Cl2 (120 mL) was added oxalyl chloride (2.1 mL, 24 mmol). The mixture was stirred for 45 minutes at ambient temperature and then was decanted into a solution of 6-(4-fluorophenyl)indole (5.1 g, 24 mmol), which was prepared as described in International Application Number PCT/US92/05890 (4 Feb. 1993). The reaction mixture was stirred for 90 minutes at ambient temperature and the imminium salt was isolated by filtration. The solids were dissolved in methanol (150 mL) and saturated aqueous NaHCO3 (200 mL) was added. The resulting precipitate was filtered and dried in a vacuum oven to give 6-(4-fluorophenyl)indole-3-carboxaldehyde (4.14 g, 72%) as a tan powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.N1C=CC=CC=1.[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:20][C:21]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 248.9 %

Procedure:
A flask was charged with (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.0 g, 5.4 mmol, Lancaster) in DCM (15 mL) to give a colorless solution. Pyridine (0.89 mL, 10.8 mmol) was added and the solution was cooled to about 0° C., followed by the addition of triphosgene (0.64 g, 2.1 mmol). The mixture was stirred for about 1 h while slowly warming to ambient temperature. To the reaction solution was added DCM (50 mL) and the solution was washed with water (20 mL) and HCl (1N, 10 mL). The organic portion was separated, dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give (R)-tert-butyl 1-(chlorocarbonyl)pyrrolidin-3-ylcarbamate (1.3 g, 98%) as a yellow oil: 1H NMR (DMSO-d6) δ 7.28 (s, 1 H), 4.03 (m, 1 H), 3.73-3.20 (m, 4 H), 2.05 (m, 1 H), 1.81 (m, 1 H), 1.39 (s, 9 H).
Reaction SMILES: P(=O)(O)(O)O.[C:6]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:17]([C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)=[C:21]([CH3:34])[CH:20]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C>[CH3:34][C:21]1[CH:20]=[C:19]([CH2:17][N:14]2[CH2:15][CH2:16][CH:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:13]2)[CH:33]=[CH:32][C:22]=1[O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(CN2CCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Yield: 71 %

Procedure:
Using a method similar to Example 362, using 3-phenyl-pyrrolidine phosphoric acid salt (1.543 g, 6.29 mmol), 6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile (compound of example 365, step 1) (1.499 g, 6.30 mmol), sodium triacetoxyborohydride (2.00 g, 9.44 mmol), and acetic acid (0.58 mL, 10.1 mmol) in 1,2-dichloroethane (50 mL), after silica gel chromatography (19:1→1:3 hexanes:ethyl acetate) provides 1.65 g (71%) of the title compound as a clear syrup: Mass spectrum (electrospray): m/z=370.1 (M+1); 1H NMR (CDCl3): 8.47 (d, 1H, J=2.4 Hz), 7.91 (dd, 1H, J=2.0, 8.3 Hz), 7.32-7.28 (m, 5H), 7.26-7.17 (m, 2H), 3.67 (s, 2H), 3.45-3.35 (m, 1H), 3.08 (t, 1H, J=9.3 Hz). 2.93-2.85 (m, 1H), 2.72 (dt, 1H, J=5.9, 8.8 Hz), 2.53 (dd, 1H, J=8.3, 9.3 Hz), 2.43-2.32 (m, 1H), 2.14 (s, 3H), 1.99-1.88 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[N:10]=[C:9]([C:20]3[N:21]=[CH:22][N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[C:9]([C:20]3[N:21]=[CH:22][NH:23][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1nc(-c2c[nH]cn2)cc1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of tert-butyl [5-(4-fluorobenzyl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazol-1-yl]acetate (0.5 g, 0.80 mmol) in CH2Cl2 (10 mL) was added dropwise TFA (10 mL) at 0° C. After the addition, the mixture was stirred at 0° C. for 2 hours. The solvent was removed in vacuo and the residue was washed with Et2O (3×10 mL) and dried in oven to yield the title compound (0.2 g, 80.0%) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[C:6]1(=[O:16])[O:11][C:9](=[O:10])[CH:8]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:7]12.OP([O-])([O-])=O.[K+].[K+].[OH-:24].[Na+]>O>[CH2:1]([O:24][C:9](=[O:10])[CH:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:7]1[C:6]([O:11][CH2:1][CH:3]1[O:5][CH2:4]1)=[O:16])[CH:3]1[O:5][CH2:4]1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: ClCC1CO1
Reactant: [OH-]
Agent: O=P([O-])([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(OCC1CO1)C1CCCCC1C(=O)OCC1CO1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
4163 g of epichlorhydrin, 693 g of hexahydrophthalic acid anhydride and 105 g of distilled water were weighed into a 6-liter four-necked flask, equipped with a reflux condenser, gas inlet pipe and dropping funnel, and heated with stirring to 90°C. A gentle stream of nitrogen was passed over the reaction mixture. After 2.5 hours, 15 g of K2HPO4 (secondary o-potassium phosphate) were added and the mixture was kept for about another 4 hours at 90°C. Thereafter, the product had an acid number of 0. It was cooled to approximately 20°C, followed by the dropwise addition over a period of 1 to 2 hours of 882 g of 45% by weight of NaOH. The sump temperature should not exceed 30°C during the addition. A water jet vacuum was then applied, and water together with excess epichlorhydrin (substantially quantitative) was distilled off. After the sump temperature had reached 90°C and the vacuum settled at approximately 20 mm, the product was taken up with 1000 g of toluene and washed with water until salt-free.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.F[C:23]1[C:28]([F:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:29][C:28]1[C:23]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[N:17]=[CH:18][CH:19]=[N:20]2)=[N:24][CH:25]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:27]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1

Procedure:
A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 65 mg, 0.36 mmol) and DIPEA (42 mg, 0.33 mmol) in dry DMSO (1.1 ml) was subjected to microwave irradiation at 140° C. for 1 hour. The reaction was filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=1.[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)#[CH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:36]#[C:35][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:25][CH:26]=1
Reactant: O=S(=O)(Oc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1)C(F)(F)F
Reactant: C#Cc1ccccn1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccccn4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzene and 2-ethynyl-pyridine.
Reaction SMILES: [CH3:1][NH2:2].Br[C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1.Cl>O>[CH3:1][NH:2][C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1
Reactant: CN
Reactant: CS(=O)(=O)Nc1cc2occ(Br)c(=O)c2cc1Oc1ccccc1
Agent: Cl
Solvent: O
Product: CNc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reaction time: 2 h
Yield: 11.1 %

Procedure:
50 ml of a 25% aqueous methylamine solution was ice-cooled. Thereto was added 4.1 g of 3-bromo-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. The mixture was stirred for 2 hours at 0°-5° C. 100 ml of water was added thereto. The mixture was adjusted to pH 4 with 4N hydrochloric acid and then extracted with 100 ml of ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 5:1 mixture of toluene and ethyl acetate) and then recrystallized from ethanol to obtain 400 mg (yield: 11.1%) of 3-methylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[N:9]3)[N:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20](C=C)=[CH:19][CH:18]=1.[CH3:25][C:26]#N>>[Cl-:15].[CH2:16]([N+:4]1([CH:25]=[CH2:26])[C:5]2[C:14](=[C:13]3[C:8](=[CH:7][CH:6]=2)[N:9]=[CH:10][CH:11]=[CH:12]3)[CH:1]=[CH:2][CH2:3]1)[C:17]1[CH:24]=[CH:23][CH:20]=[CH:19][CH:18]=1
Reactant: CC#N
Reactant: c1cnc2ccc3ncccc3c2c1
Reactant: C=Cc1ccc(CCl)cc1
Product: C=C[N+]1(Cc2ccccc2)CC=Cc2c1ccc1ncccc21
Product: [Cl-]
Temperature: 25 °C

Procedure:
A flame dried, side armed 100-mL round bottom flask, equipped with a magnetic stirring bar, was cooled under argon and charged with 4,7-phenanthroline (2.14 g, 11.86 mmols). The flask was equipped with a reflux condenser attached to an argon (g) line and charged with 4-(chloromethyl)styrene (0.905 g, 0.836 mL, 5.93 mmols) and anhydrous CH3CN (20 mL) through the side arm. The solution was heated to reflux under argon (g) for 17 h, then cooled to room temperature and precipitated with diethyl ether (30 mL). The suspension was allowed to settle and the supernatant removed via cannula. The remaining residue along with 15 mL of solvent was cannulated into a centrifuge tube, triturated with acetone (20 mL), and centrifuged (process repeated 4 times). The brownish/pink solid was triturated with diethyl ether (3×20 mL) and dried under reduced pressure. Yield: 0.376 g, 1.13 mmols (19%). 1H NMR (250 MHz, CD3OD, ppm): 5.266 (d, 1H, 11 Hz), 5.80 (d, 1H, J=17.75 Hz), 6.482 (s, 2H), 6.708 (dd, 1H, J1=1 Hz, J2=17.75 Hz), 7.374 (d, 1H, J=8 Hz), 7.496 (d, 1H, J=8 Hz) 8.00, (dd, 1H, J1=4 Hz, J2=8.5 Hz), 8.453 (dd, 1H, J1=6 Hz, J2=8.5 Hz), 8.60 (d, 1H, J=10 Hz), 8.697 (d, 1H, J=10 Hz), 9.20 (d, 1H, J=4 Hz), 9.50 (d, 1H, J=8.25 Hz), 9.65 (d, 1H, J=5.75 Hz), 10.188 (d, 1H, J=8.5 Hz). 13C NMR (62.5 MHz, CD3OD); 62.40, 121.344, 124.899, 126.023, 128.454, 129.031, 130.778, 132.161, 133.893, 134.242, 137.205, 139.848, 140.410, 140.699, 144.041, 147.976, 149.541, 154.661.