Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[OH:29])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:31]([O:34][CH:35](Br)[CH3:36])(=[O:33])[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[OH:29])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH3:36])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH:20]4[CH2:22][CH2:21]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\C4CC4)CS[C@H]23)cs1
Reactant: CC(=O)OC(C)Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)OC(=O)C1=C(/C=C\C2CC2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (318 mg) of Example 57 was dissolved in dimethylformamide (4.4 ml), to which a solution of 1-acetoxyethyl bromide (120 mg) in dimethylformamide (2 ml) was added dropwise under ice cooling. The resulting mixture was stirred for one and a half hours. The reaction mixture was diluted with ethyl acetate and the resulting precipitate was filtered off. After the filtrate was washed with water and then saturated saline, anhydrous magnesium sulfate was added to dry the solution. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel, whereby the title compound (18 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O)[CH3:2].[O-]CC.[Na+].Cl>C(=O)(OCC)OCC.C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccccc1C=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=Cc2ccccc2OCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 4-(2-formylphenoxy)butyric acid ethylester (2.4 g) in diethyl carbonate (24 ml), a solution of 20% sodium ethoxide in ethanol (4.1 g) was added at room temperature, and the solution was stirred at 50° C. for 1 hour. The solution was allowed to cool to room temperature, and neutralized with 1N hydrochloric acid. After ethyl acetate extraction, the organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) and concentration of the appropriate eluate gave colorless oil of 2,3-dihydro-l-benzoxepin-4-carboxylic acid ethylester (1.3 g, yield 61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CCNCCO
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 2-(ethylamino)ethanol were converted to yield 2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-ethyl-amino]-ethanol, MS: 450 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]=O)=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:14][CH3:15])=[N:9]2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:44])[NH:22][C@@H:23]1[CH2:28][CH2:27][C@@H:26]([CH2:29]S(C2N(C3C=CC=CC=3)N=NN=2)(=O)=O)[O:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>COCCOC.CC(=O)OCC>[C:16]([O:20][C:21](=[O:44])[NH:22][C@@H:23]1[CH2:28][CH2:27][C@@H:26](/[CH:29]=[CH:12]/[C:11]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:10]=2[N:9]=[C:8]([O:14][CH3:15])[CH:7]=[CH:6]3)[O:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CS(=O)(=O)c2nnnn2-c2ccccc2)OC1
Reactant: COc1ccc2ccc(F)c(C=O)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(F)c(/C=C/[C@@H]3CC[C@@H](NC(=O)OC(C)(C)C)CO3)c2n1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A mixture of 7-fluoro-2-methoxy-quinoline-8-carbaldehyde (5 g, 24.36 mmol; prepared according to WO 2008/126024) and (3R,6S)-[6-(1-phenyl-1H-tetrazole-5-sulfonylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (10.32 g, 24.36 mmol, prepared according to WO 2006/032466) in DME (104 mL) was cooled to −60° C. A solution of LiHMDS (1M in THF, 42 mL) was added drop wise over 30 min. The reaction was stirred 1 hour at this temperature before warming slowly to rt. Water (80 mL) and EA (80 mL) were added. The two layers were decanted and the aq. layer was extracted twice with EA (2×100 mL). The combined org. layers were washed with brine (100 mL), dried over MgSO4 and concentrated to dryness. The residue (10.5 g) was carried on without further purification. The analytical data were obtained by trituration of a small portion of the crude in diethyl ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[C:25]4[CH2:27][O:28][C:29]5[CH:47]=[C:46]6[C:32]([CH:33]=[CH:34][C:35]7[N:39]=[C:38]([C@@H:40]8[CH2:44][CH2:43][C@H:42]([CH3:45])[NH:41]8)[NH:37][C:36]=76)=[CH:31][C:30]=5[C:24]4=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH2:5]1.[CH3:48][O:49][C@H:50]([CH3:60])[C@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:52](O)=[O:53].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:59][O:58][C:56](=[O:57])[NH:55][C@@H:51]([C@H:50]([O:49][CH3:48])[CH3:60])[C:52]([N:41]1[C@@H:42]([CH3:45])[CH2:43][CH2:44][C@H:40]1[C:38]1[NH:37][C:36]2[C:46]3[C:32]([CH:33]=[CH:34][C:35]=2[N:39]=1)=[CH:31][C:30]1[C:24]2[C:25]([CH2:27][O:28][C:29]=1[CH:47]=3)=[CH:26][C:21]([C:18]1[NH:17][C:16]([C@@H:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][NH:7]3)=[N:20][CH:19]=1)=[CH:22][CH:23]=2)=[O:53]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c65)cc3-4)[nH]2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butyl(2S,4S)-4-(methoxymethyl)-2-(5-{2-[(2S,5S)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (101 mg, 0.159 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (30 mg, 0.159 mmol), HATU (61 mg, 0.159 mmol) and 2 mL 10% DIPEA in DMF was stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate was added and the product was extracted into dichloromethane, dried over sodium sulphate, filtered and concentrated under reduced pressure. This crude product was treated with 5 mL 1.25N HCl in ethanol at 50° C. for 4 h and then it was concentrated under reduced pressure. Saturated sodium bicarbonate was added and the product was extracted into dichloromethane, dried over sodium sulphate, filtered and concentrated under reduced pressure. (74.6 mg)
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].[CH2:11]([SiH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].C([Si](CC(=CC)CCC=C(C)C)(CC)CC)C>>[CH2:11]([Si:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:9][CH:8]=[C:6]([CH3:7])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1])[CH3:12]
Reactant: C=CC(=C)CCC=C(C)C
Reactant: CC[SiH](CC)CC
Agent: CC=C(CCC=C(C)C)C[Si](CC)(CC)CC
Product: CC[Si](CC)(CC)CC=C(C)CCC=C(C)C
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 0.170 ml (1.0 mmol) of myrcene, 0.192 ml (1.2 mmol) of triethylsilane, and 5.2 mg (0.01 mmol) of tetraethylammonium μ-hydridebis(pentacarbonylchromium) was heated in a sealed tube at 100° C. for 60 hours while being stirred. GLC analysis of the reaction mixture revealed that 6-(triethylsilyl)methyl-2-methyl-2,6-octadiene and 8-triethylsilyl-2,6-dimethyl-2,6-octadiene were produced at a ratio of about 7:3 in a yield of 91%. 6-(Triethylsilyl)methyl-2-methyl-2,6-octadiene:
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH2:26]([NH:30][C:31]1[N:32]=[CH:33][C:34]([C:43]([OH:45])=O)=[N:35][C:36]=1[O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:28][CH3:29].[CH3:46][O:47][C:48](=[O:55])[C:49]([NH2:54])([CH2:52][CH3:53])[CH2:50][CH3:51]>>[CH3:46][O:47][C:48](=[O:55])[C:49]([NH:54][C:43]([C:34]1[CH:33]=[N:32][C:31]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[C:36]([O:37][CH2:38][C:39]([F:40])([F:41])[F:42])[N:35]=1)=[O:45])([CH2:52][CH3:53])[CH2:50][CH3:51]
Reactant: CCCCNc1ncc(C(=O)O)nc1OCC(F)(F)F
Reactant: CCC(N)(CC)C(=O)OC
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCCCNc1ncc(C(=O)NC(CC)(CC)C(=O)OC)nc1OCC(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-butylamino-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 421.1 (M+H).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1CCCC[C@H]1CN=[N+]=[N-]
Temperature: 100 °C
Yield: 99.6 %

Procedure:
To a solution of (trans)-methyl 2-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (1.4 g, 5.6 mmol) in DMF (6 mL) was added NaN3 (0.730 g, 11.0 mmol). The mixture was heated at about 100° C. for about 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×45 mL). The combined organic layers were washed with aqueous 1 N NaOH (1×40 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give (trans)-methyl 2-(azidomethyl)cyclohexanecarboxylate (1.1 g, 100%.): 1H NMR (400 MHz, CDCL3) δ 3.69 (d, J=6.0, 3H), 3.28-3.15 (m, 2H), 2.24-2.14 (m, 1H), 1.97-1.73 (m, 5H), 1.46 (dd, J=12.2, 3.2, 1H), 1.36-1.05 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[C:21]([CH3:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1>>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[C:21]([CH3:30])=[N:20]2)=[C:16]([C:33]([F:34])([F:36])[F:35])[CH:15]=1
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=O)cc12
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N(NS(C)(=O)=O)C3=O)cc12

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-carbaldehyde (from Example 36) following General Procedure E.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH2:24][OH:25])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31]>ClC(Cl)C>[Cl:26][CH2:27][CH2:28][NH:29][C:30]([O:25][CH2:24][C@@H:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:2][CH3:1])=[O:31]
Reactant: O=C=NCCCl
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](CO)OC
Solvent: CC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)NCCCl)OC
Temperature: 80 °C

Procedure:
A solution of 0.17 g of (S)-2-O-methyl-1-O-octadecylglycerine in 10 ml of dichloroethane is treated with 1 ml of 2-chloroethyl isocyanate and heated at 80° C. for 25 hours. The solution is evaporated and the residue is chromatographed on silica gel. After elution with dichloromethane-ether (9:1), there is obtained (R)-1-O-[(2-chloroethyl)carbamoyl]-2-O-methyl-3-O-octadecylglycerine in the form of an oil.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1[O:28][C:29]([CH3:32])=[CH:30][CH:31]=1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2[O:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH:23]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ccc(CO)o1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2cc(Cl)cnc2=O)o1
Temperature: 90 °C
Yield: 22.9 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.8 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (522 mg) and 2-hydroxymethyl-5-methylfuran (628 mg) in dry N,N-dimethylformamide (10 ml) under nitrogen. The resulting solution was then stirred and heated at 90° C. under nitrogen. After 1.5 h the reaction mixture was evaporated to a brown crystalline solid (1.030 g). The solid was subjected to column chromatography on silica (70-230 mesh) (100 g) developing with chloroform-ethanol, 29:1. The resulting pale yellow solid (327 mg) was crystallised twice from acetone to give white needles of the title furan (206 mg), m.p. 166°-167° C., λmax 226 nm (ε 15,660), 332 nm (ε 2,520), λinf 247 nm (ε 3,100).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH:2][CH2:3][CH3:4].C(=O)([O-])[OH:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl.O>[CH2:2]([CH:3]1[CH2:4][O:12]1)[CH2:1][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])O
Reactant: CCC=Cc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc(CCC2CO2)cc1
Reaction time: 4 h

Procedure:
To a suspension of but-3-butenylbenzene (3 ml) and sodium hydrogen carbonate (2.5 g) in a mixture of dichloromethane (200 ml) and water (60 ml) was added small portions of m-chloroperbenzoic acid (3.5 g) at room temperature, and the mixture was stirred at the same temperature for 4 hours. After separation, the organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=100:3) to give 2-phenethyloxirane (970 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][NH2:9])([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([NH:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: NCCc1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
3-Nitrophenethylamine (5.559 g, Production Example 25b) was dissolved in pyridine (33 ml), and acetyl chloride (2.5 ml) was added dropwise thereinto under ice-cooling. After stirring at room temperature for 0.5 hr, the mixture was ice-cooled again. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (6.323 g, 91%) as a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[NH:9][C:8]3[CH:10]=[C:11]([Cl:16])[C:12]([Cl:15])=[C:13]([Cl:14])[C:7]=3[N:6]=2)[CH2:3][CH2:2]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:45]1[O:57][C@@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:46]1[O:47][C:48](=[O:50])[CH3:49])(=O)C>ClCCCl>[CH:1]1([NH:4][C:5]2[N:9]([C@H:45]3[O:57][C@@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:46]3[O:47][C:48](=[O:50])[CH3:49])[C:8]3[CH:10]=[C:11]([Cl:16])[C:12]([Cl:15])=[C:13]([Cl:14])[C:7]=3[N:6]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Clc1cc2[nH]c(NC3CC3)nc2c(Cl)c1Cl
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OC[C@@H]1O[C@H](n2c(NC3CC3)nc3c(Cl)c(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 51.9 %

Procedure:
2-(Cyclopropylamino)-4,5,6-trichloro-1H-benzimidazole (1.32 g, 4.00 mmol), N,O-bis(trimethylsilyl)acetamide (1.0 mL, 0.82 g, 4.05 mmol), trimethylsilyl trifluoromethanesulfonate (0.5 mL, 0.58 g, 2.59 mmol), 1,2,3,5-tetra-O-acetyl-L-ribofuranose (1.70 g, 5.34 mmol) and 1,2-dichloroethane (12 mL) were used according to general procedure II. The product was purified by silica gel chromatography using 60:1 dichloromethane/methanol to afford 1.11 g (52%) of a yellow foam. MS (CI): m/z 534 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:22][C:2]([CH3:1])([CH3:21])[CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:24]2[CH:25]=[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=2)[NH:29][CH:28]=[C:27]3[CH:36]2[CH2:37][CH2:38][N:39]([S:42]([CH2:45][CH3:46])(=[O:43])=[O:44])[CH2:40][CH2:41]2)[CH:9]=[N:8][CH:7]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(C)(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC(C)(C)C)c4)cc23)CC1
Yield: 34 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), (2,2-dimethylpropyl)amine (0.015 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.7 mg of the title compound (34%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.CN([CH:36]=[O:37])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:36]([OH:37])[N:10]([C:11]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:8]2=[O:9]
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1OC
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(OC)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 78.7 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-4-methoxy-N-(1-methyl-1-phenylethyl)benzamide (7.50 g, 22.8 mmol) was dissolved in THF (200-mL), and the solution was treated with TMEDA (11.0 mL, 72.9 mmol), sec-butyl lithium-hexane solution (0.95 mol/L, 77.0 mL, 73.2 mmol) and DMF (3.88 mL, 50.1 mmol), followed by purification by slurry using isopropylether and hexane to obtain 4-methoxymethoxy-5-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (6.41 g, yield 79%).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:13]=1)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:9]([O:8][CH2:7][C:6]([OH:21])=[O:5])[S:10][CH:11]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)COc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Reaction time: 2 h

Procedure:
The mixture from step (b) containing crude [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid tert-butyl ester in 5 ml of 90% aqueous TFA was allowed to stand at room temperature for 2 h. After evaporation, the crude product (815 mg) was used in the subsequent step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:15][CH:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: OB(O)c1ccc(Br)cc1F
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: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
4-Bromo-2-fluorobenzeneboronic acid (0.69 g, 3.10 mmol) was added to a solution of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (1.0 g, 2.70 mmol) in DME (30 mL), followed by addition of 2M Na2CO3 (8 mL) and Pd(PPh3)4 (0.16 g, 0.13 mmol). The reaction mixture was degassed with N2 and heated at 80° C. for 4 h, then cooled to ambient temperature. Water was added and the mixture was extracted with EtOAc (70 mL×2). The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by chromatography on a silica gel column eluted with 1:5 EtOAc/hexanes to give 0.785 g (63%) of 1,1-dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.6 Hz), 7.90-7.85 (m, 1H), 7.75-7.65 (m, 1H), 7.40-7.30 (m, 2H), 7.30-7.20 (m, 1H), 4.18 (bs, 2H), 3.89 (d, 2H, J=6.3 Hz), 2.85-2.70 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 2H); LRMS m/z 465/467 (M+H).