Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[O:17][C:13]=3[CH:12]=2)[CH:2]=1.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:25]([NH2:32])[C@@H:24]1[OH:33].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:32][C@@H:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:23][C@H:24]4[OH:33])[O:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2o1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 120 °C
Yield: 25.5 %

Procedure:
A stirred mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (108 mg, 0.346 mmol) from Step 5 of Example 56, (1R,2R)-(−)-trans-1-amino-2-indanol (104 mg, 0.698 mmol), and DIEA (90 mg, 0.698 mmol) in anhydrous DMA (1.5 mL) was sealed and heated in a Biotage microwave synthesizer at 120° C. for 30 min. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (35 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.36-8.45 (m, 2H), 8.09 (dd, J=1.3, 8.1 Hz, 1H), 7.47 (s, 1H), 7.29 (dd, J=4.7, 8.1 Hz, 1H), 7.12-7.25 (m, 6H), 5.52 (s, 2H), 5.47 (d, J=5.1 Hz, 1H), 5.02 (m, 1H), 4.34 (m, 1H), 3.15 (dd, J=7.2, 15.6 Hz, 1H), 2.73 (dd, J=7.6, 15.4 Hz, 1H). LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: Cl.CN.[CH:4]([N:7](C(C)C)CC)(C)C.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:25][O:24]2)[CH:20]=[CH:21][CH:22]=1.C(OCC)(=O)C>CO>[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]([OH:24])[CH2:25][NH:7][CH3:4])[CH:20]=[CH:21][CH:22]=1
Reactant: COCOc1cccc(C2CO2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCC(O)c1cccc(OCOC)c1
Temperature: 25 °C
Yield: 20 %

Procedure:
Methylamine hydrochloride (275 mg, 4.08 mmol) and diisopropylethylamine (601 mg, 4.66 mmol) were sequentially added to a solution of 2-(3-methoxymethoxy-phenyl)-oxirane (210 mg, 1.16 mmol) in anhydrous methanol (5 mL). The resulting mixture was maintained at ambient temperature for about 12 hours. Following standard extractive workup with ethyl acetate, the crude product was purified by flash column chromatography on silica gel (1×15 cm, dichloromethane/methanol/NH4OH=90/8/1 elution) to give the title product (49 mg, 20%). 1H NMR (300 MHz, CDCl3) δ 7.26-7.23 (m, 1H), 7.06 (s, 1H), 7.00 (d, 1H, J=7.5 Hz), 6.95 (d, 1H, J=6.9 Hz), 5.18 (s, 2H), 4.71 (d, 1H, J=5.7 Hz), 3.48 (s, 3H), 2.84-2.62 (m, 2H), 2.46 (s, 3H); LC-MS: m/z=212 (MH)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C(Cl)Cl>[C:22]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)c1cccnc1
Yield: 74.9 %

Procedure:
To a solution of 10.0 g (41.5 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 27.7 ml (200 mmol) of triethylamine in methylene chloride (100 ml), 8.86 g (49.8 mmol) of nicotinoyl chloride hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder was washed with ether and dried to obtain the desired compound (8.50 g, yield: 75.8%, pale yellow powder).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:23]1[CH:22]=[CH:21][C:20]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)=[CH:25][CH:24]=1)[CH:8]=[N:7]2
Reactant: Clc1cnc2cccc(Br)c2n1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CN1CCN(c2ccc(-c3cnc4cccc(Br)c4n3)cc2)CC1
Temperature: 105 °C

Procedure:
A microwave tube is charged with 8-Bromo-2-chloro-quinoxaline (Step 1.4, 2.5 g, 10.267 mmol), 1-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperazine (2.88 g, 9.24 mmol), K3PO4 (6.67 g, 30.8 mmol) and PdCl2(PPh3)2 (221 mg, 0.308 mmol). After several cycles of vacuum/purge with argon, a mixture of 21 ml of DMA and 560 μl deionized water is added. The reaction mixture is then heated to 105° C. for 4 h. After cooling, the suspension is poured onto de-ionized water and diluted with EtOAc. The phases are separated and the aqueous phase re-extracted twice with EtOAc. The combined organic phases are washed with saturated brine and dried over Na2SO4. After filtration, the mixture is concentrated in vacuo. The residue is purified by chromatography (silicagel, CH2Cl2:EtOH:NH3 95:4.5:0.5 from 1:0=>0:1) to afford the title compound as a yellow orange solid, Rt=0.930 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 383 (M+1, 79Br)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][CH3:12])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22]([NH:21][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[S:23])[N:7]([CH2:11][CH3:12])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCn1nc(C(C)(C)C)cc1N
Solvent: CC(C)=O
Product: CCn1nc(C(C)(C)C)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of compound 23 (5.0 g, 29.9 mmol) in 40 mL of acetone at 0° C. was added dropwise benzoyl isothiocynate (4.88 g, 29.9 mmol). The reaction mixture was gradually warmed up and stirred in an oil bath of 60° C. until TLC indicated there was no starting material remained. Concentration of the reaction mixture on rotavapor gave a yellow solid, which was further triturated with ethyl ether to yield the desired product 24.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[N:9]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]=23)=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:16][C:12]1[CH:11]=[C:10]2[C:15]([C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:8]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:9]32)=[CH:14][CH:13]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2c(-c3ccncc3)c3n(c2c1)CCCCC3
Product: CCOC(=O)C(C)(C)Oc1ccc2c(-c3ccncc3)c3n(c2c1)CCCCC3

Procedure:
The above compound was prepared from 7,8,9,10-tetrahydro-11-(4-pyridyl)-6H-azepino[1,2-a]indole-3-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>O1CCCC1>[SH:14][C:13]1[NH:10][C:5]2[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][C:6]=2[N:9]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Yield: 64.5 %

Procedure:
4-trifluoromethyl-benzene-1,2-diamine (0.5 g, 2.84 mmol) and 1,1′-thiocarbonyldiimidazole (0.84 g, 4.73 mmol) in 5 ml of tetrahydrofuran are stirred at room temperature for 48 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 10 ml ethyl acetate and washed with water (2×3 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is then purified on a silica gel column (32 g) eluted with dichloromethane. The fractions containing the expected product are concentrated under reduced pressure to yield 400 mg of 2-mercapto-6-trifluoromethyl-1H-benzimidazole. Yield=65%. Analytical LC/MS (method B): retention time=3.14 min., m/z=218.98 (positive ion mode).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.[NH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[N:15]=1>C(#N)C>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[N:19]=[C:14]([NH:13][C:11]([NH:10][S:7]([C:3]2[C:2]([CH3:1])=[CH:6][S:5][CH:4]=2)(=[O:8])=[O:9])=[O:12])[N:15]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: Cc1cscc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cscc2C)n1
Yield: 43.3 %

Procedure:
A solution of 2 g of 4-methyl-3-thiophenesulfonyl isocyanate in 5 ml of dry acetonitrile was added to 1.5 g of 2-amino-4,6-dimethoxypyrimidine in 20 ml of acetonitrile with stirring. The mixture was stirred for 16 hours at ambient temperature and filtered to yield 1.5 g of the desired product, m.p. 175°-178°.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][C:25]=2[CH:24]=1>CS(C)=O>[C:25]12[CH2:26][CH2:27][C:28]=1[CH:29]=[CH:30][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][C:5]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[C:25]4[C:28](=[CH:29][CH:30]=3)[CH2:27][CH2:26]4)[C:4]3[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=3[C:11]3[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)=[CH:24]2
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: BrCCCCc1ccc2c(c1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Brc1ccc2c(c1)C(CCCCc1ccc3c(c1)CC3)(CCCCc1ccc3c(c1)CC3)c1cc(Br)ccc1-2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To an oven-dried three-neck round-bottom flask under nitrogen, were added 25.97 g of 2,7-dibromofluorene, 32.06 g sodium hydroxide, 1.33 g KI, and 300 mL anhydrous DMSO. The 46 g 3-(4-bromobutyl)bicyclo[4.2.0]octa-1(6),2,4-triene 300 mL anhydrous DMSO was added via cannula. The reaction was heated to 80° C. After 4 hours, the reaction was quenched by the addition of DI water (10 mL). The excess salt was removed by filtration. 500 mL Ethyl acetate was added, and extracted with DI water (3×300 mL) and brine (3×300 mL). The combined organic layer was dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the solvent was removed by rotary evaporation. The product (43 g) was purified by flash chromatography using hexane. The structure was confirmed by NMR.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:18]1([CH:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:14]([O:16][CH3:17])=[O:15])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: COC(=O)C(=C1CCCN1Cc1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(c1ccccc1)C1CCCN1
Reaction time: 72 h

Procedure:
To a solution of methyl 2-(1-benzylpyrrolidin-2-ylidene)(phenyl)acetate (0.505 g, 1.64 mmol) in 5 mL of methanol was added palladium(II) hydroxide (231 mg, 1.64 mmol), and the reaction was stirred under a balloon of hydrogen gas. After 3 days, the mixture was filtered through celite, the pad was rinsed with CH2Cl2/MeOH, and the filtrate was concentrated in vacuo to provide methyl phenyl(pyrrolidin-2-yl)acetate as a mixture of two diastereomers. ESI+MS: 220.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[C@H:15]([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1Cc2ccccc2CN1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: C[C@@H]1Cc2ccccc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20].C(Cl)(=O)C([Cl:26])=O>C(Cl)(Cl)Cl>[C:1]([Cl:26])(=[O:22])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Cl

Procedure:
To a solution of 2.40 g of 5,8,11,14,17-eicosapentaenic acid in 15 ml of dry chloroform was added 1.04 ml of oxalyl chloride under argon at room temperature. The mixture was reacted for 2 hours. From the reaction mixture were removed the chloroform and the ramaining oxalyl chloride by distillation under reduced pressure to give 5,8,11,14,17-eicosapentaenoyl chloride, which was then dissolved in 15 ml of dry chloroform.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:63]([CH2:65][CH2:66][O:67][CH2:68]Cl)#[N:64].C(=O)(O)[O-].[Na+]>ClCCCl>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[O:21][CH2:68][O:67][CH2:66][CH2:65][C:63]#[N:64])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCOCCl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
N2-Phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (720 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxy methyl)guanosine (384 mg, yield 48%).
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[OH:5][C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[C:8]([SH:13])[N:7]=1.[OH-].[Na+]>O>[CH2:1]([S:13][C:8]1[NH:9][C:10](=[O:12])[CH2:11][C:6](=[O:5])[N:7]=1)[CH2:2][CH3:3]
Reactant: Oc1cc(O)nc(S)n1
Reactant: CCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCSC1=NC(=O)CC(=O)N1

Procedure:
Propyl iodide (136 ml) was added to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine (200 g) in water (800 ml), containing sodium hydroxide (55.6 g). The reaction mixture was stirred for 2 weeks then concentrated to half volume, 2N hydrochloric acid added and the product isolated by filtration (167 g).
Reaction SMILES: CON(C)[C:4](=[O:22])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][O:9][CH2:8]1.[CH:24]([Mg]Br)=[CH2:25].Cl>O1CCCC1>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][O:9][CH2:8]2)[C:4](=[O:22])[CH:24]=[CH2:25])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of N-methoxy-N-methyl-2-[4-(methylsulfonyl)phenyl]-3-(tetrahydrofuran-3-yl)propanamide (2.96 g) in tetrahydrofuran (34.6 mL) was cooled to 0° C., vinylmagnesium bromide (1.0M tetrahydrofuran solution, 34.6 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 4 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.06 g, yield 77%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([C:13]1[C:18]2[N:19]=[C:20]([C:22](OCC)=[O:23])[O:21][C:17]=2[C:16]([F:27])=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]=1[CH3:34])#[N:12].Cl>ClCCl>[F:27][C:16]1[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:14]([CH3:34])[C:13]([C:11]#[N:12])=[C:18]2[C:17]=1[O:21][C:20]([C:22]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:23])=[N:19]2
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N3CCCCC3)nc2c1C#N
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 898 μl, 925 μmol) was dropwise added to a dichloromethane (1 ml) solution of piperidine (92 μl, 925 μmol) at room temperature, and stirred for 15 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (150 mg, 463 μl) was dropwise added and stirred for 63 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature. The reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with n-hexane/ethyl acetate (4:1, v/v) gave the entitled compound (62 mg, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.Cl.[NH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[N:31](S(C3C=CC=CC=3)(=O)=O)[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([Cl:41])[C:25]=3[CH:24]=2)[C:18]1=[O:42]>>[Cl:41][C:26]1[C:25]2[CH:24]=[C:23]([CH2:22][N:19]3[CH2:20][CH2:21][C@H:17]([NH:16][S:10]([C:8]4[S:7][C:6]5[CH:14]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[CH:9]=4)(=[O:12])=[O:11])[C:18]3=[O:42])[NH:31][C:30]=2[CH:29]=[CH:28][N:27]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: NC1CCN(Cc2cc3c(Cl)nccc3n2S(=O)(=O)c2ccccc2)C1=O
Agent: Cl
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2[nH]1

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and 3-amino-1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-one hydrochloride as the starting material. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2 to give the product as a white solid.
Reaction SMILES: [CH2:1]([OH:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>CCCCCC>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:12][CH2:1][C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1)=[O:22]
Reactant: COc1ccc(CO)cc1OC
Reactant: CC(C)CCCCCCC(=O)O
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(COC(=O)CCCCCCC(C)C)cc1OC
Temperature: 50 °C
Yield: 89.1 %

Procedure:
Veratryl alcohol (734 mg, 4.53 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give veratryl 8-methylnonanoate (1.25 g, yield 89.1%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:38])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:6]([CH3:38])=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][C:8]=3[CH3:10])=[C:28]3[C:23]([CH:24]=[C:25]([F:30])[C:26]([F:29])=[CH:27]3)=[N:22]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white solid. MS: m/e=539.3 [M+H+].