Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27](C)=[CH2:28])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.I([O-])(=O)(=O)=[O:31].[Na+].O.[BH4-].[Na+]>C1COCC1.O.[Os]=O>[OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][CH:27]([OH:31])[CH3:28])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: C=C(C)Cc1ccccc1-c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)Cc1ccccc1-c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
The 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-[2-(2-methylallyl)phenyl]-2H-isoquinolin-1-one (25 mg, 0.064 mmol) obtained in Example 2-40 was dissolved in THF-water (3 ml-1 ml). Thereafter, an osmium oxide aqueous solution (0.1 mmol/ml, 0.032 ml, 0.0032 mmol) and sodium periodate (55 mg, 0.26 mmol) were added to the solution, and the obtained mixture was then stirred at a room temperature for 15 hours. Thereafter, water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate, and was then concentrated under reduced pressure. The thus obtained ketone body (24 mg) that was a roughly purified product was dissolved in methanol (2 ml) without being further purified. Thereafter, sodium borohydride (7.3 mg, 0.19 mmol) was added to the obtained solution under cooling on ice. The obtained mixture was stirred at a room temperature for 2 hours. Thereafter, the reaction solution was concentrated, and was then purified by preparative TLC (methylene chloride:methanol=10:1), so as to obtain 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-[2-(2-hydroxypropyl)phenyl]-2H-isoquinolin-1-one (15.3 mg, 61%, two-stage) in the form of white powders.
Reaction SMILES: [CH2:1]=O.[C:3]([NH2:7])([CH3:6])([CH3:5])[CH3:4].[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[OH:16]>O1CCOCC1>[OH:16][C:10]1[C:9]([Br:8])=[CH:14][C:13]([Br:15])=[CH:12][C:11]=1[CH2:1][NH:7][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C=O
Reactant: Oc1ccc(Br)cc1Br
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: CC(C)(C)NCc1cc(Br)cc(Br)c1O
Temperature: 15 °C

Procedure:
A mixture of 95 ml of 35% formaldehyde solution and 100 ml of dioxane is dropped into a solution of 80 g of tertiary butylamine in 350 ml of dioxane, cooled to 15° C, with stirring. The mixture is allowed to stand over night, then heated to 80° C. In the course of 4 hours a solution of 252 g of 2,4-dibromophenol in 250 ml of dioxane is dropped thereto, precipitating thereby the main charge of the reaction product. 1 hour after completion of this addition it is cooled, the precipitate is sucked off, washed with ethanol on the filter and dried. By concentrating the dioxane-mother liquor and the alcoholic washing liquid further material is obtained. Remaining reaction product precipitates from the dioxane concentrate in form of the hydrochloride by heating with alcoholic HCl. The hydrochloride is converted in H2O/CHCl3 in the free base with HaHCO3. Total yield = 268 g (79,5% of the theory). Recrystallization from acetic ester yields the N-(2-hydroxy-3,5-dibromobenzyl)-tert.butylamine in form of colorless felted needles, melting at 173° - 175° C.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C[O-].[Na+].O>CN1C(=O)N(C)CCC1.CC(O)=O>[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][CH2:21][N:7]2[C:8](=[O:9])[C:2]([CH3:1])=[CH:3][N:4]([C@@H:10]3[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]3)[C:5]2=[O:6])[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 70 °C

Procedure:
A solution of 280 mg AZT, 310 mg N-(3-bromopropyl)-phthalimide (BPP) and 300 ul of sodium methoxide solution (4.4M NaOMe in MeOH) in 1 ml DMPU was heated at 70° C. for one hour, then 145 mg BPP and 300 ul NaOMe solution was added and the mixture heated for another hour at 70° C. Another 175 mg BPP was added and heating was continued for a total of 4hours at 70° C. The reaction mixture was diluted with 10 volumes deionized water, acidified with 200 ul HOAc and extracted into EtOAc. The organic phase was washed with 5% NaHCO3, deionized water, 0.1M HOAc and saturated NaCl, then concentrated and chromatographed by preparative TLC on silica gel-F 2000 um using the solvent system CHCl3 /MeOH/HOAc(96.7+3.3+0.33). The product (Rf =0.35) was eluted with MeOH. It was immunologically active in an AZT assay by FPIA.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:6][NH:7][C:8]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9].[CH3:27]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]1[CH:18]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:20]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([CH3:17])[N:11]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1ncc(Br)c(C(=O)NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: ClCCl
Product: Cc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 2.28 g (5 mmol) 5-bromo-2-methyl-pyrimidine-4-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide in 20 ml N,N-dimethylformamide 0.26 g (5.5 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.4 ml (6.5 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 80 ml H2O, 80 ml brine and 80 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 80 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 19:1) to give 1.98 g (87%) 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a waxy solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([NH2:13])[CH2:10][C:11]#[CH:12].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[CH2:9]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C:11]#[CH:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCNC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
Add triethylamine (3 mL) to a suspension of but-3-ynylamine hydrochloride (200 mg, 2.1 mmol) in DCM (10 mL) and stir for 10 min at room temperature under nitrogen. Add then neat pivaloyl chloride (284.9 μL, 2.31 mmol) and stir at room temperature overnight under nitrogen. Concentrate in vacuo, take up the residue in methanol and filter through a SCX-2 cartridge eluting with methanol to obtain the title compound (265 mg, 65%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:15])=[C:7]([CH:11]=[CH:12][C:13]=2[OH:14])[C:8]([NH2:10])=[O:9])[CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:36]=[CH:35][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:37][CH2:38][CH3:39]>C(OCC)(=O)C.CCCCCC>[NH2:10][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:36]=[CH:35][C:24]3[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[O:28][C:23]=3[C:22]=2[CH2:37][CH2:38][CH3:39])=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[OH:15])=[O:9]
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OC)CC2
Reactant: NC(=O)c1ccc(O)c(CC2CC2)c1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2

Procedure:
The compound of Example 66 and the compound of Example 3 are coupled under the conditions outlined in Example 60. Chromatography of the crude phenolic ester on silica gel using ethyl acetate/hexane (3:7) as eluant affords the product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH:19]=C)[CH:16]=[C:15]([F:21])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:15]([F:21])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1)[CH:19]=[O:31]
Reactant: C=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 152.4 %

Procedure:
To the solution of 5-(2,6-difluoro-4-vinylphenoxy)-2-(trifluoromethyl)pyrimidine (1.67 g, 5.53 mmol) in dry THF (25 mL), was added 9-BBN (20 ml, 10.00 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (7 mL, 21.0 mmol), and 30% H2O2 (7 mL, 5.53 mmol). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (2.7 g, 8.43 mmol, 153% yield) as a white oil. LCMS: rt=2.97 min, [M+H+]=321
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>>[Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[N:22]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[C:37]([F:38])([F:39])[F:40])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Product: CC(C)(C)[Si](OCc1cccn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c1=O)(c1ccccc1)c1ccccc1

Procedure:
Analogously to Example 4A, 1.50 g (4.13 mmol) of the compound from Example 3A are reacted with 949 mg (4.54 mmol) of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene. The product is purified by chromatography on silica gel (mobile phase pentane/ethyl acetate=5:1), giving 1.00 g (44% of theory) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:10]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:30]=[N+:31]=[N-:32].[Na+].Cl.C(N(CC)CC)C>CN1CCCC1=O>[C:1]1([C:7]2[N:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[NH:32][N:31]=[N:30][N:20]=3)[CH:10]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCCCCOc1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: c1ccc(-c2cc(-c3ccc4c(c3)OCO4)cc(OCCCCCc3nnn[nH]3)n2)cc1

Procedure:
By using a similar procedure to that described in example 9 but with 2.4 g 6-{[6-phenyl-4-(3,4-methylenedioxyphenyl)-2-pyridyl]oxy}hexanonitrile, 1.65 g of sodium azide, 1.3 g of triethylamine hydrochloride (in place of ammonium chloride) and 90 cc of N-methylpyrrolidone (in place of dimethylformamide) as the starting material (70 hours; 150° C.), and after purification by flash chromatography on silica gel (30-60mm; eluent: ethyl acetate) and recristallization from 18 cc of acetonitrile gives 5-{5-{[6-phenyl-4-(3,4-methylenedioxyphenyl)-2-pyridyl]oxy}pentyl }-1H-tetrazole (m.p.=150° C.)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@H:14]([OH:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.CN1C=CN=C1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:17][C@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of (3aR,4R,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ol (3.2 g, 11.75 mmol) from Step 3 in dichloromethane (15 mL) was added triethylamine (4.10 mL, 29.4 mmol) followed by 1-methylimidazole (0.281 mL, 3.53 mmol). The solution was cooled to 0° C. and 4-bromobenzene-1-sulfonyl chloride (4.50 g, 17.63 mmol) was added. The solution was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (12 mL) and washed with aqueous hydrogen chloride (0.1 N, 10 mL×2) and water (10 mL). The organic phase was dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography using 0-60% dichloromethane/hexane as eluent to give (3aR,4R,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-yl 4-bromobenzenesulfonate: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.99-7.90 (m, 2H), 7.77-7.67 (m, 2H), 7.51 (t, J=7.9, 1H), 6.99 (d, J=7.3, 1H), 6.45 (d, J=8.6, 1H), 5.17 (q, J=6.1, 1H), 3.69 (dd, J=11.4, 4.6, 1H), 3.57-3.47 (m, 1H), 3.37 (dd, J=11.4, 8.9, 1H), 3.23 (dd, J=10.7, 4.5, 1H), 2.90-2.78 (m, 1H), 2.67-2.54 (m, 1H), 2.02-1.88 (m, 1H), 1.80 (dq, J=8.2, 6.0, 1H), 1.70 (dtd, J=13.5, 8.6, 7.0, 1H), 1.51-1.37 (m, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: C(O)(=O)C.Br[C:6]1[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[O:25][CH3:26])=[NH:14])=[N:8][CH:9]=[CH:10][CH:11]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C>>[CH3:26][O:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[CH2:16][NH:15][C:13]([NH:12][C:7]1[C:6]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)=[NH:14]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1ncccc1Br
Reactant: OB(O)Oc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(OC)c1CNC(=N)Nc1ncccc1-c1ccc(F)cc1
Temperature: 110 °C
Yield: 31.3 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.200 g (0.470 mmol) N-(3-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine acetate, 0.099 g (0.705 mmol) (4-fluorophenyl)boric acid, 0.149 g (1.411 mmol) sodium carbonate, and 0.038 g (0.033 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 24 hr at 110° C. under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 65 mg (0.147 mmol, 31%) pure N-(2,6-dimethoxybenzyl)-N′-[3-(4-fluorophenyl)pyridin-2-yl]guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C@@:13]34[C@@H:17]5[CH2:18][C@H:19]6[C:28](CN5CC3)=CCO[C@H:21]3CC(=O)N([C@H:12]4[C@@H:20]63)[C:6]2=[CH:7][C:8]=1OC.C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C=CN=C4C=CC=CC=34)[N:34](CC2)C1.COC1C=CC2[N:63]=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1>>[CH3:17][CH:13]([NH2:34])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1.[NH2:63][CH2:21][CH:20]1[CH2:12][CH:13]2[CH2:17][CH:18]([C:5]2([CH3:4])[CH3:6])[CH:19]1[CH3:28]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Reactant: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Product: CC(N)c1ccccc1
Product: CC1C(CN)CC2CC1C2(C)C

Procedure:
A dl-compound among the compound (I) is treated in a conventional manner with a resolution agent such as brucine, cinchonine, quinine and quaternary salts thereof or the like optical active alkaloid, α-phenethylamine (d- and l-compounds), 3-aminomethylpinane (d- and l-compounds) or the like to obtain respective diastereomer salts and then the salts are separated in a conventional manner to obtain the optical active compounds (I). The method will be explained in more detail, as to the case of that cinchonine-methohydoxide or quinine-methohydroxide is employed as the optical resolution agent. dl-compound among the compounds (I) is dissolved in methanol, ethanol, acetone or the like organic solvent, quinine-methohydroxide solution in equivalent amount is added thereto, and then the mixture is concentrated in vacuo to obtain N-methylquinium salt of the corresponding compound, as an amorphous substance. The amorphous substance is dissolved in methanol ethanol, isopropanol, acetone or the like organic solvent and the solution is left to stand to form crystals. The crystals are obtained through a filtration of the solution and subjected to recrystallization to obtain N-methylquinium salt of the d-compound. The salt was treated with hydrochloric acid and recrystallized from an organic solvent in a conventional manner to obtain the desired d-compound (I). While the mother liquor, from which the d-compound was filtered off, is concentrated to obtain N-methylquinium salts of the compounds mainly containing the l-compound and thus the salts are treated with hydrochloric acid to obtain crystals of the compounds containing mainly the l-compound. The crystals are dissolved in methanol, ethanol, acetone or the like organic solvent, cinchonine-methohydrooxide solution in equivalent amount is added thereto, and the mixture is concentrated in vacuo to obtain N-methylcinchonium salts of the compounds containing mainly the l-compound. The salts are dissolved in methanol, ethanol, isopropanol, acetone or the like organic solvent and left to stand to obtain crystals which are recrystallized to obtain N-methylcinchonium salt of the l-compound. The salt is treated with hydrocholoric acid and recrystallized from an organic solvent to obtain the desired l-compound (I).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH:24]([CH3:26])[CH3:25])[CH3:2]
Reactant: CC(C)I
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC(C)N1c2ccccc2Sc2ccc(C#N)cc21)C(C)C
Temperature: 150 °C

Procedure:
A suspension of 10-[(2RS)-1-ethylamino-2-propyl]-2-phenothiazinecarbonitrile (4.5 g), 2-iodopropane (7.2 cc) and sodium carbonate (4.6 g) in dry dimethylformamide (60 cc) is heated for 34 hours at a temperature in the region of 150° C. After cooling, the mixture is concentrated to dryness under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. The residue is taken up with ethyl acetate (200 cc), washed with distilled water (3×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (75:25 by volume) (500 cc) of ethyl acetate and cyclohexane and collecting 60-cc fractions. The combined fractions 3 to 7 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-{(2RS)-1-[N-Ethyl-N-(1-methylethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (2.37 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:25]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:24]=[CH:23][CH:28]=[CH:27][CH:26]=1.[CH3:23][C:22]1[CH2:21][C:20](=[O:36])[NH:19][C:9]2[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=Nc2ccc(OC(F)(F)F)cc2NC(=O)C1
Product: c1ccc(-c2ccccn2)cc1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethoxy-phenyl}-carbamic acid tert-butyl ester (Example M186) (255 mg, 0.495 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (137 mg, 70%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:8]1>>[CH3:18][O:17][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[O:16][CH2:2][CH2:3][O:4][CH3:5])[N:7]([CH3:6])[CH:8]=[C:9]2[C:19]1[N:27]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1.[CH3:18][O:17][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[O:16][CH2:2][CH2:3][O:4][CH3:5])[N:7]([CH3:6])[CH:8]=[C:9]2[C:19]1[NH:27][C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1
Reactant: COCCBr
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Product: COCCOc1cc2c(cc1OC)c(-c1cc3cccnc3[nH]1)cn2C
Product: COCCOc1cc2c(cc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 137.6 %

Procedure:
2-[5-Methoxy-6-(2-methoxyethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 147d, but using 0.195 g of 1-bromo-2-methoxyethane instead of 1-chloro-2-bromoethane used in example 147d, and 0.224 g of 2-[1-methyl-5-methoxy-6-hydroxyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. After purification by flash-pack chromatography (silica, 80/20 by volume ethyl acetate/cyclohexane as eluents, argon), 0.121 g of 2-[5-methoxy-6-(2-methoxyethoxy)-1-methyl-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows: