Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].N>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(F)cc1N
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1′-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52%); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19. b) A solution of 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.25 g, 8.22 mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) was heated for 18 hours at 100° C. The reaction mixture was cooled to RT and excess of POCl3 was evaporated in vacuo. The residue was neutralized with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (3×20 ml). The organic phase was washed with brine and then dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 82%); 1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m/z: (ES+) MH+, 171.34. c) 2-Chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 6.72 mmol) was charged to high pressure autoclave PV10832 (Parr 160 ml) with methylamine 40% EtOH solution (50 ml, 6.72 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The reaction mixture was evaporated and the residue dissolved in MeOH and added to an SCX column. The desired product was eluted from the column using 7M NH3/MeOH. Fractions containing product were evaporated and the residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.707 g, 64%); 1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38-6.44 (2H, m), 6.67 (1H, dd), 6.79-6.84 (1H, m); m/z: (ES+) MH+, 166.31.
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC=CC=1)[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6]>C(O)C.Cl.O>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6]
Reactant: C#CC(C)(C)C(=CCl)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C#CC(C)(C)C(=O)CCl
Yield: 82.9 %

Procedure:
275 g (1.25 moles) of 1-chloro-3,3-dimethyl-2-phenoxy-pent-1-en-4-ine in 1.25 liters of ethanol and 620 ml of concentrated hydrochloric acid are heated for 5 hours under reflux. The mixture is diluted with water and repeatedly extracted with n-hexane. After drying the extracts and stripping off the solvent, 176 g of crude product remain. Distillation gives 149.9 g (that is to say 83% of theory) of 1-chloro-3,3-dimethyl-pent-4-in-2-one of boiling point 67°-70° C./20 mm Hg.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]2[N:10]([CH3:26])[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[O:16])[C:13](=[O:14])[C:8]=2[S:7][C:6]=1[CH2:27][N:28]([CH2:30][C@@H:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:29])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[C:9]2[N:10]([CH3:26])[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[O:16])[C:13](=[O:14])[C:8]=2[S:7][C:6]=1[CH2:27][N:28]([CH2:30][C@@H:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:29]
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CN=[N+]=[N-])C[C@@H](O)c1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CN)C[C@@H](O)c1ccccn1
Yield: 78.6 %

Procedure:
A solution of 111 mg of 3-(azidomethyl)-N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 58 mg of triphenylphosphine in 2 mL of THF containing 5 drops of water is stirred overnight, then concentrated under reduced pressure with CHCl3/MeOH azeotrope. Flash chromatography on silica gel using 4-10% methanolic ammonia in CH2Cl2 provides 83.1 mg of the amine as a white solid. Recrystallization from acetonitrile furnishes white solid.
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=O)[O].[K+].[K+].P([O-])([O-])([O-])=[O:14].[Na+].[Na+].[Na+].[CH3:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[NH:29][CH2:28][CH2:27]2>CC(C)=O.C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([OH:14])[CH:25]=[C:26]2[C:30]=1[NH:29][CH:28]=[CH:27]2
Reactant: Cc1cccc2c1NCC2
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc2cc[nH]c12

Procedure:
Potassium nitrosodisulfonate (46.1 g, 172 mmol) was added to a 0.1 M aqueous solution of sodium phosphate at pH=7 (1 L) at room temperature. 7-Methylindoline (CAS #: 65673-86-1) (10.4 g, 78 mmol) was dissolved in 100 mL of acetone and added to the reaction in one portion at room temperature. After 30 minutes the reaction was diluted with ethyl acetate and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was absorbed onto silica and then purified by silica gel flash chromatography (0-50% ethyl acetate in heptanes) to provide the title compound. MS (ESI+) m/z 148.08 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])([O-])=O>C(O)C.O.NN.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cccc(C(=O)N2CCOCC2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
The compound ([13]-(132)-158) (8.63 g) prepared in Example 83 was dissolved in ethanol (400 ml), and the solution was heated to 50° C. To the suspention, a solution of 10% Pd/C (2.25 g) in ethanol and hydrazine monohydrate (4.4 ml) were added to the solution. The mixture was stirred for 30 minutes. After the reaction was completed, the catalyst was removed by filtration through celite. The solution was concentrated, and the residue was purified by silica gel column chromatography (Kieselgel 60=120 g, ethyl acetate) to obtain the above-captioned compound ([13]-(133)-158) (7.57 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([NH:10][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:19]=2[F:18])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@@H](NCc2ccc(F)cc2F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2 mmol, 1 equvi) was dissolved in dry DCM (20 ml) cooled to 0 centigrade was added 2,4-difluorobenzaldehyde (1.05 equiv), then NaBH(OAc)3 (2 equiv) and 5 drops of HOAc. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with DCM, washed with brine, and dried over anhydrous sodium sulfate. After removal of solvent, the crude product was used for the next step without further purification. MS m/e=371.4 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8]
Reactant: O=C(O)c1ncc[nH]1
Reactant: Cc1ccccc1N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.52 g, 4.64 mmol) in DMF (20 mL) was added o-toluidine (0.50 mL, 4.64 mmol), EDCHCl (1.35 g, 6.96 mmol) and HOBt (0.94 g, 6.96 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, it was poured into water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated to dryness. The crude product was purified by flash chromatography (2% to 3% MeOH/DCM) to yield 0.93 g (99%) of the title compound as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[F:10][C:5]1[CH:4]=[CH:3][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(Br)ccc1F
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: COc1cc(NCCc2ccc(C(F)(F)F)cn2)ccc1F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-fluoro-3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 315.1 [M+H]+) was prepared from 5-bromo-2-fluoro-anisole instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([N:13]=[C:14]=[O:15])([F:12])[F:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH:13][C:10]([F:12])([F:11])[F:9])=[O:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C=NC(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)NC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-chloroaniline (64 grams; 0.5 mol) in toluene (100 ml) is placed into a suitable pressure vessel, and is cooled in an acetone-dry ice bath. Trifluoromethyl isocyanate (56 grams; 0.5 mol) is added thereto and the pressure vessel is sealed. The reaction mixture is allowed to warm up to room temperature and stand for a period of about 24 hours. After this time the pressure vessel is opened and the contents are stripped of toluene under reduced pressure. The residue is recrystallized to yield N-(4-chlorophenyl)-N'-trifluoromethyl urea.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=C[C:27]=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=C[N:36]=1.N1C=CC=C(S(Cl)(=O)=O)C=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:27]=[N:36][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1cccnc1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 72 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (3 g, 9.1 mmol) and pyridine-3-sulfonyl chloride (1.93 g, 10.9 mmol) the title compound was obtained (3.1 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57-10.63 (br, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.74-8.78 (m, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.07-8.12 (m, 1H), 7.55-7.59 (m, 1H), 7.31-7.37 (m, 1H), 7.17-7.28 (m, 3H), 6.92 (d, J=5.3 Hz, 1H), 3.24-3.34 (m, 1H), 1.34 (d, J=6.8 Hz, 6H). MS (ES+): 472 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:22]([CH3:27])[CH:21]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1cc(F)ccc1N
Agent: [Na+]
Product: Cc1cc(F)ccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 34.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 278 mg of 4-fluoro-2-methylaniline in place of the 2,4-difluoroaniline. 92 mg of N-(4-fluoro-2-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:19]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNCCc1ccc(Oc2ccc(O)cc2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(CCc1ccc(Oc2ccc(O)cc2)cc1)Cc1ccccc1

Procedure:
According to scheme 1, ethyl chloroformate is added to a solution of tyramine (1), sodium hydroxide, and water to produce the [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester (2). The carbamate is treated with cesium carbonate and 4-fluorobenzonitrile in DMF to yield the corresponding biarylether 3. The nitrile functionality of the biaryl; ether 3 is converted to the N-acyl compound 4 by reaction with methyllithium followed by hydrolysis in aqueous sulfuric acid. The N-acyl compound 4 is converted to the acetate 5 by oxidation with m-chloroperbenzoic acid (MCPBA) in a suitable solvent. The acetate 5 is reduced with lithium aluminum hydride to afford the compound 4-[4-(2-methylamino-ethyl)-phenoxy]-phenol (6). The compound 6 is treated with benzaldehyde in the presence of sodium triacetoxyborohydride to produce the reductive amination product 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol 7 of formula I. Compounds of formula I wherein D is acetate and q is 0, may also be prepared according to scheme 2 below.
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.[NH2:27][C:28]1[CH:29]=[C:30]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[CH:31]=[CH:32][C:33]=1[CH3:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:34][C:33]1[C:28]([NH:27][C:14]([C:1]2[C:13]3[NH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:16])=[CH:29][C:30]([C:35]2[CH:40]=[N:39][CH:38]=[N:37][CH:36]=2)=[CH:31][CH:32]=1
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Reactant: Cc1ccc(-c2cncnc2)cc1N
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ccc(-c2cncnc2)cc1NC(=O)c1cccc2c1[nH]c1ccccc12
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (148 mg) and 1-hydroxybenzotriazole (114 mg) in dichloromethane (3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiinide hydrochloride (201 mg), and the m e was stirred for 15 minutes. After adding 5-(3-amino-4-methylphenyl)pyrimdine (136 mg) and 4dimethylaminopyridine (128 mg), the mixture was stirred for 24 hours. The mixture was evaporated under reduced pressure and the residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[6methyl-3-(pyrimidin-5-yl)-phenyl]-9H-carbazole-1-carboxamide (89 mg, 33.6%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([N:13]1[CH2:14][CH:15]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: O=C(O)C1Cc2ccccc2C1
Product: O=C(C1Cc2ccccc2C1)N1CC=C(c2c[nH]c3ccccc23)CC1

Procedure:
Prepared from compound 9a and 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:53]=[O:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:55]=[O:56].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:51])([F:52])[F:50])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:55][OH:56])[CH:53]=[O:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 25 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 71 (1.06 g, 1.39 mmol) was dissolved in 20 mL 1,4-dioxane, followed by addition of 2.3 mL 37% formaldehyde solution and 4 mL 2.9 M sodium hydroxide. The reaction mixture was stirred for 25 hours at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure before 20 mL water and 10 mL saturated sodium chloride solution were added. The reaction mixture was extracted with ethyl acetate (30 mL×3). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]-methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 7j (1.1 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[N:16]1([C:22]([CH:24]2[CH2:26][CH:25]2[CH3:27])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]([CH:24]4[CH2:26][CH:25]4[CH3:27])=[O:23])[CH2:17][CH2:18]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: CC1CC1C(=O)N1CCNCC1
Product: CC1CC1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-methylcyclopropyl)methanone, the title compound was obtained as a white solid (88% yield). 13C NMR (75 MHz, CDCl3) δ 177.1, 163.5, 159.5, 144.9, 131.3, 126.4, 115.1, 49.7, 45.2, 39.5, 37.5, 37.2, 35.3, 34.6, 29.9, 28.5, 26.5, 23.4, 8.6, 4.2. MS (ES+) m/z 360 (M+3).
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br-].[CH2:25]([Zn+])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1.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:26]1([CH2:25]/[CH:2]=[CH:3]/[C@@H:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C[C@@H](/C=C/I)c1ccc(OC2CCCCO2)cc1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C[C@@H](/C=C/Cc1ccccc1)c1ccc(OC2CCCCO2)cc1

Procedure:
To a stirred solution of 84.4 (321.9 mg, 0.748 mmol, 1 eq., MW 430.29) in THF (19 mL) at 23° C. was added Pd(PPh3)4 (86.8 mg, 0.075 mmol, 0.1 eq., MW 1155.58) followed by dropwise addition of benzyl zinc bromide solution (1.8 mL, 0.90 mmol, 1.2 eq., 0.5 M) After 3 hours, water (10 mL) was added to quench the reaction. The mixture was extracted with EtOAc (2×50 mL), dried with MgSO4, and filtered. The organic layer was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated providing the product as a colorless oil that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([NH2:12])=[N:6][NH:7]2.ClC1SC(S(N(S(C2SC(Cl)=CC=2)(=O)=O)C2C3C(=CC=CC=3OC)N(C(OC(C)(C)C)=O)N=2)(=O)=O)=CC=1.[C:50]1(=O)[O:55][C:53](=[O:54])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([N:12]1[C:53](=[O:54])[C:52]3[C:51](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:50]1=[O:55])=[N:6][NH:7]2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cccc2[nH]nc(N)c12
Agent: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: COc1cccc2[nH]nc(N3C(=O)c4ccccc4C3=O)c12
Temperature: 110 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
4-(Methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (500 mg, 3 mmol) and phthalic anhydride (680 mg, 4.6 mmol) (available from Aldrich) were dissolved in 1,4-dioxane (5 mL) at room temperature. The reaction mixture was stirred at 110° C. overnight, and then it was cooled and concentrated under reduced pressure. The residue was triturated and sonicated with 50 mL of ether. The solid was collected by filtration and dried in a vacuum oven to obtain a brown solid (711 mg, 81%). LCMS (System B) RT=2.82 min, ES+ve m/z 294 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1
Reactant: Clc1ncccn1
Reactant: OCC(O)CN1CCNCC1
Solvent: C1COCCO1
Product: OCC(O)CN1CCN(c2ncccn2)CC1

Procedure:
Grams 3.2 of 1-(2,3-dihydroxypropyl)piperazine and 1.14 g of 2-chloropyrimidine in 50 ml dioxane were refluxed for two and a half hour. The reaction mixture was then settled and the solution evaporated to dryness. The residue obtained was extracted with hot acetone and filtered to remove all impurities. After resting 1.1 g of 3-[4-(pyrimidin-2-yl)piperazin-1-yl]propane-1,2-diol were separated, which melted at 118°-120° C.