Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([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.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)#[N:22].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)([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: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 79.4 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.15 g, 0.56 mmol) was reacted with 4-cyanobenzaldehyde (0.07 g, 0.56 mmol) in the presence of glacial acetic acid (0.033 g, 0.56 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.042 g, 0.67 mmol) in methanol (5 ml) (Procedure D) to give compound 16c (0.17 g, 80%) as an oil.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=O)[N:27]=2)[CH2:20]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.[Cl-].[NH4+:34].C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]#[N:34])[N:27]=2)[CH2:20]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC1CN(c2nc(C#N)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (7.73 g, 16.6 mmol) (obtained as described in Reference Example 2(1)) in benzene (370 ml) was added a solution of 0.67M ammonium chloride-trimethylaluminium in benzene (75 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred in a water bath (50° C.) for 17 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (50 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-cyano-1,3-thiazol-2-yl)azetidine (6.98 g, yield 76%) as a pale brown solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:32])[CH2:28][CH2:29][CH2:30][CH3:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CCCCCO
Product: CCCCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and pentan-1-ol (87 μl; 0.773 mmol), example 45 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[Cl:1][C:2]1[C:21]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 76.1, 8 g, 17.43 mmol), pyrimidine-5-boronic acid (4.55 g, 34.9 mmol), PdCl2(dppf) (0.638 g, 0.871 mmol), Na2CO3 (26.1 mL of 2 M, 52.3 mmol), and DME (110 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 90° C. for 20 h. The RM was dissolved in EtOAc (200 mL), washed with water, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 750 g, EtOAc/n-hexane 1:1) and recrystallized from EtOAc/iPr2O to give the title product as a pink solid. UPLC-MS (Condition 2) tR=1.05 min, m/z=409.0/411.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.99 Hz, 2H) 8.54 (d, J=1.95 Hz, 1H) 9.01 (br.s., 1H) 9.08 (s, 2H) 9.30 (s, 1H) 10.67 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-:15])=[O:14])[N:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>N1C=CC=CC=1>[C:16]([O:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-:15])=[O:14])[N:4]=1)(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cccc2nc(CO)ccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(=O)OCc1ccc2c([N+](=O)[O-])cccc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution that consists of 390 mg (1.91 mmol) of 2-(hydroxymethyl)-5-nitroquinoline and 2.5 ml of acetic acid anhydride in 5.0 ml of pyridine is allowed to stir for 24 hours at room temperature. After repeated co-evaporation with toluene and subsequent chromatography on silica gel with hexane-ethyl acetate (0-100%), 410 mg (87% of theory) of the product is obtained.
Reaction SMILES: Cl.CN.[N:4](CCO)(CCO)[CH2:5]CO.[C:14]([CH2:17][N:18]1[C:22](=[O:23])[C:21](=[CH:24]OCC)[S:20][C:19]1=[S:28])([OH:16])=[O:15]>C(O)C>[CH3:5][NH2:4].[C:14]([CH2:17][N:18]1[C:22](=[O:23])[C:21](=[CH:24][NH:4][CH3:5])[S:20][C:19]1=[S:28])([OH:16])=[O:15]
Reactant: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Reactant: OCCN(CCO)CCO
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNC=C1SC(=S)N(CC(=O)O)C1=O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A mixture of 0.68 g (0.010 mole) of methylamine hydrochloride and 5 ml of ethanol, which was neutralized with 1.0 g (0.010 mole) of triethanolamine, was added to a mixture of 1.2 g (0.005 mole) of 3-carboxymethyl-5ethoxymethylidenerhodanine and 10 ml of ethanol. The reaction was conducted at a temperature of 50° to 60° C. for 1 hour. The reaction mixture was concentrated and the resulting residue was recrystallized from ethanol to give 1.0 g of 3-carboxymethyl-5-methylaminomethylidenerhodanine methylamine salt (yield: 79.2 %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[N:29][CH:28]=1>>[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[N:29][CH:28]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(CBr)nc1
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) by alkylation with methyl-6-(bromomethyl)-nicotinate [CAS Reg. No. 131803-48-0]. MS (m/e)=515.0 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C1COCC1.Cl.[NH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:31][N:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[NH:25][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:5]=2)=[CH:8][CH:9]=1)=[O:13]
Reactant: Cn1cccc1N
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cccc1NC(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride (295 mg) and THF (3 ml) were added to a mixture of 2-amino-1-methylpyrrole hydrochloride (202 mg), potassium carbonate (553 mg), THF (2 ml) and water (4 ml), followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with 1 N hydrochloric acid, saturated sodium bicarbonate aqueous solution and water in that order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1-3:2) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to give N-(1-methyl-2-pyrrolyl)-5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxamide (126 mg) as light yellow powder crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:23]>CC(N(C)C)=O.C(OCC)(=O)C.O>[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:25]=1)=[O:23]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: COc1ccc2nccc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3ccc(OC)cc23)c2ccccc12
Temperature: 140 °C
Reaction time: 20 h

Procedure:
1.73 g (12.5 mmol) of potassium carbonate and 0.968 g (5 mmol) of 4-chloro-6-methoxyquinoline are added to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole in 20 cm3 of dimethylacetamide under an argon atmosphere. After stirring at a temperature in the region of 140° C. for 20 hours, the reaction mixture is cooled and diluted with 200 cm3 of ethyl acetate and 200 cm3 of water. The organic phase is separated off by settling and washed with three times 200 cm3 of water and 200 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 and then 7/3 by volume)]. Concentrating these fractions to dryness under reduced pressure (2.7 kPa) results in 0.7 g of 3-methoxycarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 332 (M+•), m/e 301.
Reaction SMILES: [CH2:1]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Na+].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([S:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCNS(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCN(C(=O)c1ccccc1)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a stirring solution of N-octyl-3,4-dimethoxybenzenesulfonamide (0.213 g, 0.646 mmol) in 2.00 mL of DMF, NaH (0.028 g, 0.711 mmol; 60% in oil dispersion) was added. After 30 min, benzoyl chloride (0.085 g, 0.731 mmol) was added. After a further 1 hr, the reaction mixture was diluted with 4:1 EtOAc/hexanes and washed with water (2×). The organic layer was dried over MgSO4 and concentrated in vacuo to yield a yellow solid. Purification by flash chromatography (28% ethyl acetate/hexanes) gave 0.040 g (18%) of the title compound as a clear oil.
Reaction SMILES: ClC1C=CC(CCC(C2C=CC=CC=2F)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:22][CH:21]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1)c1ccccc1F
Agent: O=C(CCc1ccc(Cl)cc1)c1ccccc1F
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)cc1)c1ccccc1F

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(4-chlorophenyl)-1-(2-fluorophenyl)propan-1-one, (Z)-ethyl 5-(4-chlorophenyl)-3-(2-fluorophenyl)pent-2-enoate and (E)-ethyl 5-(4-chlorophenyl)-3-(2-fluorophenyl)pent-2-enoate were obtained as colourless oils.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][CH:33]([CH2:34][CH3:35])[CH2:36][CH3:37])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(CC)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(CC)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1 ethylpropyl)-3-pyridinecarboxamide (Intermediate 12, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1-ethylpropyl)-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][O:11][CH2:12][CH2:13]O)[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>N1C=CC=CC=1>[Cl:35][CH2:13][CH2:12][O:11][CH2:10][N:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]=[CH:2]1
Reactant: OCCOCn1cnc2cccnc21
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: ClCCOCn1cnc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a suspension of 0.63 g (3.26 mmol) 2-(3H-imidazo[4,5-b]pyridin-3-ylmethoxy)-ethanol and 1.71 g (6.52 mmol) triphenylphosphine in 10 ml pyridine kept under argon were added dropwise over 10 min. 0.32 ml (3.32 mmol) CCl4. The suspension was stirred at room temperature for 18 hours and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient DCM→DCM/MeOH 9/1) and triturated with diethylether to afford 0.7 g of a brownish solid. MS(ISP): 212.1 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[N+:15]([O-:17])=[O:16].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[NH2:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([O:7][C:6]2[C:5]([F:19])=[CH:4][C:3]([F:20])=[C:2]([NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=3)[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])c(F)cc1F
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: Nc1nccc(Oc2cc(NC(=O)c3cccc(OC(F)(F)F)c3)c(F)cc2F)c1[N+](=O)[O-]
Yield: 88 %

Procedure:
Method H was used with 4-(5-amino-2,4-difluorophenoxy)-3-nitropyridin-2-amine and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound as a yellow solid (0.33 g, 88%). 1H NMR δ (DMSO): 6.09 (d, 1H, Hpy,5, J=5.5 Hz), 7.26 (bs, 2H, NH2), 7.7 (m, 3H, Harom), 7.90 (s, 1H, Harom,2′), 8.0 (d, 1H, Harom), 8.06 (d, 1H, Hpy,6, J=5.5 Hz), 10.4 (bs, 1H, NHamide). 19F NMR δ (DMSO): −56.78 (s, 1F, CF3), −118.54 (s, 1F, aromF), −129.58 (s, 1F, aromF).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]CC2C=CC=CC=2)(=[O:15])=[O:14])=[O:11])[N:3]=1.C(OCC1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.CC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])(=[O:15])=[O:14])=[O:11])[N:3]=1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OCc2ccccc2)n1
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccc(COCc2ccccc2)cc1
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2O)n1

Procedure:
A stirred solution of 0.5 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-(benzyloxy)benzenesulfonamide (from b, above) in 20 ml of trifluoroacetic acid was boiled under reflux for 1.5 hours. The proton magnetic resonance spectrum indicated complete cleavage of the benzyl ether. The trifluoroacetic acid was evaporated in vacuum and the oily residue stirred with water and diethyl ether, providing white solid. The solid was dissolved in acetone and reprecipitated by dilution of the solution with hexane, yielding N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-hydroxybenzenesulfonamide as a white solid, m.p. ca. 180°. The mass spectrum showed a molecular ion, m/e 322; ##STR38## and no m/e 91 (no Ph--CH2+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[C:7]([CH2:18][OH:19])(C([O-])=O)[N:6]=1)[CH2:2][CH2:3][CH3:4].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=3)=[N:30][N:29]=[N:28]2)C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:39][CH:40]=2)[C:7]([CH2:18][OH:19])=[C:8]([N:10]2[CH:11]=[CH:12][CH:13]=[CH:14]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC1=NC(CO)(C(=O)[O-])C(n2cccc2)=N1
Product: CCCCc1nc(-n2cccc2)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the method described in Example 13, 2-butyl-5-(hydroxymethyl)-4-(1H-pyrrol-1-yl)imidazole-5-carboxylate (Example 29) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12) are reacted and deprotected to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4]/[N:5]=[CH:6]/[CH2:7][C:8]([CH3:19])([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[Cl:21][C:22]1[C:23]([F:40])=[C:24](/[CH:28]=[C:29](/[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])\[C:30]#[N:31])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([CH:4]1[CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[F:40])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[F:39])([C:30]#[N:31])[CH:6]([CH2:7][C:8]([CH3:18])([CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:5]1)=[O:20]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: COC(=O)C/N=C/CC(C)(C)Cc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1NC(CC(C)(C)Cc2ccc(OC)cc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 70.2 %

Procedure:
In a manner similar to the method described in Example 1c, [4-(4-methoxy-phenyl)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid methyl ester prepared in Example 126a (2.7 g, 9.7 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (3.1 g, 10 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (6 g, 60 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid methyl ester as a yellow solid (4 g, 70%).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.CO.[ClH:12].[CH3:13][N:14]1[CH2:46][C@@H:45]2[C@H:16]([CH2:17][C:18]3[N:19]([CH2:44]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]=3[C:27]2[C:28](=[O:43])[O:29][C:30](=O)[C:31]=2[C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH3:41])[CH:33]=2)[CH2:15]1>CN(C=O)C.C(OCC)(=O)C>[ClH:12].[CH3:13][N:14]1[CH2:46][C@@H:45]2[C@H:16]([CH2:17][C:18]3[N:19]([CH2:44]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]=3[C:27]2[C:28](=[O:43])[NH:3][C:30](=[O:29])[C:31]=2[C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH3:41])[CH:33]=2)[CH2:15]1
Reactant: CN1C[C@H]2Cc3c(C4=C(c5cn(C)c6ccccc56)C(=O)OC4=O)c4ccccc4n3C[C@@H]2C1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C[C@H]2Cc3c(C4=C(c5cn(C)c6ccccc56)C(=O)NC4=O)c4ccccc4n3C[C@@H]2C1
Temperature: 45 °C
Reaction time: 48 h
Yield: 58.9 %

Procedure:
A mixture of 1.21 g of 1,1,1,3,3,3-hexamethyldisilazane and 132 mg of methanol was added to a solution of 400 mg of trans-3-(2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione hydrochloride in 30 ml of DMF and stirred for 48 hours. A further 100 mg of methanol and 0.95 g of 1,1,1,3,3,3-hexamethyldisilazane were added, the mixture was heated to 45° C. for 2 hours and then left to stand at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, dichloromethane and methanol. The solution obtained was washed with saturated sodium bicarbonate solution and the organic layer was concentrated. A saturated solution of hydrogen chloride in ethyl acetate was added and the precipitate obtained was filtered off. The solid was suspended in water and stirred, then filtered off and dried. The solid obtained was suspended in ethyl acetate and stirred, then filtered off and dried to give 235 mg of trans-3-(2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl)-4 -(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point >330° C.