Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]1[NH:8][CH2:9][CH2:10][N:11]=1.CC(C)([O-])C.[K+].[CH2:22]([OH:26])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([O:26][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]1[NH:8][CH2:9][CH2:10][N:11]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Clc1c(C2=NCCN2)sc2ccccc12
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCOc1c(C2=NCCN2)sc2ccccc12

Procedure:
A solution of 0.1 g (0.42 mmol) of 2-(3-chlorobenzo[b]thiophen-2-yl)-4,5-dihydro-1H-imidazole and 56 mg (0.5 mmol) of potassium tert.-butoxide in 2 ml of absolute n-butanol was heated for 3 d. After cooling the mixture was filtered, the filter rinsed with dichloromethane, and the filtrate concentrated under reduced pressure. The title compound was obtained from the residue after column chromatography on silica gel with dichloromethane/ethanolic ammonia gradient.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:14][C:9]([F:13])([CH:10]([F:11])[F:12])[CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:1][Br:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(CC(F)(F)C(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Cc1cccc(CBr)c1
Temperature: 25 °C

Procedure:
A solution of 1-methyl-3-(2,2,3,3-tetrafluoropropyl)benzene (1.363 g, 6.611 mmol), N-bromosuccinimide (1.18 g, 6.61 mmol) and 2,2′-azobis(isobutyronitrile) (30 mg) in carbon tetrachloride (20 ml) was heated under reflux for 1.5 hrs. After cooling the reaction solution to room temperature, the white precipitate was collected by filtration and the precipitate was washed with hexane. The solvent of the recovered filtrate was evaporated under reduced pressure to give a crude product of 3-(2,2,3,3-tetrafluoropropyl)benzyl bromide as a colorless liquid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[N:22][C:23]=3[CH3:27])[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:28]1([CH2:34][CH2:35]C=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:27][C:23]1[N:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[CH:25]=[CH:26][C:17]([NH:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][CH2:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:9][CH2:10]1)=[N:18]2
Reactant: Cc1nccc2nc(NCCN3CCN(Cc4ccccc4)CC3)ccc12
Reactant: O=CCCc1ccccc1
Product: Cc1nccc2nc(NCCN3CCN(CCCc4ccccc4)CC3)ccc12

Procedure:
Compound 11 was prepared as described for compound 9, using 3-phenylpropionaldehyde in place of benzaldehyde. 1H NMR (CD3OD, 400 MHz) δ 8.20 (d, 1H, J=5.5 Hz), 8.10 (d, 1H, J=7.5 Hz), 7.10-7.35 (m, 6H), 6.82 (d, 1H, J=7.5 Hz), 3.60-3.70 (m, 2H), 2.50-2.90 (m, 15H), 2.30-2.45 (m, 2H), 1.75-1.90 (m, 2H). LCMS (EI) m/z 390 (M+1).
Reaction SMILES: C[O-].[Na+:3].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16]>C(O)C>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:13][CH:14]([CH3:18])[C:15]([O-:17])=[O:16])=[CH:7][CH:6]=1.[Na+:3]
Reactant: CC(S)C(=O)O
Reactant: ClCc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(SCc1ccncc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium methoxide (5.1 g., 94 mmoles) was dissolved in 50 ml. of absolute ethanol and cooled in an ice bath. A slurry of 4-picolyl chloride hydrochloride (5.0 g., 30.4 mmoles) in 45 ml. of ethanol was added and the chilled reaction mixture stirred for approximately 10 minutes. Finally, 2-mercaptopropionic acid (3.23 g., 30.4 mmoles) dissolved in 5 ml. of ethanol was added over a 10 minute period. The mixture was allowed to warm to room temperature and stirred overnight (approximately 16 hours). The reaction was filtered through filter aid to remove salts, carbon treated and concentrated to crude sodium 2-(4-picolylthio)propionate (approximately 7 g. of oil used directly in the next step).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:20])[C:12]2[C:7](=[C:8](Br)[C:9]([NH2:16])=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6](=[O:18])[NH:5][C:4]1=[O:19]>C(O)C>[CH3:2][C:3]1([CH3:20])[C:12]2[CH:11]=[C:10]3[NH:13][C:11]([C:12]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[N:16][C:9]3=[CH:8][C:7]=2[C:6](=[O:18])[NH:5][C:4]1=[O:19]
Reactant: CC1(C)C(=O)NC(=O)c2c1cc([N+](=O)[O-])c(N)c2Br
Agent: Cl
Solvent: CCO
Product: CC1(C)C(=O)NC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21

Procedure:
37 g. (100 mmole) of the above compound were deacetylated by refluxing for 20 hours in 350 ml. ethanol and 175 ml. concentrated hydrochloric acid. After cooling, the reaction mixture was poured on to ice, filtered off with suction and washed with water to give 27.4 g. (84% of theory) 4,4-dimethyl-6-nitro-7-amino-8-bromo-1,2,3,4-tetrahydroisoquinoline-1,3-dione; m.p. 218°-221° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH2:12]Cl.C1(C)C=CC=CC=1.[P:21]([S-:27])(=[S:26])([O:24][CH3:25])[O:22][CH3:23].[NH4+]>CO>[P:21]([S:27][CH2:12][C:3]1[N:4]=[C:5]2[S:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Cl:1])(=[S:26])([O:24][CH3:25])[O:22][CH3:23]
Reactant: COP(=S)([S-])OC
Reactant: O=c1c(Cl)c(CCl)nc2sccn12
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COP(=S)(OC)SCc1nc2sccn2c(=O)c1Cl
Reaction time: 6 h

Procedure:
The compound of EXAMPLE 2 (7 g) and 100 ml of toluene was stirred and heated to 70°. To this mixture was added, dropwise, a solution of 14 g ammonium dimethyl phosphorodithioate in 200 ml methanol. The resulting mixture was kept at 70° for 6 hours, then the methanol was distilled off. Toluene (400 ml) was added, and the mixture was washed with water, separated, dried and evaporated under reduced pressure. The solid which remained was washed with toluene and filtered. The solid, m.p. 125°-130°, weighed 2.5 g.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3](OS(C)(=O)=O)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1.[N-:29]=[N+:30]=[N-:31].[Na+].CS(C)=O>O>[N:29]([CH:3]([C:2]([F:28])([F:27])[F:1])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[N+:30]=[N-:31]
Reactant: CS(=O)(=O)OC(COC1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC(COC1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Temperature: 100 °C
Reaction time: 72 h
Yield: 25.6 %

Procedure:
A mixture of benzyl 4-{3,3,3-trifluoro-2-[(methylsulfonyl)oxy]propoxy}piperidine-1-carboxylate (1.31 g), sodium azide (1.00 g), 15-crown-5-ether (3.39 g) and dimethyl sulfoxide (5 mL) was stirred at 100° C. for 3 days. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (294 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](O)=[N:4][CH:3]=1.N1C=CC=CC=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:5]1[C:6]2[N:7]([CH:8]=[CH:9][N:10]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: Cc1cnc(O)c2nccn12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1cnc(Cl)c2nccn12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of 5-Methyl-imidazo[1,2-a]pyrazin-8-ol (1.32 g, 8.86 mmol) in POCl3 (25 mL) is added pyridine (0.53 mL, 6.6 mmol) and the reaction stirred at 120° C. under N2 atmosphere for 4 h 30 min. The reaction is cooled to 60° C. and poured into 80 g of ice and stirred for 1 h. The mixture is neutralized with NaOH (20%), extracted with CHCl3/IPA 9/1, dried with MgSO4 anh., filtered and concentrated to get a crude that is purified by column chromatography using a gradient of (DCM/MeOH:98/2 to 95/5) to give 8-Chloro-5-methyl-imidazo[1,2-a]pyrazine as a pale yellow solid (0.39 g, 26%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]=[C:15]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:33](=[O:34])[CH2:32][N:16]3[CH2:17][CH2:18][C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:15]3=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(4-fluorophenyl)piperazine (0.034 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (2 mL) was stirred at room temperature. After stirring overnight, the reaction mixture was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.27-7.38 (m, 8H), 7.18-7.25 (m, 2H), 6.94-7.01 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 3.73 (t, J=4.9 Hz, 2H), 3.54-3.60 (m, 2H), 3.54 (t, J=6.5 Hz, 2H), 3.02 (t, J=5.0 Hz, 2H), 2.89 (t, J=5.2 Hz, 2H), 2.82 (t, J=6.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:13]/[C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: COC(=O)c1ccc(/N=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Yield: 98.4 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (5.0 g, 27 mmol) in 42 mL of ethonal was added methyl 4-aminobenzoate (4.07 g, 27 mmol), and the reaction mixture was stirred over weekend. The yellow precipitates were filtered, and 8.47 g of (E)-methyl 4-(4-chloro-3-nitrobenzylidenamino)benzoate a yellow solid was obtained. (Yield=98%). (E)-methyl 4-(4-chloro-3-nitrobenzylideneamino)benzoate (8.47 g, 26.6 mmol) and yttrium(III) trifluoromethanesulfonate (800 mg, 1.33 mmol) was dissolved in dry tetrahydrofuran (100 mL), and then cooled below 0° C. Isobutyl aldehyde (2.30 g, 31.9 mmol) was added below 0° C. The reaction mixture was stirred at room temperature overnight. Thin layer chromatography showed most of starting material was consumed. 50 mL of ethyl acetate and 50 mL of water were added to the mixture, and the separated organic layer was washed with brine again. The organic layer was dried over sodium sulfate and purified on silica gel to afford 4.9 g of methyl 2-(4-chloro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. (Yield=47%). MS (ESI+APCI) M+1=373.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[NH:4][CH2:3][CH2:2][OH:1])[C:9]#[N:10]
Reactant: N#Cc1ccc(NCCO)c([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(NCCO)c(N)c1
Yield: 78.2 %

Procedure:
A solution of 4-(2-hydroxyethylamino)-3-nitrobenzonitrile (3.11 g) and tin chloride dihydrate (16.94 g) in ethanol (50 ml) was stirred at 70° C. for 1 hour. After completion of the reaction, the solvent was evaporated and to the obtained residue were added tetrahydrofuran and 15% aqueous sodium hydroxide solution. The mixture was stirred and insoluble material and the aqueous layer were removed. The obtained organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained solid was washed with chloroform, filtrated and dried under reduced pressure to give the title compound (2.08 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([F:28])[C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[C:12]([F:28])=[C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 42 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (190 mg, 0.32 mmol) prepared in Example 30b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (58.5 mg, 41%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3]1.[CH2:20]([N:22]([CH2:37][CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:21].N1CCCCC1>C(O)C>[CH2:37]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:11]3[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=3)[C:16]([OH:18])=[O:17])[NH:3][C:2]2=[O:1])[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:38]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cncc(C(=O)O)c4)c32)c1C
Temperature: 60 °C

Procedure:
A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (381 mg, 1.5 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (398 mg, 1.5 mmol) and piperidine (1 mL) in ethanol (5 mL) was heated in a sealed tube at 60° C. for 10 hours. The reaction was concentrated, the residue was dissolved in a mixture of water and methanol and then acidified with 1N HCl. The resulted precipitate was collected by vacuum filtration, washed with methanol and dried to give the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH3:12]>ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH2:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(N)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a solution containing 4-toluenesulfonyl chloride (10 g, 52.45 mmol) in dichloromethane (100 mL) at -78° C., liquid ammonia (20 mL) was added. After the mixture was stirred at -78° C. for 4 h, precipitates were removed by filtration and the filtrate was concentrated in vacuo to remove the solvent. The residue was then recrystallized from n-hexane/ethyl acetate (v/v=2:5) to give 7.77 g (85.7%) of 4-toluenesulfonamide.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([NH:33][C:34]([CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[O:35])=[N:29][NH:30]2)=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:42][N:39]1[CH2:38][CH2:37][CH:36]([C:34]([NH:33][C:28]2[C:27]3[C:31](=[CH:32][C:24]([NH:23][C:20]([C:18]4[CH:17]=[CH:16][C:14]5[N:15]=[C:11]([NH:10][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[CH:1]([CH3:2])[CH3:3])[NH:12][C:13]=5[CH:19]=4)=[O:21])=[CH:25][CH:26]=3)[NH:30][N:29]=2)=[O:35])[CH2:41][CH2:40]1
Reactant: CC(C)c1ccccc1Nc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: CN1CCC(C(=O)Nc2n[nH]c3cc(N)ccc23)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(C(=O)Nc3ccc4c(NC(=O)C5CCN(C)CC5)n[nH]c4c3)cc2[nH]1

Procedure:
2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol; see Example 66) was coupled with aforementioned 1-methylpiperidine-4-carboxylic acid (6-amino-1H-indazol-3-yl)-amide (0.3 mmol) using HBTU as described in general procedure D to afford the desired product, 2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid {3-[(1-methylpiperidine-4-carbonyl)-amino]-1H-indazol-6-yl}-amide. MS: m/z 551 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:11][CH3:12])=[O:9])[C:4](=O)[O:3]1.[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:3])=[CH:17][CH:18]=1
Reactant: CON(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CS(N)(=O)=O
Product: CON(CCCc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 91.2 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[3-(4-fluorophenyl)-propyl]-N-methoxy-acetamide (0.300 g, 0.89 mmol) with methanesulfonamide (0.127 g, 1.33 mmol) as described in the preparation oc compound 22 gave 0.304 g (91% yield) of the title amide as a white foam after chromatography. 1H NMR (400 MHz, CDCl3) 8: mixture keto-enol forms and of rotamers equilibrating to a major enol form after a few hours in chloroform: 1.95 (2H, m, CH2), 2.6 (2H, m, CH2), 3.34, 3.35 and 3.38 (3H, 3s, SO2CH3), 3.70, 3.71 and 3.74 (3H, 3s, OCH3), 6.57 (1H, s, CH), 7.0 (2H, m, aromatics), 7.15 (2H, m, aromatics), 9.05 (1H, broad s, NH); major form after equilibration: 1.97 (2H, m, CH2), 2.64 (2H, t, CH2), 3.38 (3H, s, SO2CH3), 3.74 (3H, s, OCH3), 6.57 (1H, s, CH), 7.0 (2H, m, aromatics), 7.15 (2H, m, aromatics), 9.05 (1H, broad s, NH). MS (ESI/pos) calculated for C15H20FN2O6S, [M+H]+: 374; found: 374.
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][CH2:19][NH2:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[C:21](OC(=O)C)(=[O:23])C.C(OCC)(=O)C>C(O)=O>[C:1]([C:4]1([CH2:17][CH2:18][CH2:19][NH:20][CH:21]=[O:23])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: O=CO
Product: NC(=O)C1(CCCNC=O)c2ccccc2-c2ccccc21
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred hot (50° C.) solution of 6.2 g (23 mM) of 9-carbamoyl-9-(3-aminopropyl)fluorene in 50 ml of 98% formic acid were added dropwise over ten minutes 17 ml of acetic anhydride. The reaction mixture was cooled to about 30° C. and stirred for one hour, and then added to 100 ml of ice water. The aqueous mixture was diluted by addition of 100 ml of ethyl acetate, and the organic layer was separated, washed with two 50 ml portions of 5% w/v aqueous sodium bicarbonate, twice with 5 ml portions of 1N hydrochloric acid, again with sodium bicarbonate, and finally with water. The solution was dried and the solvent was removed by evaporation under reduced pressure to provide 2.0 g of 9-carbamoyl-9-(3-formamidopropyl)fluorene. mp 160°-161° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[N+:11]([O-:24])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cncc(OCc2ccccc2)c1
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc(OCc2ccccc2)c1

Procedure:
A solution of 3-(benzyloxy)-5-bromopyridine (from step 1) (1.0 eq.) and meta-chloroperbenzoic acid (mCPBA) (4.0 eq.) in dichloromethane (0.1 M) was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with dichloromethane three times. The combined organic layers were dried over anhydrous MgSO4 and concentrated en vacuo. The crude residue was purified by a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane to give 3-(benzyloxy)-5-bromopyridine 1-oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:10]=2[N:11]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[N:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(F)nc12
Product: Fc1ccc2ncnc(Cl)c2n1
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of 6-fluoro-3H-pyrido[3,2-d]pyrimid-4-one (0.20 g, 1.21 mmol) in POCl3 (30mL) is heated under reflux with stirring until homogeneous (2 h), and then for a further 1 h. Excess POCl3 is removed under reduced pressure, and the residue is partitioned between CH2Cl2 and saturated aqueous NaHCO3. Workup of the organic portion gives crude 4-chloro-6-fluoropyrido[3,2-d]pyrimidine (100%) as an unstable white solid which is used directly in the next step.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][N:11]=[C:12]=[S:13]>C1(C)C=CC=CC=1>[CH3:10][NH:11][C:12]([N:2]([CH3:1])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[S:13]
Reactant: CN=C=S
Reactant: CNCc1cccnc1
Solvent: Cc1ccccc1
Product: CNC(=S)N(C)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
In 30 ml of toluene was dissolved 2.5 g (0.02 mole) of N-methyl-N-3-pyridylmethylamine followed by addition of 1.5 g (0.02 mole) of methyl isothiocyanate and the mixture was stirred at room temperature overnight. Finally, the solvent was distilled off to give 3.8 g of N-methyl-N'-methyl-N'-3-pyridylmethylthiourea as a yellow viscous oil. This oily product was purified by silica gel column chromatography using HeOH-CHCl3 (1:10) as an eluent to give crystals.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:47]([Cl:53])=[N:48][CH:49]=[CH:50][C:51]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:47]([Cl:53])=[N:48][CH:49]=[CH:50][C:51]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccnc(Cl)c1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(Cl)ccnc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-2,4-dichloropyridine hydrobromide and isolated as light green solid. MS (m/e): 442.3 (MH+).