Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1.C(=O)([O-])O.[Na+]>COCCOC.O.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>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC1(C)OB(c2cc(F)ccc2N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cc(F)ccc3N)[nH]c2c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.35 g, 6.98 mmol) obtained in the same manner as in the method described in WO03/010140 and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (1.99 g, 8.38 mmol) in 1,2-dimethoxyethane (24 ml) and water (12 ml) were added sodium hydrogen carbonate (2.00 g, 24.0 mmol) and tetrakis(triphenylphosphine)palladium (400 mg, 0.34 mmol), and the mixture was heated under reflux for 14 hr. The mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1-3:1) to give methyl 2-(2-amino-5-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (2.44 g, yield 95.7%).
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11](F)[CH:10]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:17]([NH:24][C:11]1[CH:10]=[C:9]([NH2:8])[C:14]([F:15])=[CH:13][N:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(F)ncc1F
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: Nc1cc(NCc2ccccc2)ncc1F
Yield: 58.4 %

Procedure:
To 1 ml of N-methylpyrrolidone was added 410 mg of 4-amino-2,5-difluoropyridine together with 930 mg of benzylamine, and the mixture was allowed to react in nitrogen atmosphere at 150° C. for 3 days and allowed to cool. After adding 30 ml of chloroform, the mixture was washed twice with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 15 g; eluent: chloroform: methanol, 1:0 and then, 50:1) to obtain 400 mg of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[N:7]=[C:8]([CH2:12][C:13]#[N:14])[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[CH:3]1[C:2]([Cl:1])=[CH:11][C:10]2[NH:9]/[C:8](/[NH:7][C:6](=[O:15])[C:5]=2[CH:4]=1)=[C:12](/[C:26]([C:25]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=1[Cl:23])=[O:27])\[C:13]#[N:14]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: N#CCc1nc(=O)c2ccc(Cl)cc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1/NC(=O)c2ccc(Cl)cc2N1
Yield: 25.7 %

Procedure:
To solution of 2-(7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (24.9 mg, 113 μmol) and triethylamine (17.4 μL, 125 μmol) in dioxane (4 mL) was added 2,4-dichlorobenzoyl chloride (15.9 μL, 113 μmol), and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin D (5) (11.4 mg, 26%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.47-7.52 (m, 2H), 7.56 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H), 7.77 (d, J1=1.8 Hz, 1H), 7.90 (br s, 1H), 8.04 (d, J=8.5 Hz, 1H). 13C NMR (500 MHz, DMSO-d6) δ ppm 72.44, 116.56, 118.79, 118.85, 125.74, 127.65, 128.66, 129.2, 129.65, 130.49, 134.81, 138.21, 140.03, 155.62, 157.98, 188.6. HRMS (m/z): [M+Na]+ calc. for C17H8N3O2Cl3Na, 413.9580; observed, 413.9583.
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:25]=[C:26]([C:30]1[N:38]2[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:32][C:31]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:17][C:2](=[CH2:1])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])[C:26](=[O:25])[C:30]3[N:38]4[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:32][C:31]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Reactant: C=C(C)CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CN1CCN(c2ccc(NC(=O)C(=O)c3c(-c4ccccc4)cc4n3CCCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
To an ice-cold solution of 4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 89, 500 mg, 2.16 mmol) and triethylamine (0.6 mL, 4.32 mmol) in dry DCM (12 mL) was added a solution of oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 726 mg, 2.52 mmol) in DCM (5 mL). The mixture was warmed to room temperature and stirred for 30 min then diluted with DCM, washed successively with water, sodium bicarbonate solution and brine, then dried over sodium sulfate. Concentration gave a residue which was purified by preparative TLC using ethyl acetate and hexane (3:7) as eluent to afford N-{4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (220 mg, 21%) as a yellow powder.
Reaction SMILES: I[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:11]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26](N(OC)C)=[O:27])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].[NH4+]>O1CCCC1>[Si:11]([O:18][CH2:19][CH:20]1[CH2:21][CH2:22][CH:23]([C:26]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[O:27])[CH2:24][CH2:25]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)C1CCC(CO[Si](C)(C)C(C)(C)C)CC1
Reactant: Ic1ncnc2[nH]ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CCC(C(=O)c2ncnc3[nH]ccc23)CC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex-tetrahydrofuran solution (1.3 M, 39.2 mL, 51.0 mmol) was added dropwise to 4-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.00 g, 20.4 mmol) obtained in Reference Synthetic Examplea 1 in tetrahydrofuran (50 mL) at −50° C., and stirred at −50° C. for 1 hour. The reaction mixture was mixed with 4-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methoxy-N-methylcyclohexanecarboxamide (6.44 g, 20.4 mmol) in tetrahydrofuran (30 mL) at −50° C. and then stirred at room temperature for 23 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 (v/v)) to give the title compound as a colorless oil (5.14 g, yield 67%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>C(OCC)(=O)C.CO>[CH:26]1([NH:29][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:28][CH2:27]1
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Reactant: NC1CC1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCCNC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
The compound (300 mg, 1.59 mmol) obtained in Example 25b was dissolved in ethyl acetate (16 mL), triethylamine (0.323 mL, 2.39 mmol) and methanesulfonyl chloride (0.147 mL, 1.90 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Insoluble matter was removed by filtration through celite, the solvent was evaporated under reduced pressure, the resulting residue was added dropwise to a solution of cyclopropylamine (1.82 g, 31.8 mmol) in methanol (3 mL) under ice cooling, and the mixture was stirred at 60° C. for 72 hours. The solvent was evaporated under reduced pressure, 1 N sodium hydroxide was added to the resulting residue, and the mixture was extracted with ethyl acetate (×3). The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1→10:1, v/v) to give the title compound (215 mg; yield, 59%) as a yellow oily substance.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:1]1(=[O:12])[O:13][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2ccccc2C(=O)O1
Temperature: 25 °C
Yield: 100 %

Procedure:
2 g (11.1 mmol) of homophthalic acid was dissolved in 30 ml toluene, and 1.6 ml (16.7 mmol) of acetic anhydride was added. The mixture was heated to the reflux temperature and reacted for 0.5 h. Then, the reaction mixture was cooled to the room temperature and concentrated to dry in a reduced pressure to obtain 1.8 g of a product as a pale yellow solid with the yield of 100%. m.p. 140-142° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)(Cl)(Cl)Br.C1CCN2C(=NCCC2)CC1>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[CH:14][CH:15]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)C1COC(c2ccc(CNC(=O)OC(C)(C)C)cc2)=N1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)c1coc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of methyl 2-[4-(N-Boc-aminomethyl)-phenyl]4,5-dihydrooxazol-4-ylcarboxylate (25.5 g, 76.3 mmol) in dichloromethane (100 ml) was added CBrCl3 (8.23 ml, 83.9 mmol) and DBU (12.5 ml, 83.9 mmol). After stirring at room temperature overnight, the reaction was concentrated and the product isolated by flash chromatography over silica gel. Recrystallization from hot methanol provided methyl 2-[4-(N-Boc-aminomethyl)-phenyl]-oxazole-4-carboxylate (18.4 g, 55.4 mmol) as pale yellow crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]([OH:19])=[O:18])=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:20][C:21]([Cl:25])([Cl:24])[CH2:22]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:20][C:21]([Cl:25])([Cl:24])[CH2:22][O:18][C:17](=[O:19])[CH2:16][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[O:12][C:11](=[O:15])[CH:10]=1
Reactant: CC(=O)Oc1ccc2c(CC(=O)O)cc(=O)oc2c1
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(CC(=O)OCC(Cl)(Cl)Cl)cc(=O)oc2c1
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a suspension of 7-acetoxycoumarin-4-acetic acid 5 (945 mg, 3.6 mmol, 1 eq) in 47 mL of anhydrous dichloromethane at room temperature under nitrogen was added 2,2,2-trichloroethanol (431 μL, 4.5 mmol, 1.25 eq). A solution of N,N′-dicyclohexylcarbodiimide (818 mg, 4 mmol, 1.1 eq) in 10 mL of anhydrous dichloromethane was added. The reaction mixture was stirred for 15 min, after which it was diluted with dichloromethane and filtered. The filtrate was concentrated under vacuum. Column chromatography on silica gel (CH2Cl2 then CH2Cl2:EtOAc, 10:1) afforded product 6a (1.37 g, 96%): Rƒ 0.78 (CH2Cl2:EtOAc, 5:1); 1H NMR (300 MHz, CDCl3): δ 7.61 (d, 1 H, J5,6 8.7 Hz, H-5), 7.15 (d, 1 H, J6,8 2.1 Hz, H-8), 7.07 (dd, 1 H, J6,8 2.3, J5,6 8.7 Hz, H-6), 6.42 (s, 1 H, H-3), 4.77 (s, 2 H, CH2CCl3), 3.91 (2 s, 2 H, CH2CO2), 2.33 (s, 3 H, OAc); 13C NMR (75 MHz, CDCl3): δ 168.6, 167.0, 154.5, 153.5, 146.5, 125.5, 118.5, 117.0, 116.5, 110.9, 74.6, 37.7, 21.2; ESI-MS: m/z 393 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C[C@H]1Cc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@H](NCCc2ccccc2)C[C@H]1Cc1ccccc1
Yield: 59.3 %

Procedure:
1 g (3.44 mmol) of (2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine is reacted in analogy to Example 11a with 1 ml (4.48 mmol) of phenylacetaldehyde, 0.433 g (6.89 mmol) of sodium cyanoborohydride, 0.791 g (9.64 mmol) of sodium acetate and 434 μl of acetic acid to give the title compound (805 mg, 60%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.35, FD-MS: M+ =394.
Reaction SMILES: C(O)C.[OH-].[K+].C([O:8][C:9](=[O:30])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][CH2:18][C:17]2=[CH2:29])C>O>[CH2:29]=[C:17]1[C:16]2[C:20](=[CH:21][C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:14]([O:13][CH2:12][CH2:11][CH2:10][C:9]([OH:30])=[O:8])[CH:15]=2)[CH2:19][CH2:18]1
Reactant: C=C1CCc2cc(CCCCCC)c(OCCCC(=O)OCC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C1CCc2cc(CCCCCC)c(OCCCC(=O)O)cc21
Yield: 9.9 %

Procedure:
A mixture of 20 ml of ethanol, 0.975 mg (155 mmol) of potassium hydroxide, 1.2 g (35 mmol) of ethyl4-(3-methylene-6-hexylindan-5-yloxy)butyrate and 10 ml of water is heated for 5 hours at the reflux point of the solvents. The ethanol is evaporated off, the residue is taken up in water and the impurities are extracted with ether. The aqueous phase is acidified and then extracted with ether. Concentration of the solvents gives 1.1 g of product, which is purified by flash chromatography (50/50 heptane/ethyl acetate) to give a solid m.p.: 90° C. (0.8 g; 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=1.C=O.[BH3-][C:26]#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)=[C:6]([N:17]([CH2:18][CH2:19][O:20][CH3:21])[CH3:26])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: COCCNc1cc(C(=O)OC)ccc1N1CCN(C)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCCN(C)c1cc(C(=O)OC)ccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
To a solution of 170 mg of 3-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (0.55 mmol, 1 eq.) in 5 mL of acetic acid were added 3 mL of aqueous solution of formaldehyde and the resulting mixture stirred for 10 minutes at room temperature; a solution of NaCNBH3 (680 mg, 11 mmol, 20 eq.) in 3 mL of MeOH was then added at 0° C. and the solution stirred for 5 minutes. The solvent was removed and the crude washed with water and dichloromethane. The combined organic layers were evaporated and the crude was purified by flash column chromatography, using dichloromethane-methanol 95:5 as eluant, affording 150 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:51]=[CH:50][C:26]([C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)=[C:35]([N+:47]([O-:49])=[O:48])[CH:34]=4)(=[O:32])=[O:31])=[O:28])=[C:25]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([O:59]COC)[CH:54]=4)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1>O1CCCC1.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:51]=[CH:50][C:26]([C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)=[C:35]([N+:47]([O-:49])=[O:48])[CH:34]=4)(=[O:32])=[O:31])=[O:28])=[C:25]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([OH:59])[CH:54]=4)[CH:24]=3)[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: COCOc1cccc(Oc2cc(N3CCN(CC4=C(c5ccc(Cl)cc5)CC(C)(C)CC4)CC3)ccc2C(=O)NS(=O)(=O)c2ccc(NC3CCN(C)CC3)c([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cccc(O)c3)cc2[N+](=O)[O-])CC1

Procedure:
A suspension of EXAMPLE 176E (35.5 mg) in tetrahydrofuran (3 mL) and HCl (1.25M in methanol, 2 mL) was stirred for 1 hour at 60° C. The product was concentrated. The crude product was purified by RP HPLC (C8, 30%-100% CH3CN/water/0.1% TFA) to yield the product. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 9.31 (s, 1H), 8.10 (s, 1H), 7.66-7.73 (m, 2H), 7.56 (d, 1H), 7.34-7.38 (m, 2H), 7.02-7.09 (m, 2H), 6.95-7.02 (m, 1H), 6.65 (dd, 1H), 6.34 (s, 1H), 6.29 (d, 1H), 6.20 (d, 1H), 6.14 (d, 1H), 4.14 (dd, 1H), 3.75 (s, 1H), 3.05 (d, 4H), 2.68-2.80 (m, 3H), 2.20 (d, 6H), 2.08 (d, 2H), 1.97 (s, 2H), 1.69-1.79 (m, 2H), 1.63 (s, 1H), 1.39 (d, 2H), 1.21-1.36 (m, 9H), 0.94 (s, 6H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH2:7]([N:9]1[C:13]2[CH:14]=[CH:15]C(C([O-])=O)=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:21][C:22]1[N:23]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[N:24]=[CH:25][CH:26]=1)[CH3:8]>CN(C=O)C.ClCCl>[CH2:10]([NH:9][C:1]([C:2]1[CH:15]=[CH:14][C:13]2[N:9]([CH2:7][CH3:8])[C:10]([CH2:21][C:22]3[N:23]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[F:34])[N:24]=[CH:25][CH:26]=3)=[N:11][C:12]=2[CH:17]=1)=[O:5])[C:21]#[CH:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCn1c(Cc2ccnn2-c2cc(F)ccc2F)nc2cc(C(=O)[O-])ccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccc2c(c1)nc(Cc1ccnn1-c1cc(F)ccc1F)n2CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.5 eq of 2M in dichloromethane) is added dropwise to a solution of 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxylate (368 mg) in DMF (5 drops) and dichlormethane (30 mL) at 0° C. The mixture is stirred at 0° C. for 0.5 h, then at room temperature for 1 h. The solution is concentrated, the residue taken up in DMF (30 ml), excess propargylamine added, and the mixture stirred for 6 h. Dilute aqueous sodium bicarbonate is added then extracted with dichloromethane (3×), the combined organic layers washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 462 mg of crude N-propargyl 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-1H-benzimidazole-5-carboxamide.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:37]3[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (69%).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[NH:10][C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1cccc(COc2ccc(Nc3ncnc4cc(-c5ccco5)[nH]c34)cc2Cl)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→1:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (122 mg).