Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N2CCCN([C:12]([CH:14]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:15]3)=[O:13])CC2)CCC1.O=S(Cl)Cl.[N:32]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:21]([O:20][C:18]([N:16]1[CH2:17][CH:14]([C:12]([N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:33][CH2:34]2)=[O:13])[CH2:15]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a stirred solution of benzyl 3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidine-1-carboxylate (1.0 g, 4.25 mmol) in DCM (20 mL) was added SOCl2 (0.754 g, 0.460 mL, 6.38 mmol) and the resulting mixture was stirred for 2 hours at room temperature. LCMS analysis showed incomplete conversion so a further 1.0 eq of SOCl2 (501 mg, 305 μL) was added and the reaction stirred for a further 19 hours. Volatiles were removed at reduced pressure and the crude acid chloride dissolved in DCM (10 mL) and added dropwise to a solution of tert-butyl 1,4-diazepane-1-carboxylate (0.658 g, 5.10 mmol, 1.2 eq) and DIPEA (1.67 g, 12.75 mmol, 3.0 eq) in DCM (10 mL) at 0° C. The resulting solution was stirred at room temperature for 17 hours and then quenched by addition of NaHCO3 (5 mL). The reaction was diluted with DCM (10 mL) and the phases separated. The organic was washed with brine (5 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 98:1.2:0.8 to 97:2.7:0.3 gradient of DCM/MeOH/NH3) gave the title compound (1.54 g, 86%).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:41])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:41])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (154 mg, 0.23 mmol) was dissolved in dichloromethane (1.2 ml) and trifluoroacetic acid (0.72 ml, 9.35 mmol) was added. The orange reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in dichloromethane (1.2 ml) and ethylenediamine (1.0 ml, 14.8 mmol) was added. The solution was stirred at room temperature for 1.5 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washing with water (hot), ethyl acetate and dichloromethane then dried under high vacuum to afford 37 mg (33%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white powder. MS: (M+H)+=463; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.70 (br. s., 1H), 9.15 (s, 1H), 8.73 (d, J=8.7 Hz, 1H), 8.47 (t, J=7.4 Hz, 2H), 7.98 (s, 1H), 7.27 (d, J=8.7 Hz, 1H), 4.47-4.84 (m, 3H), 4.18 (s, 3H), 4.02-4.32 (m, 2H), 3.86 (br. s., 1H), 1.42 (d, J=4.5 Hz, 3H).
Reaction SMILES: [Br-:1].CNCCC[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][P+:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8].Cl.[N:34]1([C:39](=[NH:41])[NH2:40])[CH:38]=[CH:37][CH:36]=N1.[CH:42](N(CC)C(C)C)(C)C>CN(C)C=O>[Br-:1].[NH2:40][C:39]([N:34]([CH3:42])[CH2:38][CH2:37][CH2:36][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][P+:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8])=[NH:41]
Reactant: CNCCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N=C(N)n1cccn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Product: CN(CCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=N)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-{[4-(methylamino)butanoyl]amino}butyl)(triphenyl)phosphonium bromide (690 mg, 1.30 mmol) was dissolved in N,N-dimethylformamide (1.4 mL). The resultant solution was treated with 1H-pyrazole-1-carboximidamide hydrochloride (216 mg, 1.47 mmol) and N,N-diisopropylethylamine (0.27 mL, 1.54 mmol). The reaction was stirred overnight at room temperature. More 1H-pyrazole-1-carboximidamide hydrochloride and N,N-diisopropylethylamine can be added to effect further conversion. The reaction mixture in N,N-dimethylformamide was used in the purification without isolation.
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH:6]([C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C:4]1=[O:13].C(OC=C)(=O)C>ClCCl>[OH:1][CH2:2][N:3]1[C@@H:6]([C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C:4]1=[O:13]
Reactant: C[Si](C)(C)C#CC1CC(=O)N1CO
Solvent: C=COC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)C#C[C@H]1CC(=O)N1CO
Temperature: 37 °C
Reaction time: 32 h
Yield: 76.8 %

Procedure:
To a solution of N-hydroxymethyl-4-(2-trimethylsilylethynyl)-2azetidinone (250 g) in dichloromethane (6.5 L) was added vinyl acetate (350 ml) and Lipase PS (trademark; Amano Pharmaceutical Co., Ltd.) (190 g). The mixture was warmed to 37° C. and stirred for 32 hours. Catalyst was filtered off and washed with dichloromethane. Solvent was evaporated in vacuo. The residue was subjected to silica gel column chromatography eluting with (n-hexane:EtOAc=8:2 to 0:1) to give (R)-N-hydroxymethyl-4-(2-trimethylsilylethynyl)-2-azetidinone (192 g).
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl.[OH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[NH:13])=[CH:10][CH:9]=1.[CH3:17][O-].[Na+].[CH2:20]([OH:22])[CH3:21]>CO.O.C(O)(=O)C>[OH:22][C:20]1[CH:17]=[N:13][C:12]([C:11]2[CH:15]=[CH:16][C:8]([OH:7])=[CH:9][CH:10]=2)=[N:14][CH:21]=1
Reactant: CCO
Reactant: C[O-]
Reactant: N=C(N)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Oc1ccc(-c2ncc(O)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a one-liter flask, 30 g (0.09 moles) of 2benzyloxytrimethinium perchlorate (prepared essentially according to the procedure of A. Holy and Z. Arnold, Collection Czechoslov. Chem. Commun. 38, 1372 (1973)), 15.6 g (0.09 moles) of p-hydroxybenzamidine hydrochloride, 82.5 ml (0.36 moles) of 25% sodium methoxide in methanol, and 500 ml of ethanol were combined. The resulting mixture was heated to reflux overnight, and then cooled to room temperature. Then, 75 ml of glacial acetic acid and 300 ml of deionized water was added to the flask, resulting in precipitation of the product. The product was collected by filtration, washed with water, and air dried. The yield of 5-benzyloxy-2-(4-hydroxyphenyl)pyrimidine was 23.06 g (92%). This material was then hydrogenated on a Parr Hydrogenator with catalytic 10% palladium on carbon in tetrahydrofuran under 413.7 kPa hydrogen pressure for about 18 hours. When the hydrogenation was complete, the catalyst was removed by filtration, and the solvent was removed on a rotary evaporator to yield 5-hydroxy-2-(4-hydroxyphenyl)pyrimidine. The final product, 5-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)-2-(4hydroxyphenyl)pyrimidine, was prepared from 5-hydroxy-2-(4-hydroxyphenyl)pyrimidine and 5-butoxy-2,2,3,3,4,4hexafluoropentyltrifluoromethanesulfonate (prepared essentially as in Example 2) essentially as described in Example 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1)=[O:29].C[OH:43]>N1C=CC=CC=1>[ClH:27].[C:12](/[C:11](/[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:14]\[C:15]1[S:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][N:36]3[CH:33]3[CH2:34][CH2:35][N:30]([C:28]([OH:43])=[O:29])[CH2:31][CH2:32]3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1)#[N:13]
Reactant: O=C(Cl)N1CCC(N2CCCCC2)CC1
Reactant: CO
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(C4CCCCN4C4CCN(C(=O)O)CC4)CC3)s2)cc1OC
Product: Cl
Yield: 30 %

Procedure:
Compound 6 (2.00 g) was dissolved in pyridine (50 mL), and 1-chlorocarbonyl-4-piperidinopiperidine (2.50 g) was added to the solution, followed by stirring under reflux for 2 hours. After completion of reaction, methanol was added to the reaction mixture, followed by stirring for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was extracted with chloroform and purified water. The organic layer was dried over sodium sulfate anhydrate, and the solvent was evaporated to dryness. The residue was recrystallized from ethyl acetate, to thereby yield the target product (yield: 974 mg, 30%).
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH:19]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20](O)=[O:21])=[C:17]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:16]3=[N:15]2)=[CH:10][CH:9]=1.CO.O>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]([CH:19]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:20][OH:21])=[C:17]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:16]3=[N:15]2)=[CH:12][CH:13]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.8 %

Procedure:
Borane-tetrahydrofuran complex (920 ul, 920 umol; 1 M solution in THF) was added to an ice cold solution of [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (143 mg, 370 umol; example 9.3) in THF (1.5 ml). The solution was stirred at ambient temperature for 14 h and cooled to 0° C. Methanol (1.5 ml) and water (1.5 ml) were added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, the residue was dissolved in methanol (4.5 ml) and heated under reflux conditions for 30 min. The solvent was removed under reduced pressure and the residue purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (70 mg, 188 umol; 51%) as colorless oil. MS: m/e=373.2 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.C1(C)CCC(C(C)C)C(S(O[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)(=O)=O)C1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:43][C:42]([F:44])([F:45])[C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)[CH:41]=[CH:40][CH:39]=1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: CC1CCC(C(C)C)C(S(=O)(=O)OCCc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)c1
Temperature: 65 °C

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (6.15 g, 0.023 mole), 2-(3-trifluoromethylphenyl)ethyl menthanesulfonate (7.27 g, 0.027 mole) and K2CO3 (10.6 g) in 125 ml dimethylformamide was heated at 65° C. for 5 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])C=[CH:7][C:8]=1[O:9][CH3:10].ClC([O:15]C)Cl.Cl[Sn](Cl)(Cl)Cl.Cl[CH:23](Cl)[CH3:24].Cl>ClCCl>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:11]=[O:15])=[C:23]([CH3:24])[CH:7]=1
Reactant: COc1ccc(C)cc1OC
Reactant: COC(Cl)Cl
Reactant: CC(Cl)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-dimethoxytoluene (15 g) and dichloromethylmethyl ether (34.5 g) in dichloromethane (200 ml), at 0° C., was added SnCl4 (100 ml) and, subsequently, further dichloroethane (200 ml). The resultant suspension was stirred at 0° C. for 20 minutes and then stirred overnight at ambient temperature before being poured into 3N HCl (500 ml) at 0° C. Extraction into dichloromethane, drying of the organic phase and evaporation gave 4,5-dimethoxy-2-methylbenzaldehyde (15.2 g); NMR (CDCl3) 2.6(s,3H); 3.90(s,3H); 3.94(s,3H); 6.68(s,1H); 7.3(s,1H); 10.2(s,1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]=[C:32]([O:35][CH3:36])[NH:31][C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]=[C:32]([O:35][CH3:36])[N:31]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2[nH]1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2n1Cc1ccccn1
Reaction time: 28 h
Yield: 43.4 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazole (100 mg) and 2-chloromethylpyridine hydrochloride (29 mg) in N,N-dimethylformamide (2 ml) was added potassium carbonate (93 mg) at ambient temperature, and the mixture was stirred for 28 hours at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol=12:1, V/V; chloroform:methanol=12:1, V/V) to give 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-pyridylmethyl)-1H-benzimidazole (50 mg) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:26][CH:27]([CH3:36])[CH2:28][C:29](=O)[C:30](OCC)=[O:31].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[NH:15][C:30](=[O:31])[C:29]([CH2:28][CH:27]([CH3:36])[CH3:26])=[N:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(C)C
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Cc1nc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]c1=O
Reaction time: 4 h
Yield: 12.6 %

Procedure:
To a stirred and cooled (0° C.) solution of 9.1 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine in 80 parts of acetic acid and 20 parts of water were added portionwise 5.8 parts of ethyl 4-methyl-2-oxopentanoate. Upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into 100 parts of water and the whole was neutralized with a sodium hydroxide solution 3N. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off (the filtrate was set aside) and dried, yielding 1.5 parts (12.6%) of 6-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]-3-(2-methylpropyl)-2(1H)-quinoxalinone; mp. 209.7° C. (comp. 178)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:30])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][C:17]=3[F:29])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].Br[CH2:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=1)=[O:34]>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:30])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][C:17]=3[F:29])[N:10]([CH2:32][C:33](=[O:34])[NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(C(=O)N4CCCC4)cc3F)nc12
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Product: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(C(=O)N3CCCC3)cc1F)n2CC(=O)Nc1ccc(Cl)cn1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester was prepared by a procedure according to example 36 (ii) starting from 40.0 mg (0.10 mmol) 2-[2-Fluoro-4-(pyrrolidine-1-carbonyl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester and 29.2 mg (0.12 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester as a colorless amorphous solid.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:7]=[C:6](O)[N:5]([CH3:9])[N:4]=1.CN(C)[CH:13]=[O:14].P(Cl)(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][C:6]1[N:5]([CH3:9])[N:4]=[C:3]([CH:2]([F:10])[F:1])[C:7]=1[CH:13]=[O:14]
Reactant: Cn1nc(C(F)F)cc1O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)c(C=O)c1Cl

Procedure:
To a solution of 137.5 g (929 mmol) of 3-(difluoromethyl)-1-methyl-1H-pyrazol-5-ol in 136 ml (1858 mmol) of dimethylformamide and 750 ml of toluene was added dropwise with cooling 571 g (3716 mmol) of phosphoryl chloride. The mixture was heated for 3 hours under reflux and allowed to cool, and the reaction mixture wash carefully poured into 41 of ice water. The product was extracted three times, each time with 1500 ml of ethyl acetate, and the combined organic phases were washed twice with saturated sodium bicarbonate solution and finally with saturated sodium chloride solution, dried over sodium sulphate and concentrated. 138 g (with a purity of >99% (GC)) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (II-1) in the form of a yellow-brown solid was obtained, which was used without further purification in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[C:12]([NH:15]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=[C:10]([CH:35](OCC)[O:36]CC)[N:9]=2)=[C:4]([F:42])[C:3]=1[O:43][CH3:44].S(=O)(=O)(O)O.C(Cl)Cl>C(#N)C.O>[NH2:15][C:12]1[C:13]([F:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:43][CH3:44])[C:4]=2[F:42])[N:9]=[C:10]([CH:35]=[O:36])[CH:11]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C=O)cc(N)c2F)c1F

Procedure:
In a typical reaction, 2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine is treated with a 1 M (molar) solution of sulfuric acid in a mixture of acetonitrile-water. The mixture is heated at reflux until the reaction is complete. The mixture is added to methylene chloride, and the organic layer is separated, washed with brine and dried. The solvent is evaporated to provide crude 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].[N+:20]([O-])([OH:22])=[O:21].O>C(OC(=O)C)(=O)C>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 97 %

Procedure:
To a suspension of 4′-cyano-p-toluenesulfonanilide (1153 g (4.23 mol) in acetic anhydride (2306 ml), fuming nitric acid (294.3 g (4.53 mol) was added dropwise, keeping the temperature at 50° C. with stirring, over a period of 100 minutes. After completion of the addition, the reaction mixture was stirred at 50° C. for 1.5 hours. Then, 1.75 ml (0.042 mol) of fuming nitric acid was further added and stirring was continued for another one hour at 50° C. To the resulting mixture, after being left to cool to room temperature, water (7000 ml) was then added to make crystals to deposite. After stirring under cooling with ice for one hour, the crystals were filtered and washed with water to give 1305 g (97%) of 4′-cyano-2′-nitro-p-toluenesulfonanilide as yellow crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:14][CH2:11][C:12]#[CH:13])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 26.6 g (189 mmol) of 4-fluoronitrobenzene, 20.8 g (377 mmol) of propargylamine, 11 g (189 mmol) of potassium fluoride, and 26 g (188 mmol) of potassium carbonate in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere for twenty hours. The reaction mixture is poured into 1.5 l of water and stirred at room temperature for two hours. The yellow solid is filtered, rinsed with water, and then isopropyl alcohol. The product is dried in vacuo at 50° C. for two days to give 16.27 g (49%) 4-nitro-N-2-propynylbenzenamine; mp 150°-153° C.