Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)#[N:2].[C:11]1(=[O:18])[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][C:24](=[NH:26])[NH2:25])[CH3:20]>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:1]#[N:2])[C:12]2[C:11](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=2[NH:25][C:24]=1[NH2:26])=[O:27])[CH3:20]
Reactant: N#Cc1ccccc1C=O
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1ccccc1C#N
Yield: 49 %

Procedure:
Upon heating a solution of 6.5 g of 2-cyanobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 5 hours, 2-amino-4-(2-cyanophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 165°C (ethanol) is obtained. Yield: 49% of theory.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:29]=[CH:28][C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([C:23](O)=[O:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH3:30])=[O:6])[CH2:3][CH2:2]1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:26][CH3:27])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[CH:28]=[CH:29][C:8]([NH:7][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])=[C:9]([CH3:30])[CH:10]=1)=[O:24]
Reactant: COCCN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(C)c3)c2cc1C(=O)O
Product: COCCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(C)c3)ccnc2cc1OC
Yield: 49.73 %

Procedure:
4-(4-((Cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylic acid (30 mg, 0.0736 mmol) and 2-methoxyethylamine (0.0123 ml) were used for reaction in the same manner as Example 458, and after purification by NH silica gel column chromatography (ethyl acetate:methanol=10:1), the obtained crystals were suspended in acetone:diethyl ether=1:5, filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (17 mg, 0.0366 mmol, 49.73%) as light yellow crystals.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][O:14][C@@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:20][C@H:17]([O:18][CH3:19])[C:16]1=[O:33].O>CCOCC>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][O:14][C@@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:20][C@H:17]([O:18][CH3:19])[C@:16]1([CH2:2][CH3:1])[OH:33]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: O
Solvent: CCOCC
Product: CC[C@]1(O)[C@@H](OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To diethyl ether (300 mL) at −78° C. was slowly added EtMgBr (3.0 M, 16.6 mL) and then dropwise the compound from Step B of Example 2 (4.80 g, 10.0 mmol) in anhydrous Et2O (100 mL). The reaction mixture was stirred at −78° C. for 15 min, allowed to warm to −15° C. and stirred for another 2 h, and then poured into a stirred mixture of water (300 mL) and Et2O (600 mL). The organic phase was separated, dried (MgSO4), and evaporated in vacuo. The crude product was purified on silica gel using ethyl acetate/hexane (1:2) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (3.87 g) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC2CCN(C)CC2)cc1

Procedure:
1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-methoxybenzylamine (1.37 g, 1.0 eq.).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]2)=[C:8]([Cl:18])[CH:7]=1)[CH3:5].[OH-].[K+].O>C(O)C>[Cl:18][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:19])=[O:2])[CH:11]=[CH:10][C:9]=1[N:12]1[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13]1
Reactant: COC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Yield: 94.7 %

Procedure:
3.0 g (10 mmoles) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid methyl ester, 1.4 g of potassium hydroxide, 1.5 ml of water and 20 ml of ethanol are heated to the boil for 2 hours, the alcohol is distilled off, water is added and extraction with benzene is effected. This is followed by clarification of the aqueous phase with activated charcoal and acification with 2 N hydrochloric acid to produce 2.7 g (95% of theory) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)-phenyl]propionic acid (m.p. 102° to 103° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[C:20]([F:25])[N:19]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:10][C:22]2[CH:21]=[C:20]([F:25])[N:19]=[C:18]([F:17])[CH:23]=2)[CH:3]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(O)cc(Cl)c1
Reactant: Fc1cc(F)nc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2cc(F)nc(F)c2)c1
Temperature: -50 °C

Procedure:
Compound 1-4 (577 mg; 3.76 mmol) and potassium carbonate (779 mg; 5.64 mmol) were added to a solution of 2,4,6 trifluoropyridine (500 mg; 3.76 mmol) in DMF with stirring at −50° C. The reaction mixture was slowly warmed to room temperature and then diluted water and EtOAc, after which the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water (3×), brine (2×), dried over MgSO4, and concentrated to an oil. The crude residue was purified via column chromatography (0-25% EtOAc in hexanes.) to give the title compound. MS M+1=266.9. 1H NMR (CDCl3): 6.32 (m, 2H), 7.30 (m, 1H), 7.36 (m, 1H), 7.56 (m, 1H).
Reaction SMILES: [Cl: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.C[O:15][C:16]([CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[S:27](Cl)(=[O:29])=[O:28])[CH2:19]1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:27]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:25]=3[CH2:26][CH:18]([C:16]([OH:17])=[O:15])[CH2:19]4)(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Product: O=C(O)C1Cc2cccc(S(=O)(=O)N3CCN(c4ccc(Cl)cc4)CC3)c2C1

Procedure:
The compound 4-[4-(4-chloro-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 1-(4-chloro-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): 7.58 (d, 1H), 7.56 (d, 1H), 7.43 (t, 1H), 7.23 (d, 2H), 6.92 (d, 2H), 3.50-3.41 (m, 2H), 3.40-3.29 (m, 1H), 3.28-3.13 (m, 6H), 3.12-3.04 (m, 4H); MS (ESI): 420.9 (M+H).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[F:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([I:20])=[CH:19][C:13]=2[F:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1c(F)cncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
25 g 3,5-difluoroisonicotinic acid (157.141 mmol, 1 eq.) and 37,245 g 2-fluoro-4-iodoaniline (157.141 mmol. 1 eq.) were dissolved in 1275.5 mL of dry THF and put under a nitrogen atmosphere. The mixture was cooled with an ice bath to +3° C., upon which 471.422 mL lithium hexamethyldisilazide (LiHMDS) solution (1M in THF; 471.422 mmol, 3. eq.) were added slowly. Upon completion of addition of the base, the reaction mixtures was allowed to warm to rt and stirring was continued for 18 h. The reaction mixture was concentrated in Vacuo and then partitioned between aq. sodium hydroxide solution (2N, 800 ml) and dichloromethane. The separated organic phase was washed twice with sodium hydroxide solution (2N, 300 ml each). The combined aqueouse layers were cooled to 0° C. and treated with HCl (conc., 222 ml) until ph=2 was reached. The resulting yellow suspension was stirred for 18 h at room temperature and then the precipitate was filtered off to yield 5.15 g (13.01 mmol, 8%) of the analytically pure target compound as a tanish solid. The organic filtrate formed a suspension as well. This precipitate was filtered off as well and rinsed twice with dichloromethane. The precipitate was suspended in water (400 ml), cooled to 0° C. and treated with HCl (conc., 20 ml) until ph=1 was reached. The resulting yellow suspension was stirred for 18 h at room temperature and then the precipitate was filtered off to yield 28.27 g (71.41 mmol, 45%) of the analytically pure target compound as a yellowish solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[Cl:12].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][Cl:23])=[CH:7][C:6]=1[Cl:12]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: O=C(Cl)CCCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)CCCCl)cc1Cl
Reaction time: 4 h

Procedure:
To a solution of 4-amino-2-chlorobenzoic acid methyl ester hydrochloride (0.52 g) and DIEA (0.27 mL) in CH2Cl2 (20 mL) at 0° C. under N2 was added 4-chlorobutyryl chloride (0.3 mL) and the mixture was stirred for 4 h at that temperature. DMAP (0.23 mmol) was added and the mixture was stirred at room temperature overnight. 4-Chlorobutyryl chloride (0.3 mL) and DIEA (0.09 mL) were added and the mixture was stirred for 24 h. The mixture was diluted with CH2Cl2 (100 mL) and the solution was washed successively with 1N HCl, std. NaHCO3, brine, dried and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 3:1) to yield 4-(4-chlorobutyryl)amino-2-chlorobenzoic acid methyl ester (0.64 g). ESMS: m/z 290 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.[OH:15][OH:16].CS(O)(=O)=[O:19]>>[C:8]([O:10][OH:19])(=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:3]([O:15][OH:16])=[O:2])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)O
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: OO
Product: O=C(OO)c1ccc(C(=O)OO)cc1
Reaction time: 2 h

Procedure:
10 g (51.5 m mols) terephtalic acid dimethylester was dissolved in 100 g methane-sulfonic acid under agitation at room temperature. The solution was cooled to 15° C., whereupon 15 g (0.309 mol) 70% hydrogen peroxide was added by drops under agitation. The temperature was increased and kept at 50° C. for 2 hours. The product was cooled to 0°-10° C., whereupon the solid particles were filtered off, washed with 4×30 ml ice-water and dried in a desiccator until constant weight.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[I:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([N:24]3[CH:25]=[C:21]([I:20])[N:22]=[CH:23]3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.7) (1.97 g, 6.0 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as an off-white solid (2.67 g, 92%). MS (ISP) 485.1 [(M+H)+]; mp 223° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][CH2:39][N:40]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:49]=[N:50][C:44]=3[NH:43][C:42](=[O:56])[CH2:41]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13])[C:53](=[O:54])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[CH2:41][N:40]([CH2:39][CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:46][C:45]=2[CH:47]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Reactant: CNCc1c(C)oc2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Yield: 68 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(2-methyl-benzofuran-3-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(3-morpholin-4-yl-propyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.24 g, 68%) was prepared as a white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.86 (br s, 1H), 10.47 (br s, 1H), 8.54 (br s, 1H), 8.38-8.29 (m, 1H), 7.78-7.46 (m, 3H), 7.32-7.15 (m, 3H), 4.97-4.74 (m, 2H), 4.02-3.91 (m, 5H), 3.87-3.79 (m, 4H), 3.63 (br s, 2H), 3.45-3.29 (m, 4H), 3.27-3.15 (m, 4H), 3.07-2.82 (m, 3H), 1.93 (br s, 2H); MS (ESI) m/e 518 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Si:26]([O:25][CH2:24][CH2:23][N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:3][C:2]([CH3:21])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:14][CH:13]=2)[CH2:20][CH2:19]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)cc2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(N3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)cc2)OC1(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (0.1 g, 0.5 mmol, from Boron Molecular), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.18 g, 0.75 mmol) and cesium carbonate (0.32 g, 1.0 mmol) in acetonitrile (2.0 mL) was stirred at 40° C. overnight. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-30%) to afford the desired product (0.2 g, 88%). LCMS calculated for C24H44BN2O3Si (M+H)+: m/z=447.3. Found 447.3.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].Cl[C:37](OCC)=O>>[C:2]1([CH3:37])[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]2[CH2:23][CH2:24][N:25]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: CCOC(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)Nc3ccccc3C)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid o-tolylamide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and butyryl chloride for ethyl chloroformate. Wt.: 29 mg (33%). 1H NMR (300 MHz, CDCl3) δ 8.66 (d, 1H), 8.45 (d, 1H), 8.34 (d, 1H), 8.04 (d, 1H), 7.78 (d, 1H), 7.71 (m, 2H), 7.60 (s, 1H), 7.30 (m, 2H), 7.20 (m, 2H), 4.75 (d, 1H), 4.29 (d, 1H), 3.66 (d, 1H), 3.31 (m, 1H), 2.95 (m, 1H), 2.60 (m, 1H) 2.34 (s, 3H), 2.20 (m, 2H), 1.70 (m, 2H), 1.23 (m, 3H), 0.89 (t, 3H); LC/MS m/z 492 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[N:20][CH:21]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
1 g of methyl 6-chloronicotinate was reacted via Procedure O to yield methyl 6-(methylsulfonyl)nicotinate. 1 g of methyl 6-(methylsulfonyl)nicotinate was hydrolyzed via Procedure M to give 6-(methylsulfonyl)nicotinic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(methylsulfonyl)nicotinic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonyl)nicotinamide.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([O:24]C4C=CC=CC=4)=O)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(#N)C>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:24])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)Oc3ccccc3)nc2n1
Solvent: CC#N
Product: Cc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)N3CCN(C)CC3)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
Following the procedure of Example 11 but starting with 2-(7-methyl-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (4.9 g.) and 4-methylpiperazine (6 g.) in acetonitrile (40 cc.) and stirring the reaction mixture for 24 hours at 25° C., a crude product (4.2 g.) is obtained. This product is triturated in diethyl ether (42 cc.) and then recrystallised from diisopropyl ether (300 cc.). 2-(7-Methyl-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (1.1 g.), melting at 190° C., is thus obtained.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccc(Cl)cc21
Reaction time: 6 h
Yield: 60.4 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 273 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3.11 g, 2.1 mL, 27.3 mmol) at 20° C. After 6 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (5 mL) and ethylenediamine (1.23 g, 1.38 mL, 20.5 mmol) added. The mixture was stirred for 15 h, then concentrated in vacuo. The residue was triturated with water and the solid obtained by filtration. Purification by chromatography (silica, 25 g pre-packed SiliCycle cartridge, 0-5% methanol in dichloromethane gradient increasing over 15 min) gave N-tert-butyl-2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (63 mg, 165 μmol, 60%) as a pale yellow powder. MS (M+Na)+=405; 1H NMR (CDCl3) δ: 11.84 (br. s., 1H), 9.05 (s, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.14 (d, J=3.4 Hz, 1H), 7.96 (s, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.08 (dd, J=8.5, 1.7 Hz, 1H), 4.04 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C(#N)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:21][CH:18]2[CH2:20][CH2:19]2)=[C:3]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:4]2=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (950 mg, 0.0037 mole) in acetonitrile, cyclopropyl amine (0.525 ml, 0.0074 mole) was added. After stirring for about 2 hours at 110° C., acetonitrile was removed under reduced pressure. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give light yellow solid compound. Yield: 1 g. m/z: (M++1) 275.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Si:25]([O:15][C@H:13]1[CH2:14][N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]#[N:9])=[CH:5][N:4]=2)[C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1c1ncc(C#N)cc1Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1c1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of methyl (2S,4R)-1-(3-chloro-5-cyanopyridin-2-yl)-4-hydroxypyrrolidine-2-carboxylate (0.270 g; 0.96 mmol) and imidazole (0.098 g; 1.44 mmol) in DMF (3 mL) was added tert-butyl dimethylsilylchloride (0.159 g; 1.05 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. Further imidazole (0.049 g; 0.72 mmol) and tert-butyldimethylsilyl chloride (0.080 g; 0.53 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The organic phase was poured through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (6:1) to afford the title product (0.311 g, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.16 (1H, d, J=2 Hz), 7.57 (1H, d, J=2 Hz), 4.79 (1H, t, J=8 Hz), 4.46-4.44 (1H, m), 4.17-4.13 (1H, dd, J=11.2, 4.8 Hz), 3.77-3.74 (1H, m), 3.63 (3H, s), 2.15 (1H, m), 1.96 (1H, m), 0.79 (9H, s), 0.14-0.02 (6H, m).