Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([C:18]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19]1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:16][C:18]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19]2)[CH2:13][CH2:14]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COC(=O)C1(C=O)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a stirred mixture of tert-butyl(piperidin-4-ylmethyl)carbamate (12.8 g, 60 mmol) and methyl 1-formylcyclobutanecarboxylate (2.13 g, 15 mmol, Davis, Charles R.; Swenson, Dale C.; Burton, Donald J., J. Org. Chem., 1993, 58, 6843) in tetrahydrofuran (50 mL) was added acetic acid (8.6 mL, 150 mmol) at ambient temperature. After 30 min, sodium triacetoxyborohydride (12.7 g, 60 mmol) was added to the mixture. Then, the mixture was heated to 60° C. for 2 h. After cooling, the reaction mixture was poured into sat. NaHCO3 aq. The aqueous layer was extracted with CH2Cl2 for 3 times. The combined organic phase were washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (1:1) to give 4.25 g (83%) of the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH2:7][C:6]=2[CH:14]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:18][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:14]=1
Reactant: O=C(O)C1CCc2cc(Cl)ccc2O1
Reactant: C=CCN
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=CCNC(=O)C1CCc2cc(Cl)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.1 g of 6-chloro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (1A) (Witiak et al. (1971), supra) in 15 ml of thionyl chloride was refluxed for 45 minutes. The excess thionyl chloride then was stripped off and the residual liquid taken up in 50 ml of methylene chloride. To this stirred solution was added dropwise a solution of 2.5 g of 2-propenamine in 10 ml of methylene chloride. The resulting mixture was stirred at room temperature overnight, then was washed with water, dried (MgSO4) and stripped of solvent. Dry column chromatography of the solid product through silica gel, using Solvent No. 3 (a 4:30:66 by volume mixture of tetrahydrofuran, ethyl acetate and hexane) as eluent, followed by recrystallization of the product from ethylene chloride and hexane gave 1, as a pale yellow solid, mp: 112.5°-114° C. Example 2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][N:12]([C:20](Cl)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH2:39])[C:35]([CH3:40])=[N:34]1>C(N(CC)CC)C>[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH:39][C:20]([N:12]2[CH2:13][CH:14]([CH2:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:31])[CH:11]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])=[O:21])[C:35]([CH3:40])=[N:34]1
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Cc1nn(C)cc1CN
Solvent: CCN(CC)CC
Product: Cc1nn(C)cc1CNC(=O)N1CC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 9, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonylchloride prepared in Example 8 (57 mg, 0.12 mmol) was reacted with C-(1,3-dimethyl-1H-pyrazol-4-yl)methylamine (Oakwood) (22 mg, 0.18 mmol) and triethylamine to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amide as a white solid (Yield, 19 mg, 28%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([O:19][C:12]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([CH3:9])[CH:11]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)ncn2)ccc1[N+](=O)[O-]

Procedure:
0.40 g (2.68 mmol) 4,6-dichloropyrimidine, 0.42 g (2.74 mmol) 3-methyl-4-nitrophenol and 0.40 g (2.89 mmol) potassium carbonate in 2.0 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17](Cl)(=[O:19])=[O:18])=[CH:3]1.[CH3:21][NH:22][CH3:23]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17]([N:22]([CH3:23])[CH3:21])(=[O:19])=[O:18])=[CH:3]1
Reactant: CNC
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(C(F)(F)F)cc21
Product: CN(C)S(=O)(=O)c1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Reaction time: 27 h

Procedure:
1-Methyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-sulphonyl chloride (12.4 g) was added to a stirred solution of dimethylamine in industrial methylated spirit (33% w/w; 230 ml) and the mixture was kept at ambient temperature for 27 hours. The mixture was evaporated to dryness and the residue was recrystallised from industrial methylated spirit using charcoal to give the novel compound 1,N,N-trimethyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-sulphonamide, m.p. 221°-223°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](\[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)/[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: COc1cc(/C(C#N)=C\c2ccc(C)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc(/C(C#N)=C\c2ccc(C)c(N)c2)cc(OC)c1OC
Reaction time: 1 h
Yield: 78 %

Procedure:
84 mg of (E)-3-(3-nitro-4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-ene-nitrile was dissolved in 8 ml of acetic acid then zinc was added to the mixture. The mixture was stirred vigorously for 1 hour then filtered and concentrated. The residue was purified on a silica gel plate (dichloromethane) to give 60 mg of the intended compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: Cn1ccnc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1ccnc1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Yield: 83.5 %

Procedure:
Add 4-(N-tert-Butoxycarbonyl-aminomethyl)phenylboronic acid (1.9 g, 7.4 mmol), 2-bromo-1-methyl-1H-imidazole (800 mg, 5.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (287 mg, 0.25 mmol) and potassium carbonate (860 mg, 6.2 mmol) to a flask containing toluene (10 mL). Heat the mixture in a sealed flask at 90° C. for 16 h. Cool the mixture, dilute with EtOAc (50 mL), filter through Celite®, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc/methanol (49:50:1) to obtain the desired intermediate (1.2 g, 83%). GC-MS m/z: 287 (M+).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH2:54])[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:54][CH2:53][CH2:52][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN1CCN(CCN)CC1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NCCN5CCN(C)CC5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 2-(4-methylpiperazin-1-yl)-ethanamine as the aniline component. (17%, MS=633.4 (M+H))
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:31][CH3:32])(=O)=O.C(OCC)C>CN(C)C=O>[O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH2:31][CH3:32])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
5.36 g of 3-(4-phenoxybenzoyl)acrylic acid were dissolved in 30 ml of dimethylformamide, and then 1.36 g of potassium carbonate and 3.08 g of diethyl sulfate were added. The mixture was stirred at room temperature for 3 hours. Diethyl ether was added to the reaction mixture, which was then washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed by evaporation under reduced pressure. The residue was purified first by silica gel column chromatography, eluted with a mixture of hexane and diethyl ether, then by recrystallization from hexane to give 4.36 g of ethyl 3-(4-phenoxybenzoyl)acrylate.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[N:85]1[CH2:90][CH2:89][N:88]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][CH2:86]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[N:85]1[CH2:86][CH2:87][N:88]([C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:89][CH2:90]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Yield: 85 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (product of step 1 of example 114) (120 mg, 0.165 mmol) was hydrolyzed with lithium hydroxide (35 mg, 0.827 mmol) in THF/methanol/water (5/5/2 mL) to afford 80 mg (85% yield) of the titled compound. MS: m/z=571.6 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[N:9]O)[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=NO)c12
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C#N)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde oxime (165 mg, 0.352 mmol) was taken up in DCM (6 ml) and triphenylphosphine (92 mg, 0.352 mmol) was added, followed by iodine (89 mg, 0.352 mmol). The resulting mixture was stirred at room temperature overnight. Saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (0-25% EtOAc-hexanes) gave 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbonitrile (42B). 1H NMR (500 MHz, DMSO-d6) δ 7.37 (m, 9H), 7.13 (m, 6H), 5.89 (s, 1H), 3.40 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6](=[O:9])[CH:7]=[CH2:8])[CH2:2]C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([N:5]2[CH2:1][CH2:2][CH:8]=[CH:7][C:6]2=[O:9])=[CH:15][CH:14]=1
Reactant: C=CCCN(C(=O)C=C)c1ccc(OC)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: COc1ccc(N2CCC=CC2=O)cc1
Temperature: 40 °C
Yield: 99.7 %

Procedure:
To a solution of N-but-3-en-1-yl-N-(4-methoxyphenyl)acrylamide (180 mg, 0.78 mmol) in degassed methylene chloride (200 mL) was added Grubbs catalyst (32 mg, 0.039 mmol) and the mixture was heated to 40° C. overnight. All volatiles were removed and the resulting material was subjected to flash chromatography (Hexanes:EtOAc 1:1) to yield 1-(4-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one (158 mg, 98%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.NC(N)=[S:27].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[C:16]1([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=1[C:10]1[C:9]([CH3:20])=[N:8][N:7]2[C:2]3[S:27][CH2:23][CH2:22][C:3]=3[C:4]([CH3:21])=[N:5][C:6]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCS4)c(C)c1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (500 mg, 1.38 mmol), thiourea (105 mg, 1.38 mmol) and sodium carbonate (180 mg, 1.73 mmol) in ethanol (10 mL) was heated under reflux for one hour. After overnight, water was added and the resulting crystals were collected by filtration. The crystals were washed with water, to give the title compound (436 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[C:13]2[S:17][CH3:18])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.Cl.[CH2:21]([O:23][CH2:24][CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[N:35]1[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][C@:44]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:48][CH2:47][NH:46][CH2:45]2)[CH2:37][CH2:36]1)[CH3:22].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:21]([O:23][CH2:24][CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[N:35]1[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][C@:44]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:48][CH2:47][N:46]([C:5]([C:4]3[CH:8]=[C:9]([N:12]4[CH:16]=[N:15][N:14]=[C:13]4[S:17][CH3:18])[CH:10]=[CH:11][C:3]=3[O:2][CH3:1])=[O:7])[CH2:45]2)[CH2:37][CH2:36]1)[CH3:22]
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnc2SC)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnc5SC)ccc4OC)C3)CC2)nc2ccccc21
Yield: 17.1 %

Procedure:
To a mixture of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid (0.27 g, 0.42 mmol), 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.23 g, 0.42 mmol), 1-hydroxybenzotriazole hydrate (0.068 g, 0.51 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.97 g, 0.51 mmol), add via syringe under argon anhydrous dichloromethane (15 mL). Add diisopropylethylamine (0.22 mL, 1.26 mmol) and stir at room temperature for 20 hours. Dilute with dichloromethane and wash twice with water. Wash with saturated NaHCO3 solution, dry (MgSO4) the organic phase, filter and concentrate to an oil. Purify the oil by flash chromatography (silica gel, 3.5×15.2 cm) eluting with dichloromethane and then with 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.051 g of the title compound, Rf=0.26 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)#[N:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[CH2:2])#[N:7]
Reactant: [Li]CCCC
Reactant: N#Cc1cccc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (75 g, 209.71 mmol) in dry THF (750 mL) at 0° C. under nitrogen was added dropwise n-BuLi (83 mL, 2.5 M in hexanes, 207.50 mmol). The mixture was warmed to room temperature. 3-Cyanobenzaldehyde (25 g, 190.65 mmol) was added as a solid in 5 g batches, and the mixture was stirred at room temperature overnight. The reaction was quenched in water, and the solvent was removed under vacuum. The residue was dissolved in the minimal amount of THF, and triphenylphosphine oxide was precipitated using ether. The solid was filtered through diatomaceous earth, and the filtrate was concentrated. Distillation by Kugelrhor at 90° C./33 Pa (0.25 mm Hg) gave the product as a colorless oil (15.5 g, 62%).
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[OH-].[Na+]>CCOC(C)=O>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[CH2:2][C:1]([OH:7])=[O:12])=[O:6])=[CH:16][CH:15]=1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 47.7 %

Procedure:
A solution of homophthalic anhydride (4.0 g, 24.7 mmol) in 250 mL of CHCl3 was treated with 4-chloroaniline (3.31 g, 25.9 mmol). After 16 h, the mixture was poured into EtOAc and 1 N NaOH. The aqueous layer was washed with EtOAc, then brought to a pH of 2-3 by addition of 1 N HCl. The aqueous layer was washed with EtOAc (2×), and the combined extracts were dried (MgSO4) and concentrated. Recrystallization of the residue from EtOAc/hexanes yielded 3.41g (48%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:25]([NH2:27])=[O:26])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34].C(O)C(N)(CO)CO.CCOC(C)=O>N1C=CC=CC=1>[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH:1][C:2]1[CH:29]=[CH:28][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:25]([NH2:27])=[O:26])=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]([S:19]([N:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])=[CH:17][CH:18]=4)[C:12]=3[C:4]=2[CH:3]=1)=[O:34]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Agent: NC(CO)(CO)CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Reaction time: 14 h
Yield: 44.1 %

Procedure:
To a stirred solution of 8-amino-1-{4-[(dimethylamino)sulfonyl]phenyl}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (Example 46) (1.52 g, 3.70 mmol) in pyridine (25 mL) at RT was added 2-chlorobenzoic chloride (970 mg, 5.55 mmol). After 14 h, trisamine (1 g) was added and the mixture was stirred for 2 h. The mixture was filtered through a silica gel pad with EtOAc and concentrated. Column chromatography (silica gel, EtOAc) gave the title compound as a yellow solid (900 mg, 1.63 mmol, 44%). Its structure was confirmed by 1H NMR and MS (551, M+1). C27H24ClN5O4S, Calc.: C: 58.96; H: 4.40, N: 12.73; Found, C: 58.66; H: 4.65, N: 12.58.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH:9]=[O:10])=[CH:3][CH:2]=1.[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12]>>[CH2:11]([O:13][CH:14]1[CH2:15][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:9][O:10]1)[CH3:12]
Reactant: O=C/C=C/c1ccccc1
Reactant: C=COCC
Product: CCOC1CC(c2ccccc2)C=CO1

Procedure:
treating cinnamic aldehyde with ethyl vinyl ether to afford 2-ethoxy-4-phenyl-3,4-dihydro-2H-pyran, hydrogenating the resulting product to afford 3-cyclohexylpentane-1,5-diol and finally heating the above diol in the presence of a dehydrogenation catalyst to afford 3-cyclohexyl-pentanolide; or