Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].C1(C(C2C=CC=CC=2)=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])C=CC=CC=1.[CH3:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([Cl:32])=[O:31].Cl>C1COCC1>[ClH:32].[NH2:14][CH:15]([C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[CH3:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(=O)c1ccccc1C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Under nitrogen, 4.2 g (0.038 mol) of potassium tert-butoxide were suspended in THF. The mixture was cooled to −78° C., and 10.0 g (0.037 mol) of ethyl N-(diphenylmethylene)glycinate, dissolved in THF, were added dropwise. After 40 min at −78° C., the solution was transferred into a cooled dropping funnel (−78° C.) and added dropwise to a solution, cooled to −78° C., of 2-methylbenzoyl chloride in THF. After 1 h of stirring at −78° C., the reaction mixture was allowed to warm to 0° C. over a period of 2 h. The mixture was hydrolyzed using 10% strength hydrochloric acid, and stirring was continued. The solvents were removed and the residue was taken up in water and washed with MTBE. The aqueous phase was concentrated, methanol was added to the residue and the mixture was filtered. Concentration of the filtrate gave 6.2 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[CH2:15]([NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: C1CCOC1
Product: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 50.0 g (0.24 mole) of 4-chloro-3-nitroquinoline in 300 ml of tetrahydrofuran was added, in small portions, 52.7 g (0.72 mole) of isobutylamine. The mixture was heated at its reflux temperature for one hour and was then evaporated in vacuo. Water was added to the residue, and the solid was separated by filtration. The solid was suspended in one liter of water, and was dissolved by the gradual addition of concentrated hydrochloric acid (to pH 3 to 4) followed by filtration of the solution. The filtrate was basified (to pH 9 to 10) by the addition of concentrated ammonium hydroxide to provide bright yellow 4-(isobutylamino)-3-nitroquinoline, m.p. 119°-121° C. The structural assignment was supported by infrared spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[N:6][CH:7]=1.C1C(=O)N([Br:18])C(=O)C1>CC#N>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[N:6][C:7]=1[Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(CCO)cn1
Solvent: CC#N
Product: Nc1ncc(CCO)nc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-aminopyrazin-2-yl)ethanol (30 mg, 0.216 mmol) in CH3CN (719 μL) was added NBS (38.4 mg, 0.216 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched by sat. NaHCO3, then extracted by EtOAc, The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo yielding crude 2-(5-amino-6-bromopyrazin-2-yl)ethanol which was used in next step reaction without purification. LCMS (m/z): 218.0/220.0 (MH+), 0.33 min.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:24]3[CH:23]=[CH:22][C:21]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:20]([F:19])[C:25]=3[F:26])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)cc1
Product: O=C(O)CCc1ccc(OCc2csnc2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-chlorophenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 2H), 7.66 (d, J=7.0 Hz, 2H), 7.43 (d, J=7.5 Hz, 2H), 6.84 (m, J=8.1 Hz, 1H), 6.64 (m, J=7.2 Hz, 1H), 2.95 (m, 2H), 2.68 (m, 2H).
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[CH:12][C:13](O)=[O:14])(=O)=O)=CC=1.ClC(N(C)C)=C(C)C.[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:29]=[CH:30][C:31]=1/[CH:32]=[CH:33]/[CH2:34][OH:35].CN(C)C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[N+:11](=[CH:12][C:13]([O:35][CH2:34]/[CH:33]=[CH:32]/[C:31]1[CH:30]=[CH:29][C:28]([NH:36][C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])=[CH:27][C:26]=1[F:25])=[O:14])=[N-:10]
Reactant: O=C(Nc1ccc(/C=C/CO)c(F)c1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NN=CC(=O)O)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of glyoxylic acid p-toluenesulfonylhydrazone (24 g, 0.10 mol, prepared as described by C. J. Blankley, F. J. Sauter and H. O. House, Organic Syntheses, Coll. Vol. V, p. 258; John Wiley, New York (1973)) in CH2Cl2 (600 mL) at 23° C. was added commercially available 1-chloro-N,N,2-trimethyl-1-propenylamine (15 mL, 0.114 mol, 1.14 equiv.) over 5 min. The reaction mixture was stirred at the same temperature for 40 min. The reaction mixture was then cooled to 0° C. and benzyl 3-fluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (23 g, 0.077 mol) was added in one portion followed by the addition of N,N-dimethylaniline (12 mL, 0.095 mol). After 30 minutes, triethylamine (53 mL, 0.385 mol) was added and the mixture stirred for 30 minutes at 0° C. and 15 minutes at room temperature. The reaction mixture was then concentrated to a volume of about 100 mL and 500 mL of water added. The mixture was extracted with two portions of diethyl ether and the combined organic solutions washed with saturated NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by column chromatography (0-25% ethyl acetate-hexane) provided the title compound as a yellow solid.
Reaction SMILES: CON(C)[C:4](=[O:28])[C@H:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:30][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[CH2:13]([O:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][C@@H:5]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C:4](=[O:28])[CH3:30])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -30 °C
Yield: 75 %

Procedure:
N-Methoxy-N-methyl-(R)-5-(Benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)-pentanamide (305) (10 g, 24 mmol) was dissolved in THF (250 mL) and the solution was cooled to −30° C. in a dry-ice acetone bath. MeMgBr (3M in Et2O, 123 mL, 369 mmol) was added drop-wise over 30 minutes. The bath temperature was slowly allowed to increase to 0° C. and then was maintained at 0° C. until TLC showed no further reaction progress (˜80-90% complete). Saturated NH4Cl (aq) was then slowly added to the reaction mixture at 0° C. and the THF was removed under reduced pressure. The resulting aqueous solution was then extracted with EtOAc and the extracts were washed with water and then brine. The residue was then purified by column chromatography (EtOAc/hexanes) to give (R)-6-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)-2-hexanone (306), (6.5 g, 18 mmol, 75% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1O.[Cl:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)=[O:14]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[N:15]([C:13](=[O:14])[CH2:12][Cl:11])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=1
Reactant: CCc1ccc(NC(=O)CCl)cc1
Reactant: Oc1c(F)ccc(F)c1F
Product: CCc1ccc(N(C(=O)CCl)c2c(F)ccc(F)c2F)cc1

Procedure:
Same procedure as example 6a, starting from 2,3,6-trifluorophenol and 2-chloro-N-(4-ethylphenyl)acetamide. The crude intermediate N-(2′,3′,6′-trifluorophenyl)-4-ethylaniline was roughly purified by filtration on silica using toluene as eluent.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCl>[CH2:16]([C:11]1([CH2:14][OH:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCC1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: OCC1(Cc2ccccc2)CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
1,4-Dibenzyl-4-hydroxymethyl-piperidine (1.0 g, 3.4 mmol) in dichloromethane (20 ml) are treated with 1-chloroethyl-chloroformate (0.48 ml, 4.3 mmol, dissolved in 1.5 ml dichloromethane) and the resulting solution is stirred at 0° C. for 30 min. The solvent is removed in vacuo and the resulting residue refluxed in methanol (20 ml) for 40 min. After removel of the volatile components in vacuo, the title compound is isolated by flash chromatography (silca, eluent dichloromethane/methanol/triethylamine (9:1:0.1, then 4:1:0.1 followed by 3:1:0.1)) as a brown resin in 40% yield. MS 206(M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][N:6]2[CH:13]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C1COCC1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][N:6]3[CH:13]=2)[CH2:26][CH2:27]1
Reactant: COc1ccc2nc(CCl)cn2c1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2nc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)cn2c1
Temperature: 75 °C
Yield: 47.7 %

Procedure:
A mixture of 2-(chloromethyl)-6-methoxyimidazo[1,2-a]pyridine (0.1392 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.1662 g), triethylamine (Aldrich; 0.11 mL), and THF (2 mL) is stirred at 75° C. until the reaction is complete by thin layer chromatography. The cooled mixture is concentrated under reduced pressure and partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and crystallized from ethyl acetate/ether to give 0.132 g of the title compound in two crops; mp 129.5-130.5° C.; MS m/z 390, 392; IR (mineral oil) 1479, 1166, 799, 1510, 1219 cm-1 ; 1H NMR (CDCl3) δ2.76, 3.08, 3.77, 3.81, 6.93, 6.97, 7.17, 7.34, 7.45, 7.49, 7.60.
Reaction SMILES: [Si]([CH2:17][CH2:18][NH2:19])(OCCOC)(OCCOC)OCCOC.[Si:20]([CH2:30][CH2:31][CH2:32][NH2:33])([O:27][CH2:28]C)([O:24][CH2:25]C)[O:21][CH2:22]C.[Si](CCCN)(OCCOC)(OCCOC)OCCOC.[Si](CCCOCCCN)(OCC)(OCC)OCC.[Si](COCCN)(OCC)(OCC)OCC.[Si](CCCOCCN)(OCC)(OCC)OCC.[Si](CCCN)(OC)(OC)OC>>[Si:20]([CH2:30][CH2:31][CH2:32][NH:33][CH2:17][CH2:18][NH2:19])([O:27][CH3:28])([O:24][CH3:25])[O:21][CH3:22]
Reactant: COCCO[Si](CCN)(OCCOC)OCCOC
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: CCO[Si](CCCOCCCN)(OCC)OCC
Agent: CCO[Si](CCCOCCN)(OCC)OCC
Agent: CCO[Si](COCCN)(OCC)OCC
Product: CO[Si](CCCNCCN)(OC)OC

Procedure:
(CH3OCH2CH2O)3Si(CH2)2NH2 ; (C2H5O)3Si(CH2)3NH2 ; (CH3OCH2CH2O)3Si(CH2)3NH2 ; (C2H5O)3Si(CH2)3O(CH2)3NH2 ; (C2H5O)2C6H5Si(CH2)3NH2 ; (C2H5O)3SiCH2O(CH2)2NH2 ; (C2H5O)3Si(CH2)3O(CH2)2NH2 ; (C2H5O)2CH3Si(CH2)3NH2 ; and (CH3O)3Si(CH2)3NH2.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:10]([OH:19])(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].C(OCC)(=O)C>CO>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:10]([O-:19])(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O-:17])=[O:16]
Reactant: O=C(O)CCCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C([O-])CCCCC(=O)[O-]
Yield: 146.2 %

Procedure:
10.00 g of the metformin free-base and 4.411 g of adipic acid were stirred in 150 ml of methyl alcohol at 40° C., and then ethyl acetate was added thereto. The produced crystal was filtered and dried in hot air, thus obtaining 12.06 g (yield: 98.9%) of metformin adipate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[H-].[Na+].F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>CN(C=O)C>[CH:29]([C:28]1[CH:31]=[CH:32][C:25]([O:1][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:26][CH:27]=1)=[O:30]
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Temperature: 70 °C

Procedure:
A solution was prepared of 9.8 g (35 mmol) of 1-hydroxy-2-(3-methoxyphenyl)-6-methoxynaphthalene in 490 mL of DMF under a nitrogen atmosphere and to this solution was slowly added 1.47 g (36.8 mmol) of 60% NaH in mineral oil. After ten minutes, 7.5 mL (70 mmol) of 4-fluorobenzaldehyde was added and the reaction mixture was heated to 70° C. for sixty-four hours. The reaction mixture was evaporated to dryness and the residue partitioned between water and EtOAc. The EtOAc layer was dried with Na2SO4 and chromatographed on a silica gel column eluted with EtOAc-hexane (1:9)(v/v). The final product was further purified by crystallization from MeOH. This yielded 2.4 g of the title compound as a tan solid, mp 145-146° C.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[H-].[Na+].[CH2:19]1[O:29][C:22]2([CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[O:21][CH2:20]1>[Cl-].[NH4+]>[CH3:6][O:7][C:8](=[O:9])[CH:10]=[C:25]1[CH2:26][CH2:27][C:22]2([O:29][CH2:19][CH2:20][O:21]2)[CH2:23][CH2:24]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a DMF (50 mL) solution of trimethyl phosphonoacetate (26 mL), sodium hydride (purity: 55% or higher, 7.03 g) was added in small portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. A DMF (50 mL) solution of 1,4-cyclohexanedione monoethylene ketal (25.2 g) was added, thereto in small portions at room temperature. This suspension was stirred for 19 hours and diluted with a saturated aqueous solution of ammonium chloride, followed by two extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (29.7 g, 87%) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C1COCC1.C(OCC)C.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][S:2]([C:5]1[O:9][C:8](/[C:10](=[N:20]/[S@@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])/[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCC(=O)c1ccc(S(C)(=O)=O)o1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(5-methanesulfonyl-furan-2-yl)-propan-1-one (1.1 g, 5.5 mmol) in THF (30 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (0.750 g, 6.06 mmol) and titanium (IV) isopropoxide (6 mL, 25 mmol) and the mixture was warmed at reflux. After 18 hours, the mixture was cooled to room temperature, and diluted with diethyl ether (100 mL) and water (6 mL). The mixture was stirred for 10 minutes, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0-80% EtOAc-hexanes to afford (R)-2-methyl-propane-2-sulfinic acid[1-(5-methanesulfonyl-furan-2-yl)-prop-(E)-ylidene]-amide.
Reaction SMILES: [OH: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.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>CN1CCCC1=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1

Procedure:
Under nitrogen, 420 g (2.36 mol) N-(4-Hydroxyphenyl)-piperazine, 520.6 g (3.30 mol) 1-chloro-4-nitrobenzene and 457.5 g (3.54 mol) N,N-Diisopropylethylamine (Hünig's Base) are suspended in 1260 ml N-Methylpyrrolidone and heated to 120°-125° C. The clear solution is stirred at 120°-125° C. and the reaction is followed by HPLC. After complete reaction (5-7 hours) the solution is cooled to 75°-80° C. and 6.3 liters of isopropanol are added over a period of about 30 minutes to the reaction mixture while keeping the temperature at 75°-80° C. (slight heating is necessary). Towards the end of the addition the product starts to precipitate (yellow crystals). The suspension is cooled to 20°-25° C. and stirred overnight at this temperature. Afterwards the suspension is cooled to −10° to −5° C. and stirred for 30 minutes. The product is filtered off, washed with 1.7 liters isopropanol, followed by 5×840 ml warm (35°-40° C.) water. The product is dried under vacuum at 50° C. (slight stream of nitrogen) to constant weight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13]1)(=[O:11])=[O:10].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13]1)(=[O:11])=[O:10]
Reactant: CN1CCNCC1
Reactant: N#Cc1ccnc(N2CC[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(S(=O)(=O)[C@H]3CCN(c4nccc(C#N)n4)C3)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
In a 10 mL round-bottomed flask, (S)-2-(3-(2-chloro-4-fluorophenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile (example 73) (50 mg, 136 μmol, 1 eq) was combined with acetonitrile (4 mL) to give a light yellow solution. 1-Methylpiperazine (20.7 mg, 22.9 μl, 204 μmol, 1.5 eq) and DIEA (35.2 mg, 47.6 μl, 273 μmol, 2 eq) were added. The reaction mixture was heated to 60° C. and stirred for 20 h. After that, 1-methylpiperazine (0.7 eq) and of DIEA (1 eq) were added. The reaction mixture was stirred at 60° C. for 5 h. After that, additional 1-methylpiperazine (1 eq) and DIEA (1.2 eq) were added. The reaction mixture was stirred at 60° C. for 16 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into aqueous 5% Na2CO3 solution and extracted with EtOAc (3×10 mL). The organic layers were combined and washed with saturated aqueous NaCl solution (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, CH2Cl2/MeOH 98/2) to yield a light yellow foam (42 mg, 69%). MS: m/z=447.1409 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[C-]#N.[Na+]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: [C-]#N
Agent: [Na+]
Product: COc1cc2c(cc1O)CCC2=O

Procedure:
1,4-Dihydroindeno[1,2-c]pyrazoles of general formula (13), wherein X3, R4, R5, and R6 are as defined in formula (I), can be prepared as described in Scheme 3. 5,6-Dimethoxy-1-indanone, purchased from Aldrich Chemical Co., can be treated with sodium cyanide to provide 5-hydroxy-6-methoxy-1-indanone. 5-Hydroxy-6-methoxy-1-indanone can be treated with nitric acid and sodium nitrite to provide 5-hydroxy-6-methoxy-4-nitro-1-indanone. 5-Hydroxy-6-methoxy-4-nitro-1-indanone can be treated with iodomethane and then methodology described in Scheme 2 to provide compounds of general formula (12). Compounds of general formula (12) can be treated with a reducing agent, including iron metal in the presence of acetic acid, to provide amines of general formula (13).
Reaction SMILES: O[CH:2]([CH3:21])[CH:3]([NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[C:4]1[CH:9]=[CH:8][C:7](C)=[CH:6][CH:5]=1.[P+3]=O.[CH2:24]1C2C(CCCC2)CCC1>>[CH3:24][C:8]1[CH:9]=[C:4]([C:3]2[C:2]3[C:18](=[CH:17][CH:16]=[C:15]([CH3:19])[CH:21]=3)[C:13]([CH3:14])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCC2CCCCC2C1
Reactant: Cc1ccc(C(NC(=O)c2cccc(C)c2)C(C)O)cc1
Agent: O=[P+3]
Product: Cc1cccc(-c2ncc(C)c3ccc(C)cc23)c1
Reaction time: 5 h

Procedure:
N-(2-hydroxy-1-p-tolyl-propyl)-3-methylbezamide (2.1 mmol), phosphorus (V) oxide (10 mmol) and decahydronaphtalene (50 mmol) were put in a dried two-neck round-bottom flask. Then, the mixture was stirred at 120 for 5 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane and water and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography. The eluate was distilled under reduced pressure. The residue was recrystallized from dichloromethane and petroleum ether, and filtered to yield 1-(3-methylphenyl)-4,7-dimethylisoquinoline.
Reaction SMILES: [NH:1]([C:8]1[CH2:18][C:17]([C:19](OCC)=[O:20])=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][C:9]=1[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH:28]1[CH:29]=[C:30]2[C:19]([C:17]3[C:16]([NH:24][C:25]2=[CH:26][CH:27]=1)=[CH:15][C:9]1[C:10]([C:3]2[C:2]([NH:1][C:8]=1[CH:18]=3)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:11])=[O:20]
Reactant: CCOC(=O)C1=C(Nc2ccccc2)CC(C(=O)OCC)=C(Nc2ccccc2)C1
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Yield: 95.3 %

Procedure:
A suspension of 250 g of diethyl 2,5-dianilino-3,6-dihydroterephthalate in 1 l of water was metered at 650° C. in the course of 1 hour in a nitrogen stream (1.5 m3) through a one-material nozzle into a tubular reactor (50 mm in diameter, 300 mm in length) in a axial direction. Using a wet collector, 183 g of quinacridone were isolated.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])(=[O:3])N.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])([OH:20])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1cc2c(=O)c3ccccc3ccn2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2c(=O)c3ccccc3ccn2c1

Procedure:
To 2-carbamoyl-11H-pyrrolo[2,1-b][3]benzazepine-11-one (27 g., 0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C. is added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to yield 2-carboxy-11H-pyrrolo[2,1-b] [3]benzazepine-11-one.