Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C@@:5]([C:21]([OH:23])=[O:22])([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[N:6]([N+:13]([O-:15])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:4])=[O:3].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:29].C[N:45]([CH3:48])[CH:46]=[O:47]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[C:46]1(=[O:47])[NH:45][C:48](=[O:29])[CH:16]=[CH:5]1.[N+:2]([C@@:5]([C:21]([OH:23])=[O:22])([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[N:6]([N+:13]([O-:15])=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: CN(C)C=O
Agent: Cl
Agent: NCCCC[C@@](C(=O)O)(N(c1ccccc1)[N+](=O)[O-])[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: O=C1C=CC(=O)N1

Procedure:
An aliquot (1.5 ml) of 5.5 mM dinitrophenyl-L-lysine hydrochloride in 0.1M sodium phosphate buffer, pH 7.0, containing 5 mM EDTA was incubated with 0.15 ml of 5.5 mM N-succinimidyl-6-maleimidohexanoate in N,N-dimethylformamide at 30° C. for 30 minutes.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.C(OC(=O)C1C=C(F)C=NC=1Cl)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:35]1[O:39][C:38]2[CH:40]=[C:41]([OH:44])[CH:42]=[CH:43][C:37]=2[O:36]1.[OH-].[Li+]>O.O1CCOCC1.C(O)C>[O:36]1[C:37]2[CH:43]=[CH:42][C:41]([O:44][C:2]3[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[CH:40][C:38]=2[O:39][CH2:35]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: CCOC(=O)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-fluoro-nicotinic acid (synthesized in accordance with the procedures described in European patent: EP 0634413 A1) was converted to the corresponding ethyl ester with anhydrous ethanol and excess thionyl chloride, then worked up in the usual manner. To 2-chloro-5-fluoro-nicotinic acid ethyl ester (5.0 g) in an oven-dried 250 mL flask was added cesium carbonate (9.60 g), sesamol (4.07 g), and 50 mL of anhydrous dioxane. The reaction was stirred overnight at 100° C. Lithium hydroxide (2.94 g) in 10 mL water was added, and the reaction was again allowed to stir overnight at 100° C. The dioxane was then evaporated under a nitrogen stream. The residue was then taken up in 50 mL water, acidified with conc. hydrochloric acid to pH=3, and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The dried residue was washed with ethyl acetate (20 mL) and dried under high vacuum, giving the title compound (2.96 g).
Reaction SMILES: [Na].Cl.C(O[C:6](=[NH:8])[CH3:7])C.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1>C(O)C>[NH:8]=[C:6]([N:16]([C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:19][CH:18]=1)[NH2:17])[CH3:7]
Reactant: CCOC(C)=N
Reactant: Cc1ccc(C(=O)NN)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(=N)N(N)C(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
1.65 g (72 mmol) of sodium are dissolved in 80 mL ethanol. 8.89 g (72 mmol) of ethylacetimidate hydrochloride in 160 mL ethanol are added at ambient temperature and the precipitated sodium chloride is filtered off. The filtrate is combined with 6.00 g (40 mmol) 4-methyl-benzoic acid hydrazide and stirred overnight. The reaction mixture is evaporated down and cooled. The precipitated solid is filtered off and washed with cold ethanol and diethyl ether (5.7 g of white solid). A further 1.2 g of solid are obtained from the filtrate after the removal of the solvent by distillation and recrystallisation from ethanol. Yield: 6.93 g (91%); mass spectroscopy [M+H]+=192.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[C:12]([NH:15][CH:16]1[CH2:45][C:20]2=[CH:21][N:22]([S:27]([C:30]3[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][C:33]([CH:39]([CH3:41])[CH3:40])=[CH:32][C:31]=3[CH:42]([CH3:44])[CH3:43])(=[O:29])=[O:28])[C:23]3[CH:24]=[CH:25][CH:26]=[C:18]([C:19]=32)[C:17]1([OH:48])[CH:46]=[CH2:47])(=O)[CH3:13].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:12]([NH:15][CH:16]1[CH2:45][C:20]2=[CH:21][N:22]([S:27]([C:30]3[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][C:33]([CH:39]([CH3:40])[CH3:41])=[CH:32][C:31]=3[CH:42]([CH3:44])[CH3:43])(=[O:28])=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[C:18]([C:19]=32)[C:17]1([OH:48])[CH:46]=[CH2:47])[CH3:13]
Reactant: C=CC1(O)c2cccc3c2c(cn3S(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)CC1NC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC1(O)c2cccc3c2c(cn3S(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)CC1NCC
Yield: 37.8 %

Procedure:
LAH (5 equivalents) was allowed to react with a THF solution (14.3 ml) of 4-acetylamino-3,4-dihydro-5-hydroxy-1-(2,4,6-triisopropylphenylsulfonyl)-5-vinyl-5H-benz[cd]indole (750 mg, 1.43 mmol) and was refluxed for 3 hours to complete the reaction. Ethanol was added to the reaction mixture to inactivate the excess amount of LAH and was added aqueous solution of Na2SO4. The reaction mixture was subjected to extraction with ethyl acetate. The extract was washed with an aqueous saline solution and, then, dried (anhydrous Na2SO4) and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, eluting with ethyl acetate to afford 275 mg (38%) of the title compound as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12]C(=O)OC(C)(C)C)[CH2:5]2.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH2:12])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CNc2ccc(Br)cc2C1
Reaction time: 3 h
Yield: 220.2 %

Procedure:
To a solution of (6-Bromo-1,2,3,4-tetrahydro-3-quinolinyl)carbamic acid, 1,1-dimethylethyl ester (652 mg, 2 mmol) in dichloromethane at RT under argon was added trifluoroacetic acid (1 mL). After 3 hours, the mixture was concentrated. Chloroform (10 mL) was added and concentrated again in vacuo to afford the title compound (1 g), an oil, which was used without further purification. MS; M(+H)+=227.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[Cl:24][S:25]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([F:1])=[CH:3][C:4](/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][C:6]=2[F:15])=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccccc2)c(F)c1
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)Cl)cc2)c(F)c1

Procedure:
To a solution of (E)-ethyl 3-(3,5-difluoro-4-phenoxyphenyl)-2-methylacrylate (intermediate 41.2) (1 g, 3.14 mmol) in DCM (3.14 mL) under N2 was added chlorosulfonic acid (0.419 mL, 6.28 mmol) dropwise. After 1 hour an additional 0.209 mL chlorosulfonic acid was added. After an additional hour the reaction mixture was quenched with ice-water and extracted into EtOAc (2×200 mL). The combined organic layers were dried briefly (<10 min) over Na2SO4 and concentrated to recover 1.283 g of the title compound (98%) as a yellow oil.
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)(=[O:12])=[O:11])=[CH:6][C:5]=1C)C.[F:22][C:23]([F:35])([F:34])C1C=CC(S(Cl)(=O)=O)=CC=1>>[F:22][C:23]([F:35])([F:34])[C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH:14]2[CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH2:19]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(=O)CC2)cc1C
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C1CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Intermediate 123 was prepared by a method analogous to the method of preparing Intermediate 122 using 4-trifluoromethyl benzensulfonyl chloride instead of 4-ethoxy-3-methylbenzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:14][C:15]1[N:19]=[CH:18][N:17]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:6]=2[Cl:9])[N:16]=1
Reactant: Nc1nc[nH]n1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 100 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) and potassium carbonate (296 mg), the mixture was heated at 100° C. for 2 hrs. The reaction was cooled to room temperature, diluted with water (100 ml) and extracted with ether (100 ml). The organic extracts were evaporated to dryness to give the title compounds as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[C:10]1=[NH:22].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCCl>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[N:11]1[CH2:12][CH2:13][N:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:10]1=[N:22][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=NC(=O)c1ccccc1
Yield: 74 %

Procedure:
A mixture of 1.0 g (3.4 mmoles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine, prepared as described in Example 1, Method (a), 10 ml of 1,2-dichloroethane, 0.33 ml (0.32 g, 4.0 mmole) of dry pyridine and 0.46 ml (0.56 g, 4.0 mmoles) of benzoyl chloride is heated on a steam bath for 2 hours. The cooled mixture is washed thrice with 10 ml of water each, thrice with 10 ml of 10% aqueous sodium hydrogencarbonate solution each, and again thrice with 10 ml of water each, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. 1.0 g (74.1%) of crude 1,3-bis(2',6'-dimethylphenyl)-2-benzoylimino-imidazolidine are obtained. After recrystallization from aqueous methanol the product melts at 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(c1cccc2c(Cl)nccc12)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(S(=O)(=O)c2cccc3c(Cl)nccc23)C1

Procedure:
Substantially the same procedures as in Example 4 were repeated except that 1.8 g of 3-hydroxypyrrolidine was used in place of 2.1 g of 4-hydroxypiperidine to obtain 1-(1-chloro-5-isoquinolinesulfonyl)-3-hydroxypirrolidine. Then, in substantially the same manner as in Example 10, 2.5 g of the thus obtained 1-(1-chloro-5-isoquinolinesulfonyl)-3-hydroxypirrolidine was reacted in dichloromethane with 1.08 g of oxalyl chloride, 0.67 g of dimethylsulfoxide and 0.60 g of triethylamine to obtain 1-(1-chloro-5-isoquinolinesulfonyl)-3-pyrrolidone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](ON2C(=O)CCC2=O)=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:41][C@H:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[OH:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:40])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:41][C@H:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43][CH2:44][C:45]([OH:46])=[O:47])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH:8]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Reaction time: 4 h

Procedure:
To a solution of 5-[9-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (62 mg, 0.11 mmol) in dry DMF (1 ml), H-Glu-OtBu (0.027 g, 0.13 mmol) and DIPEA (0.05 ml) was added. The mixture was stirred over night under nitrogen for 4 h. The mixture was concentrated. The residue was redissolved in EtOAc and washed with 0.1 N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give a syrup.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH2:18][OH:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCc1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
A mixture of [5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanol (Example 48) (9.74 g, 28.4 mmol) and manganese dioxide (24.6 g, 283.6 mmol) in methylene chloride (584 mL) was stirred at room temperature under a nitrogen atmosphere overnight (15 h). The reaction mixture was filtered through diatomaceous earth to remove the manganese dioxide. Concentration of the filtrate provided the crude material as a dark solid. The crude material was purified by trituration with toluene to give 5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (6.36 g, 65%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ4.84 (4H, s), 6.60 (1H, s), 6.95 (1H, s), 7.21-7.33 (10H, m), 8.63 (1H, s), 9.75 (1H, br s), 9.86 (1H, s).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2cccc(C)n2)C[C@@H]1C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cccc(C)n2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(6-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate for a preparation see Intermediate 69) (107.9 mg, 0.208 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined and concentrated in vacuo to give a residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.22 mL, 0.220 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-(6-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (79.5 mg, 0.161 mmol, 77% yield) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[Cl:31].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH:35]=O.[C:42]([OH:45])(=[O:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:42]([OH:45])(=[O:44])[CH3:43].[Cl:31][C:3]1[CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][CH2:35][C:34]1[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:33]=1[Cl:32]
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reactant: O=Cc1c(F)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NCc5c(F)cccc5Cl)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00045 mol) in 1,2-dichloroethane (20 mL) was reacted with 2-chloro-6-fluorobenzaldehyde (0.076 g, 0.00048 mol), acetic acid (0.095 g, 0.00159 mol) and sodium triacetoxyborohydride (0.336 g, 0.00159 mol) at ambient temperature. An additional three equivalents of sodium triacetoxyborohydride (1.008 g, 0.00477 mol) were added in three 24 hour intervals, after which time all the starting material had been consumed. The solvents were removed in vacuo and the residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with chloroform (2×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile-0.1M ammonium acetate over 15 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give to give trans 3-{3-chloro-4-[(2-chloro-6-fluorobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.074 g, 0.00011 mol):
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:21])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(NCc2cccs2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: O=C(O)c1cccc(NCc2cccs2)c1C(=O)O

Procedure:
3-[(Thiophen-2-ylmethyl)-amino]-phthalic acid dimethyl ester (0.88 g, 2.88 mmol) was treated in the same manner as described above for the synthesis 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([CH3:26])[CH:19]=2)=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:15])[CH3:14].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[CH3:15][N:13]([CH2:12][C:11]1[CH:16]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=[CH:9][C:10]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([CH3:26])[CH:19]=1)[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ccc(Oc2ccc(N)cc2CN(C)C)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ccc(Oc2ccc(NS(C)(=O)=O)cc2CN(C)C)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (371 μL, 4.79 mmol) was added to a solution of the aniline of Example 103 (725 mg, 2.4 mmol) and Et3N (1 mL, 7.17 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 h the reaction was allowed to warm to room temperature before the solvent was removed in vacuo. 2M NaOH (10 mL) was added to the residue and the mixture was stirred overnight. The resulting clear solution was neutralised by the addition of sat aq NH4Cl and extracted with DCM (2×30 mL). The combined organic layers were dried (MgSO4) and evaporated to give an oil. This was taken up in EtOAc (10 mL), the HCl salt was precipitated by the addition of 1M ethereal HCl and the product (669 mg, 67%) was collected by filtration; δH (d6-DMSO, 400 MHz) 2.23 (3H, s), 2.42 (3H, s), 2.75 (6H, s), 3.04 (3H, s), 4.38 (2H, s), 6.84 (1H, d), 6.93 (1H, d), 6.98 (1H, s), 7.17-7.25 (2H, m), 7.50 (1H, s); MS m/z (ES+) 381 (MH+).
Reaction SMILES: Cl.[CH:2]1([C:5](=[NH:8])[O:6][CH3:7])[CH2:4][CH2:3]1.Cl.N[CH:11](CO)[C:12]([O:14][CH3:15])=[O:13].C(=O)(O)[O-].[Na+]>ClCCl>[CH:2]1([C:5]2[O:6][CH2:7][CH:11]([C:12]([O:14][CH3:15])=[O:13])[N:8]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)C(N)CO
Reactant: COC(=N)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1COC(C2CC2)=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.3 %

Procedure:
Into a 500-mL 3-necked round-bottom flask were placed methyl cyclopropanecarbimidate hydrochloride (13.6 g, 100.00 mmol, 1.00 equiv.), methyl 2-amino-3-hydroxypropanoate hydrochloride (17.6 g, 112.82 mmol, 1.10 equiv.) and dichloromethane (150 mL). The resulting solution was stirred for 24 hours at room temperature, then added sodium bicarbonate (16.8 g, 200.00 mmol, 2.00 equiv.). The resulting solution was stirred for 24 hours at room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 8 g (47% yield) of methyl 2-cyclopropyl-4,5-dihydrooxazole-4-carboxylate as a colorless oil.
Reaction SMILES: ClC1C(Cl)=CC=CC=1C=O.Cl[C:12]1[N:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])=[CH:16][CH:17]=1.[C:26]([NH:29][NH2:30])(=O)[CH3:27]>C(O)CCC>[CH3:27][C:26]1[N:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[Cl:25])[CH:16]=[CH:17][C:12]2=[N:30][N:29]=1
Reactant: Clc1ccc(-c2cccc(Cl)c2Cl)nn1
Reactant: CC(=O)NN
Agent: O=Cc1cccc(Cl)c1Cl
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(Cl)c3Cl)nn12

Procedure:
As described in Example 35, 2,3-dichlorobenzaldehyde is converted to 3-chloro-6-(2,3-dichlorophenyl)pyridazine. A mixture of this compound and acetic acid hydrazide in n-butanol is refluxed for 24 hours to give the product of the example.