Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([OH:39])[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([O:39][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[F:22])=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=3)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1
Reactant: COc1ccc(F)c(-c2ccc(CBr)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1ccnc(O)c1)C1CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-(bromomethyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (200 mg) in toluene (3.0 mL) were added ethyl 3-cyclopropyl-3-(2-hydroxypyridin-4-yl)propanoate (141 mg) and silver carbonate (166 mg), and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, and filtered. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (218 mg) as a pale-yellow oil.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[K+]>CO>[C:11]1([S:17][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:1]([OH:3])=[O:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1
Reactant: O=C1OCc2ccccc21
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccccc1CSc1ccccc1
Yield: 78 %

Procedure:
A mixture of 67.1 gm of phthalide, 51.3 ml of thiophenol, 35.1 gm of potassium methylate and 250 ml of methanol was refluxed. Subsequently, the obtained 2-(phenylmercapto-methyl) -benzoic acid (yield: 78% of theory, m.p. 108°-110° C.) was esterified with methanol/thionylchloride by standing at -40° C. After standing overnight at room temperature, methyl 2-(phenylmercapto-methyl)-benzoate (yield: 89% of theory, b.p. 145° C. at 0.07 mm Hg) was obtained, which was converted into 2-(phenylmercapto-methyl)-phenyl carbinol (yield: 97% of theory, m.p. 64°-65° C.) by reduction with lithium aluminum hydride in diethyl ether.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH2:13]1)=[O:10].[C:19]([C:21]1[CH:38]=[CH:37][C:24]([O:25][CH2:26][CH:27]([NH:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[CH3:28])=[CH:23][CH:22]=1)#[N:20].O>C(Cl)Cl>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH:27]([NH:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:34])[CH3:35])[NH:32][C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH2:13]2)=[O:10])[CH3:28])=[CH:37][CH:38]=1)#[N:20]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: CC1CCCC(OC(=O)Cl)C1
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1CCCC(OC(=O)N[C@H](C(=O)NC(C)COc2ccc(C#N)cc2)C(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.5 %

Procedure:
0.4 g of N-methylmorpholine, and subsequently 0.8 g of 3-methylcyclohexyl chloroformate were added to a suspension containing 1.0 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a white crystal (yield: 80% ).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24](=[O:27])[NH:25][NH2:26]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24](=[O:27])[NH:25][N:26]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: Cc1cccc(Cl)c1NC(=O)NN
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: Cc1cccc(Cl)c1NC(=O)NN=c1c(=O)c2ccccc2c1=O

Procedure:
ninhydrin, 4-(2-chloro-6-methylphenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]=[C:12]([CH2:15][OH:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[Na+].[Na+].CI.[Cl-].[Na+]>CO.ClCCl>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[N:11]([CH3:18])[C:12]([CH2:15][OH:16])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1nc(CO)[nH]cc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: CO
Product: Cn1c(CO)ncc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 49.2 %

Procedure:
5-(Benzyloxy)-2-(hydroxymethyl)-4(1H)-pyrimidinone (2.3 g) are dissolved in 20 ml of absolute methanol. The solution is treated with 4.24 g (40 mmol) of sodium carbonate and 10 ml of methyl iodide and stirred at room temperature for 4 days. Now, 400 ml of dichloromethane and 100 ml of saturated sodium chloride solution are added thereto, the organic phase is separated, dried over sodium sulphate and concentrated. The residue is chromatographed of 100 g of silica gel (0.063-0.2 mm). The two products are eluted in succession with dichloromethane/methanol (9:1 v/v). There are obtained 1.2 g of 5-(benzyloxy)-2-(hydroxymethyl)-3-methyl-4(3H)-pyrimidinone as white crystals from ether, m.p. 83°-84° C. 5-(Benzyloxy)-2-(hydroxymethyl)-1-methyl-4(1H)-pyrimidinone also forms white crystals from ether, m.p. 172°-173° C. 0.6 g is obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]1([C@H:19]([CH3:25])[C:20](OCC)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OS([O-])(=O)=O.[K+]>C1COCC1>[O:21]=[C:20]([C@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:25])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)[C@@H](C)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@@H](C)c1ccccc1)OC
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a stirring solution consisting of dimethyl methylphosphonate (1.392 g, 11.22 mmol) in THF (20 mL) at −78° C. was slowly added n-butyllithium solution (6.6 mL, 11 mmol, 1.6 M solution in hexane). The mixture was stirred for 30 minutes, after which time a mixture consisting of (S)-ethyl 2-phenylpropanoate (1.0 g, 5.6 mmol) in THF (10 mL) was slowly added, and the mixture stirred at −78° C. for two hours before being allowed to rise to room temperature overnight. The reaction mixture was treated with 5% aqueous KHSO4 and extracted with ethyl acetate three times. The combined organic layer was twice washed with a solution of 50:50 water-brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (80:20 v/v) afforded the title compound (1.03 g, 72%) as a colorless oil; TLC Rf 0.4 (solvent system 80:20 v/v ethyl acetate-heptane); MS (ESI+) m/z 257.1 (M+H)+; 1H NMR (CD3OD) δ 7.37-7.22 (m, 5H), 4.01 (q, J=6.71 Hz, 1H), 3.74-3.69 (m, 6H), 3.27-3.2 (m, 1H), 3.09-2.97 (m, 1H), 1.37-1.34 (m, 3H); [α]Tλ=α/cl, [α]21.9D=0.946/(0.01859 g/1.5 mL)(0.5)=+152.6° (c=1.24, CHCl3).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[CH3:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:25]3\[C:26](=[O:32])[NH:27][C:28]4[C:24]\3=[C:23]([CH3:22])[CH:31]=[CH:30][CH:29]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: Cc1cccc2c1CC(=O)N2
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cccc(C)c43)c(C)c2C1=O
Yield: 44.1 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 4-methyl-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 16 (25 mg, yield 44.1%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][N:9]=[CH:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH:25]=[O:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(O)(=O)C>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=[C:10]([C:11](=[O:13])[CH3:12])[C:25]=2[OH:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Reactant: CC(=O)C=NNCc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)c1nn(Cc2ccccc2)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 6 h
Yield: 11 %

Procedure:
2-Oxopropanal benzylhydrazone (2.314 mmol, 408 mg) synthesized in the same manner as in Reference Synthetic Examples 1 and 2 and (4-tert-butylphenyl)(oxo)acetaldehyde (1.929 mmol, 366.9 mg) synthesized in Reference Synthetic Example 4 were dissolved in acetic acid (9 mL) and stirred at 100° C. for about 6 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/AcOEt=3/1, and 4/1) to give the desired product as a yellow solid (74.1 mg, yield 11%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[O:26][CH3:27])[C:20]([OH:22])=[O:21])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:28][C:29]([NH2:31])=[NH:30])=[N:5][CH:4]=1.[H-].[Na+].Cl[C:35]1C2C(=CC=C(S(NC3C=C(C=CC=3OC)C(OC)=O)(=O)=O)C=2)C(Cl)=CN=1>CS(C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[O:26][CH3:27])[C:20]([O:22][CH3:35])=[O:21])(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:28][C:29]([NH2:31])=[NH:30])=[N:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: COC(=O)c1ccc(OC)c(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
3-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-4-methoxybenzoic acid hydrochloride ##STR12## Guanidine hydrochloride (179.8 mg, 1.88 mmol) was added in one portion to a suspension of NaH (54.9 mg, 80% dispersion by wt in mineral oil, 1.83 mmol) in DMSO (10 mL) and the mixture was heated at 60° C. under N2 for 20 min. Methyl 3-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}-4-methoxybenzoate (238.6 mg, 0.541 mmol) was added and the mixture heated at 90° C. for 24 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3 to 90:10:1) as eluant to give methyl 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-4-methoxybenzoate (203.2 mg, 0.43 mmol) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])=[O:4].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]([CH2:16][C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)[C:5]([C:3]([OH:2])=[O:4])=[CH:13]2
Reactant: COC(=O)c1cc2cccc(C)c2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: Cc1cccc2cc(C(=O)O)n(Cc3cccc4ccccc34)c12

Procedure:
Using general procedure B, 7-methyl-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 314.3 ([M−H]−).
Reaction SMILES: Cl.[OH:2][C:3]1([C:7]([OH:9])=[O:8])[CH2:6][NH:5][CH2:4]1.[CH2:10]=O>O.O.[Pt]=O>[CH3:10][N:5]1[CH2:6][C:3]([OH:2])([C:7]([OH:9])=[O:8])[CH2:4]1
Reactant: C=O
Reactant: O=C(O)C1(O)CNC1
Agent: O=[Pt]
Agent: Cl
Solvent: O
Product: CN1CC(O)(C(=O)O)C1
Reaction time: 46 h
Yield: 74.9 %

Procedure:
To a solution of 500 mg (3.26 mmoles) of 3-hydroxyazetidine-3-carboxylic acid hydrochloride in 15 ml of water are added 1.06 ml of 37% formalin and 250 mg of platinum oxide monohydrate, and the mixture is kept at ambient temperature under atmospheric pressure for 46 hours. The catalyst is filtered off and washed with water. The combined filtrate and washings are evaporated under reduced pressure. The residue (0.79 g) is dissolved in 10 ml of water, adsorbed on 30 ml of Amberlite IR-120 B (H+), and eluted with 100 ml of 2 N aqueous ammonium hydroxide solution. The eluate is evaporated under reduced pressure. The residue (431 mg) is crystallized from water-acetone to yield 1-methyl-3-hydroxyazetidine-3-carboxylic acid as prisms.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:16]=1)=[CH:7][CH:6]=2.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]3[CH2:34][CH2:35][N:36](C(OC(C)(C)C)=O)[CH2:37][C:32]3=[N:31][CH:30]=2)=[CH:25][C:24]=1[O:45][CH3:46]>>[CH3:46][O:45][C:24]1[CH:25]=[C:26]([C:29]2[N:33]3[CH2:34][CH2:35][NH:36][CH2:37][C:32]3=[N:31][CH:30]=2)[CH:27]=[CH:28][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:16]=1)=[CH:7][CH:6]=2
Reactant: CC(C)(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Reactant: COc1cc(-c2cnc3n2CCN(C(=O)OC(C)(C)C)C3)ccc1N
Product: COc1cc(-c2cnc3n2CCNC3)ccc1Nc1cc2cc(-c3cnn(CC(C)(C)O)c3)ccc2cn1

Procedure:
The title compound was prepared according to the method described for Example 110 using 1-(1-(4-(3-chloroisoquinolin-6-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 22) and tert-butyl 3-(4-amino-3-methoxyphenyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (Preparation 89).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=2)=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-Bromomethyl-4-trifluoromethyl-benzene (1.55 g, 6.49 mmol) and 1-(4-hydroxy-phenyl)-propan-2-one (1.46 g, 9.74 mmol) were stirred in acetonitrile (65 mL) along with cesium carbonate (5.3 g, 16.23 mmol). After stirring at room temperature for two days the reaction was heated to 60° C. for 3 hours. After cooling the reaction was submitted to standard aqueous workup then purified on silica gel (0-100% (2% MeOH in EtOAC) to hexanes) to yield the title compound.
Reaction SMILES: [Cl-:1].[N:2]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)=O.[OH-].[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl>O>[ClH:1].[ClH:1].[NH2:2][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: [Cl-]
Reactant: O=Nc1ccc(O)c2ncccc12
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(O)c2ncccc12
Temperature: 40 °C
Yield: 152.9 %

Procedure:
5-nitroso-8-hydroxyquinoline chloride (40 g) was added to a mixture of water (160 ml) and 5N-NaOH (260 ml) and heated to 40° C. Na2S2O4 (95 g) was added to the reaction mixture wraith increasing temperature to 75-80° C. The reaction mixture was cooled to 50° C. and 12N-HCl (250 ml) was added to it. Then the reaction mixture was cooled to 0° C. and filtered to give 5-amino-8-hydroxyquinoline dihydrochloride (34 g, 69%).
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:17]=3)=[CH:14][N:15]=[C:9]2[CH:8]=1)=O.O.[NH2:33]N>C(O)(=O)C>[N:2]1[N:33]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)[NH:4][CH:3]=1
Reactant: CN(C)/C=N/C(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nnc[nH]4)ccn23)c1
Temperature: 90 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridine-7-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamide (17 mg, 0.04 mmol) in acetic acid (0.5 ml) was added hydrazine hydrate (5 μl, 0.1 mmol). The reaction mixture was heated at 90° C. for 30 min before being cooled to room temperature. The volatiles were removed in vacuo and the residue azeotroped with toluene. Trituration of the residue with Et2O afforded a pink solid (12 mg). MS: [M+H]+ 402.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:30](=[O:32])[CH3:31])=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 361 μmol, example 30 (step 1) in DCM (2 mL) was added DIEA (62.8 μL, 361 μmol) and acetic acid anhydride (34.0 μL, 361 mop. The resulting mixture was then stirred at RT for 16 h. Then, H2O (1 mL) was added and the mixture was extracted with DCM (2×5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 320 (M+H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.C(N(CC)CC)C.[CH3:37][N:38]1[CH:42]=[C:41]([C:43](Cl)=[O:44])[CH:40]=[N:39]1>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([C:43]([C:41]3[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=3)=[O:44])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)c2cnn(C)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.033 mmol) (chiral material, from Example 1, step 7, peak 1) and triethylamine (14 μL, 0.098 mmol) in methylene chloride (0.2 mL) was added 1-methyl-1H-pyrazole-4-carbonyl chloride (from Maybridge, 6.1 mg, 0.042 mmol). The resulting mixture was stirred overnight at room temperature. The solvents were evaporated and the crude material was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 7.1 mg (44%) of the product. The product was isolated as a single enantiomer. LCMS calculated for C24H28ClN8O2 (M+H)+: m/z=495.2; Found: 495.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[C:5]([N+:15]([O-])=O)[CH:4]=1>C(O)(=O)C.[Zn]>[NH2:15][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)/C=C/c1ccc(OC)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc(OC)cc1N
Temperature: 50 °C
Reaction time: 4 h
Yield: 23.4 %

Procedure:
To a solution of methyl(2E)-3-(4-methoxy-2-nitrophenyl)acrylate (Intermediate 5, 4.9 g, 20.66 mmol) in acetic acid (150 mL) at room temperature under nitrogen was added zinc powder (7.7 g, 118 mmol) in portions. After 4 hours, another 5 g of zinc was added and the resulting reaction mixture was heated at 50° C. for two hours. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel with hexanes/ethyl acetate (3:1) to give 1.0 g (23% yield) of product as a yellow solid, mp 149° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7](Br)[CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:52]([C:54]([OH:87])([CH2:85][CH3:86])/[CH:55]=[CH:56]/[C:57]1[CH:62]=[CH:61][C:60]([C:63]([CH2:82][CH3:83])([C:66]2[CH:71]=[CH:70][C:69](B3OC(C)(C)C(C)(C)O3)=[C:68]([CH3:81])[CH:67]=2)[CH2:64][CH3:65])=[CH:59][C:58]=1[CH3:84])[CH3:53].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:6]=[C:7]([C:69]2[CH:70]=[CH:71][C:66]([C:63]([CH2:64][CH3:65])([C:60]3[CH:61]=[CH:62][C:57](/[CH:56]=[CH:55]/[C:54]([CH2:85][CH3:86])([OH:87])[CH2:52][CH3:53])=[C:58]([CH3:84])[CH:59]=3)[CH2:82][CH3:83])=[CH:67][C:68]=2[CH3:81])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: COC(=O)Cc1ccc(OC)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)OC)ccc3OC)c(C)c2)cc1C)CC
Temperature: 100 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
(3-Bromo-4-methoxy-phenyl)-acetic acid methyl ester (Example 175-(1); 42 mg, 0.162 mmol), palladium acetate (2.5 mg, 0.011 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.0 mg, 0.022 mmol), potassium phosphate (69 mg, 0.324 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 28; 53 mg, 0.108 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (35.0 mg, 60%).