Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[NH:7][C:6]1=[O:22])(=O)C.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K].[I-].[Na+].CN(C)C=O>O>[C:12]1([C:10]2[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[NH:7][C:6](=[O:22])[CH:5]([N:27]3[C:26](=[O:28])[C:25]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]4[C:23]3=[O:33])[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)OC1N=C(c2ccccc2)c2ccccc2NC1=O
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
A mixture of (3RS)-1,3-dihydro-3-acetoxy-5-phenyl-2H-1,4-benzodiazepine-2-one (11.75 g), potassium phthalimide (11.1 g), sodium iodide (60 g) and N,N-dimethylformamide (80 ml) was stirred for 45 minutes at 90° to 95° C. The reaction mixture was poured into a cold water (1 l). The precipitates were collected by filtration, washed with water and recrystallized from ethanol to give (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (8.32 g).
Reaction SMILES: [CH3:1][C:2]([CH3:32])=[CH:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:21][CH2:20][CH:19]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH:18]12.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([N:17]3[CH2:21][CH2:20][CH:19]4[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:24][CH:18]34)[N:5]([CH2:4][CH:3]=[C:2]([CH3:32])[CH3:1])[C:9]=2[CH:10]=1
Reactant: CC(C)=CCn1c(N2CCC3CN(C(=O)OC(C)(C)C)CC32)nc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)=CCn1c(N2CCC3CN(C(=O)OC(C)(C)C)CC32)nc2ccc(N)cc21
Yield: 95 %

Procedure:
A solution of 49 mg (0.11 mmol) of tert-butyl 1-[1-(3-methylbut-2-enyl)-6-nitro-1H-benzimidazol-2-yl]hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate in 7.5 ml of ethanol was added dropwise to a suspension of 62 mg (1.11 mmol) of iron and 11 mg (0.20 mmol) of ammonium chloride in 0.75 ml of water, and the mixture was boiled at reflux for 3 hours. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure. The 43 mg of the desired product thus obtained were used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]5[CH2:28][O:27]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>CO>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][C@H:26]([OH:27])[CH2:28][NH:36][CH3:35])=[CH:22][CH:23]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCOCc1nc(-c2ccc(OC[C@H](O)CNC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate B2) in 4 mL of methylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[H][H]>CO.[Ni]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(O)c(F)cc1F
Yield: 90.5 %

Procedure:
24 g of 2,4-Difluoro-5-nitrophenol, dissolved in 120 ml of methanol, are subjected to hydrogenation at a hydrogen pressure of 20-40 bar at 25°-45° C. in the presence of 2 g of Raney nickel. When constant pressure is reached (i.e. when the take-up of hydrogen is complete), the pressure is released and the mixture is cooled, the solution is free from catalyst by filtration, and the methanol is subsequently removed by distillation at reduced pressure. 18 g (GC purity 97.5%) of 2,4-difluoro-5-aminophenol are obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][CH2:45][NH2:46]>>[C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:46][CH2:45][CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: NCCc1ccccn1
Product: O=C(NC(CCNCCc1ccccn1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method B as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-(2-pyridinyl)ethanamine, the title compound was obtained in 97.4% purity by HPLC.
Reaction SMILES: O[CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH2:6]1.Cl>CO>[C:11]1([C:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:3]=[CH:2][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[CH2:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCc2cc(C(O)CCN3CC=C(c4ccccc4)CC3)ccc2N1
Agent: Cl
Solvent: CO
Product: O=C1CCc2cc(C=CCN3CC=C(c4ccccc4)CC3)ccc2N1

Procedure:
1.0 Gram of 6-[1-hydroxy-3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyril was dissolved in 30 ml of methanol, then 2 ml of concentrated hydrochloric acid was added to the solution and the mixture was refluxed by heating for 2 hours. The reaction mixture was concentrated under a reduced pressure, then thus obtained residue was treated with 50 ml of 0.5% of sodium hydroxide and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried, next chloroform was removed by distillation at a room temperature then the residue thus obtained was crystallized from ethanol to obtain 0.6 g of 6-[3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl)-1-propenyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][C:10]1[NH:11][C:12]([CH3:15])=[CH:13][CH:14]=1>C(Cl)Cl>[C:5]([NH:8][CH2:9][C:10]1[NH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(CN)[nH]1
Solvent: ClCCl
Product: CC(=O)NCc1ccc(C)[nH]1

Procedure:
6.0 g (0.06 mol) of acetic anhydride in 20 ml of methylene chloride are added dropwise to 6.4 g (0.06 mol) of 2-(amino-methyl)-5-methyl-pyrrole (compare Example 11) in 20 ml of methylene chloride at 10° C. After a reaction time of 2 hours at room temperature, the mixture is concentrated and the residue is chromatographed over a silica gel column.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15](=[O:17])[NH2:16])[CH:9]=2)=[O:5])C.Cl>O1CCOCC1.O.O>[C:15]([C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[CH:12][CH:11]=1)(=[O:17])[NH2:16]
Reactant: CCOC(=O)c1cc2ccc(C(N)=O)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1ccc2cc(C(=O)O)[nH]c2c1
Yield: 70 %

Procedure:
Treat a solution of 6-carbamoyl-1H-indole-2-carboxylic acid ethyl ester (54 mg, 0.23 mmol) in dioxane/water (5:1, 12 mL) with LiOH monohydrate (14 mg, 0.33 mmol). Stir the reaction at rt overnight. Concentrate the reaction to dryness and dissolve the residue in water (5 mL) to form a solution. Acidify with 1 M HCl solution to form a solid. Collect by filtration and dry to give the desired product 6-carbamoyl-1H-indole-2-carboxylic acid as a solid in 70% yield (33 mg, 0.16 mmol).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[C:2]#[CH:3].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:3][C:2]1[O:16][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:14])([F:15])[F:13])[CH:7]=2)=[N:4][CH:1]=1
Reactant: C#CCNC(=O)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 110 °C
Yield: 97.2 %

Procedure:
N-2-Propyn-1-yl-3-(trifluoromethyl)benzamide (Example 370A) (7.0 g, 30.8 mmol) was suspended in sulfuric acid (95˜98%, 15 mL). The mixture was heated at 110° C. for 15 min. After cooling down, ice was added and solution was neutralized with 5N NaOH to pH 7 at 0° C. The mixture was extracted with Et2O three times and the combined organic layers were washed with brine once and dried over MgSO4. Concentration and purification by radial chromatography (0-20% EtOAc-hexanes gradient) afforded the title compound (6.8 g, 97% yield): MS (ES) m/z 228 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16]CC)=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[OH-].[Na+].C(O)C.Cl>O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[N:6][N:5]([CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])[C:9]=2[CH:10]=1)([OH:16])=[O:15]
Reactant: CCOC(=O)c1ccc2nnn(Cc3ccc(Cl)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2nnn(Cc3ccc(Cl)cc3Cl)c2c1
Yield: 90.6 %

Procedure:
1-(2,4-Dichlorobenzyl)-6-(ethoxycarbonyl)benzotriazole (0.60 g) was refluxed under heating in a mixed solvent of 5% aqueous solution of sodium hydroxide (6 g) and ethanol (20 g) for 0.5 hr. After cooling, concentrated hydrochloric acid (4 ml) and water (10 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate, concentrated and dried to give the objective compound (0.50 g) as a crude product.
Reaction SMILES: [C:1]([C:4]1([CH3:18])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[S:3])[NH2:2].Br[CH2:20][C:21]([CH3:23])=O>C(O)C>[CH3:9][C:6]1([CH3:10])[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]([CH3:18])([C:1]2[S:3][CH:20]=[C:21]([CH3:23])[N:2]=2)[CH2:8][O:7]1
Reactant: CC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)C(N)=S
Solvent: CCO
Product: Cc1csc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)n1

Procedure:
A solution of 244 mg of tert-butyl 4-carbamothioyl-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate and 0.1 ml of 1-bromoacetone in 10 ml of ethanol was stirred at 75° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 102 mg of tert-butyl 2,2,4-trimethyl-4-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(F)cc3F)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 353(MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[N:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccc(O)cc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and tyramine in DME. ES-MS m/e (%): 376 (M+H+, 100).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 193 °C
Reaction time: 4.5 h
Yield: 92.5 %

Procedure:
In 13.4 mL of N-methyl-2-pyrrolidinone were dissolved 6.49 g (20 mmol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 2.68 g (10.0 mmol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, heated to 191-195° C. under a nitrogen atmosphere and stirred for 4.5 hours. After cooling to room temperature, 20 mL of water and 1.01 g (2 mmol) of sodium hydrogencarbonate were added and extracted twice with 30 mL of ethyl acetate. The extract was washed with 20 mL of water three times and the organic layer was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to be eluted with ethyl acetate:methanol:triethylamine (100:5:1). The desired fraction was collected and concentrated to provide 5.14 g of the crude title compound. Purity 83%, yield 77%, determined from the integral values of the proton NMR.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:18]([F:32])[CH:17]=2)=[C:6]1[CH3:33].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:34])=[O:2])[C:6]([CH3:33])=[C:7]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)(=[O:23])=[O:24])=[C:18]([F:32])[CH:17]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)c3ccc(F)cc3)c(F)c2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(S(=O)(=O)c3ccc(F)cc3)c(F)c2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
A mixture of {5-fluoro-3-[3-fluoro-4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}acetic acid methyl ester (0.14 g) and tetrahydrofuran (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (2.0 mL), and the resulting mixture was stirred at 40° C. for 1 hour. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (3.5:6.5 to 9:1, by volume) to afford the title compound as a white solid (0.046 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[O:15][C:16]1[CH:17]=[C:18]([N:23](C(C)(C)C)C(=O)[O-])[CH:19]=[CH:20][C:21]=1[CH3:22])(=[O:3])[CH3:2].[OH-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[O:15][C:16]1[CH:17]=[C:18]([NH2:23])[CH:19]=[CH:20][C:21]=1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(Oc3cc(N(C(=O)[O-])C(C)(C)C)ccc3C)ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc2c(Oc3cc(N)ccc3C)ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
3-(8-Acetylaminoquinolin-4-yloxy)-4-methylphenyl-t-butylcarbamate (120 mg, 0.26 mmol) was dissolved in a 1:1 (by volume) mixture of dichloromethane and trifluoroacetic acid, which was then stirred at room temperature for one hour. When the reaction was completed, the resultant was neutralized with 1 M sodium hydroxide. The resultant was extracted with dichloromethane and water, and combined organic layers were dried with anhydrous sodium sulfate, and then filtered. After the solvent was removed by vacuum distillation, filtered a brown solid product to obtain 86 mg of the desired compound (yield 88.6%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1[N+:11]([O-:13])=O.O.[NH2:15][NH2:16].Cl>C(O)C.O>[OH:13][N:11]1[C:3]2[CH:4]=[CH:5][CH:9]=[CH:10][C:2]=2[N:16]=[N:15]1
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: On1nnc2ccccc21

Procedure:
Referring to FIG. 1, 1-hydroxybenzotriazole-6-carboxylic acid is formed in two steps from 4-chloro-3-nitrobenzoic acid. In the first step, 4-chloro-3-nitrobenzoic acid and hydrazine monohydrate are heated at reflux in ethanol to yield a crude precipitate. In the second step, the crude precipitate is dissolved in water and acidified with HCl to pH 1 to yield 1-hydroxybenzotriazole, a peach colored precipitate. Confirmation of the compound can be conducted by NMR spectroscopy and high resolution mass spectroscopy (HRMS), as well as other detection methods determined by one of skill in the art.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31])=[O:4])[N:6]=1)#[N:26]
Reactant: CC(C)(N)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NC(C)(C)CC(=O)O)nc(C#N)c3c2)cc1
Yield: 21.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-amino-3-methyl-butyric acid (100 mg) and NaOMe (45 mg) in DMA (1.5 mL) was microwaved at 150° C. for 3 h. The mixture was cooled, diluted with water, acidified with 2 M HCl solution, solids were collected with filtration, washed with water, air dried then the residue was further column purified to give the desired product (27 mg). LC MS ESI+: 436 (M+1)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][CH2:18][C@H:17]([N:21]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)[C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:16]3[CH:43]=[C:44]([CH3:51])[C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:15]2=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=1)[CH2:28][N:21]([C@H:17]1[CH2:18][CH2:19][CH2:20][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]2[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[C:44]([CH3:51])=[CH:43][C:16]1=2)[C:22]1[N:23]=[N:24][N:25]([CH3:27])[N:26]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C1CCN(Cc3ccccc3)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 5 h
Yield: 48.3 %

Procedure:
Subject a mixture of (S)-[1-(1-benzyl-piperidin-4-yl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.130 g, 0.179 mmol) and palladium on carbon (10% by weight, wet, 0.050 g) in methanol (10 mL) to an atmosphere of hydrogen gas (35 psi) at room temperature on a Parr shaker apparatus. After 5 h, filter the mixture through celite and the concentrate the filtrate under reduced pressure. Purify the resulting residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as white solid (0.055 g, 48%): 1H NMR (CDCl3, 300 MHz) δ 1.63-2.13 (m, 10H), 2.34 (s, 3H), 2.82-3.0 (m, 3H), 3.10-3.22 (m, 1H), 3.33-3.41 (m, 1H), 4.09-4.13 (m, 1H), 4.14 (s, 3H), 4.74-4.97 (m, 2H), 5.12 (bs, 1H), 5.34-5.49 (m, 1H), 6.89 (s, 1H), 7.32 (s, 1H), 7.60 (s, 1H), 7.71 (s, 1H); ESI MS m/z 726 [C28H30F9N7+H]+.
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]([O:17]C)=[N:15][C:14]2[C:9]1=[N:10][C:11]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:12][C:13]=2[NH2:19].C(N(CC)C(C)C)(C)C.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl-]>CN(C=O)C>[NH2:19][C:13]1[N:12]=[C:11]([O:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[N:10]=[C:9]2[C:14]=1[NH:15][C:16](=[O:17])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1nc2c(N)nc(OC3CCCCC3)nc2n1CCCCCl
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(OC2CCCCC2)nc2c1[nH]c(=O)n2CCCCN1CCCCC1
Yield: 14.1 %

Procedure:
Sodium iodide (0.006 g, 0.04 mmol) was added to a stirred mixture of 9-(4-chlorobutyl)-2-(cyclohexyloxy)-8-(methyloxy)-9H-purin-6-amine (0.103 g, 0.303 mmol), N,N-diisopropylethylamine (0.105 ml, 0.079 g, 0.609 mmol) and piperidine (0.120 ml, 0.103 g, 1.215 mmol) in DMF (1.5 ml). The resultant mixture was heated at 80° C. for 20 hours when LCMS showed the formation of two products, one corresponding to displacement of the chloride by piperidine and the second corresponding to concomitant hydrolysis of the 8-methoxy moiety. The reaction mixture was partitioned between dichloromethane (6 ml) and water (6 ml) and the phases separated using a hydrophobic frit. The solvent was removed from the organic phase under a stream of nitrogen in a blow-down unit and the residue was dissolved in 1:1 MeOH:DMSO (2 ml) and separated by mass directed autopreparation (Method A) to afford the title compound as a white solid (16.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:16])[C:6]=2[CH:17]=1.Br.C1C2C(=CC=CC=2)C=CC=1CS[C:31](=[NH:33])[CH3:32]>C(O)C>[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([NH:1][C:31](=[NH:33])[CH3:32])[CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[NH:8]1
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1O2
Reactant: CC(=N)SCc1ccc2ccccc2c1
Agent: Br
Solvent: CCO
Product: CC(=N)Nc1ccc2c(c1)C(=O)Nc1ccccc1O2
Temperature: 25 °C

Procedure:
To a stirred solution of 2-amino-10H-dibenzo[b,f][1,4]oxazepin-11-one (Example 4, 50 mg, 0.22 mmol) in 4 mL of ethanol at 0° C. was added thioacetimidic acid naphthalen-2-ylmethyl ester hydrobromide (65 mg, 0.22 mmol). The reaction was warmed to room temperature overnight. The mixture was concentrated at reduced pressure and partitioned between water (5 mL) and ethyl acetate (25 mL). The aqueous layer was separated and evaporated under vacuum (yield 70 mg, 92%). H1 NMR (DMSO d6) δ: 11.15 (bs, 1H), 10.68 (s, 1H), 9.44 (bs, 1H), 8.56 (bs, 1H), 7.71-7.70 (m, 1H), 7.54-7.53 (m, 2H), 7.40-7.36 (m, 1H), 7.20-7.17 (m, 3H), 2.31 (s, 3H), MS (ES): MH+ 268.3.