Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.S(OC)(O[CH3:15])(=O)=O>[OH-].[Na+]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH3:15])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: CSc1nc(O)cc(O)n1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(O)nc(SC)n1
Temperature: 25 °C

Procedure:
15.8 g (0.2 mol) of 2-methylthio-4,6-dihydroxypyrimidine are added while stirring well, to 100 cc of 2N sodium hydroxide solution and the mixture is stirred at 50° for half an hour. The mixture is subsequently cooled to room temperature and 13.9 g (0.11 mol) of dimethyl sulphate are added dropwise, while stirring; by the addition of sodium hydroxide solution 2N the pH value is kept at between 8 and 8.2. After the dropwise addition a precipitate is obtained. The mixture is stirred at 50° for a further 21/2 hours, whereby the pH value is kept at between 8 and 8.3, then cooled to 0° and filtered. The obtained white powder has an M.P. of 193°-195°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12].[Li+].[OH-].C(O)C>C1COCC1>[CH3:12][C:8]1[C:7]2[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[CH:6]=2)[NH:10][N:9]=1
Reactant: CCOC(=O)c1cc(OC)c2[nH]nc(C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2c(C)n[nH]c12
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 7-methoxy-3-methyl-1H-indazole-5-carboxylate (516 mg, 2.08 mmol) in THF (17 mL) was added 1 M LiOH (4.2 mL, 4.2 mmol) and the mixture was heated at reflux overnight. Analysis indicated the presence of small amounts of unreacted starting material; therefore, a small amount of ethanol was added to assist in solubilizing materials. Heating was continued for an additional 2 hours before concentrating to dryness. The residue was triturated with 1 N HCl, the solids were isolated by filtration, washed with water and air dried overnight to provide the title compound as an off-white solid (417 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[O:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1>>[Br:30][C:31]1[O:35][C:34]([C:36]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]3)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:37])=[CH:33][CH:32]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(Br)o2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 5-bromofuran-2-carboxylic acid (41.0 mg, 0.21 mmol).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=1[Cl:26]>>[Cl:18][C:19]1[CH:24]=[C:23]([N:13]2[CH2:14][CH2:15][C:16](=[O:17])[N:10]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:11][CH2:12]2)[CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: Clc1ccc(I)cc1Cl
Product: O=C1CCN(c2ccc(Cl)c(Cl)c2)CCN1CCCN1CCCCC1

Procedure:
The title compound was prepared from 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (Example 33B) and 1,2-dichloro-4-iodo-benzene in analogy to example 33. MS: 384.4 (MH+, 2Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([CH3:37])[CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([CH3:37])[CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2(C)CC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
100 mg (178 μmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoyl}amino)benzoate (racemate) and 274 μl (3.56 mmol) of TFA were reacted according to General Method 2. The reaction mixture was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 107 mg (27% of theory)
Reaction SMILES: [C:1]1([C:7]([NH:12][CH3:13])([CH2:10][CH3:11])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26]Cl)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[O:22][CH3:23])[CH2:26][O:9][CH2:8][C:7]([NH:12][CH3:13])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10][CH3:11]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CCC(CO)(NC)c1ccccc1
Product: CCC(COCc1cc(OC)c(OC)c(OC)c1)(NC)c1ccccc1

Procedure:
Prepared by the process of Example 3 from 2-phenyl-2-methylamino-1-butanol and from 3,4,5-trimethoxy-α-chlorotoluene; the product is obtained in the form of a colourless and viscous oil which is analytically pure and appropriate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][CH:4]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[N:5][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cncc2ccccc12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2cncc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of the title compound from Step A above (1.94 g, 12.2 mmoles) in anhydrous pyridine (14 mL) at 0° C. was added 4-toluenesulfonyl chloride (2.784 g, 14.6 mmoles) and the mixture was stirred at 0° C. for 2.5 h. The solution was evaporated to dryness and the product was azeotroped with toluene and then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, filtered and evaporated to give the title compound which was used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[O:34])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)c(C)c1
Yield: 55 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (26 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 41 mg (yield 55%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[C:20]([F:33])[CH:19]=1>C(OCC)C>[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([S:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[C:20]([F:33])[CH:19]=1
Reactant: CCCN(CCC)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCOCC
Product: CCCN(CCC)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2.6 g of 2,6-difluorobenzoyl isocyanate in 15 ml of diethyl ether was added over 30 seconds to 5.4 g of 38C. The solution was stirred at ambient temperature for 2.5 hours after which a slight precipitate formed. 50 ml of petroleum ether was added, and the resulting suspension was cooled in a freezer (-5° to 0° C.) for 3 hours. The precipitate which formed was filtered off and recrystallised from a 1:1 v:v mixture of diethyl ether and petroleum ether, to give 2.3 g of 38, as white crystals, m.p.: 118°-121° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:4]=1.[C-:19]#[N:20].[Na+]>CN(C=O)C.O>[C:19]([CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:4]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(CC#N)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (5.18 g, 16.59 mmol) in DMF (30 mL) was added sodium cyanide (1.626 g, 33.2 mmol) and stirred at 25° C. for 4 hours. After this time, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The extracts were combined and the resulting solid precipitate was filtered. The filtrate was dried over MgSO4, filtered and the solvent removed in vacuo. This residue was purified by chromatography using 120 g RediSep column and eluting with 0-100% EtOAc/CH2Cl2 gradient. The desired fractions were combined and evaporated in vacuo to provide the title compound. LRMS (M+1): 259.1.
Reaction SMILES: C(N(CC)C(=O)O[CH2:6][N:7]1[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]1=[O:15])C.[CH3:19][S:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>C(#N)C>[CH3:19][S:20][C:21]1[N:22]([CH2:6][N:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]2=[O:15])[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CSc1nc2ccccc2[nH]1
Reactant: CCCC1CC(=O)N(COC(=O)N(CC)CC)C1
Solvent: CC#N
Product: CCCC1CC(=O)N(Cn2c(SC)nc3ccccc32)C1
Yield: 40.3 %

Procedure:
A solution of (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate a26 (1 eq, 3.18 mmol, 0.5 g) and 2-(methylthio)-benzimidazole (1.25 eq, 3.90 mmol, 0.64 g) in acetonitrile (4 ml) was heated under reflux for 42 h. The solvent was evaporated under reduce pressure and purification by preparative chromatography on reverse phase afforded 390 mg of 1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one 90 (HPLC purity (U.V.): 85%; Yield: 40.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[N:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][C:31](O)=[O:32])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][N:18]([C:31](=[O:32])[CH2:30][S:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Reactant: O=C(O)CSc1ccncc1
Product: O=C(CSc1ccncc1)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Yield: 93.8 %

Procedure:
The title compound (548 mg, 94%) [MS (FAB, M+H)=483.1] was prepared similarly from 1-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-piperazine (400 mg, 1.21 mmol) and (4-pyridinylthio)acetic acid (410 mg, 2.42 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][N:6]([C@H:14]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:36])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2)=[O:16])C(OC(C)(C)C)=O)[CH3:2].[ClH:47]>O1CCOCC1>[ClH:47].[CH2:1]([O:3][C:4](=[O:46])[CH2:5][NH:6][C@H:14]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:36])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([NH2:35])=[N:30][CH:29]=[CH:28]2)=[O:16])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CN[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.150 g of {[2-{2-(S)-[(1-Amino-isoquinolin-6-ylmethyl)-carbamoyl]-pyrrolidin-1-yl}-1-(R)-(4-methoxybenzyl)-2-oxo-ethyl]-tert.-butoxycarbonyl-amino}-acetic acid ethyl ester were treated with 5 mL of HCl in dioxane (5M solution) and the mixture was stirred for 3 h at ambient temperature. The solvent was distilled off and the remaining white solid was washed with diethyl ether and dried. Yield: 0.100 g (80%); (+)-APCI-MS: 534 (MH+).
Reaction SMILES: [CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([O:22][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1c2c(oc3cc(O)ccc13)C(=Cc1ccccc1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3c(oc2c1)C(=Cc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Benzylidene-6-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one (1.5 g) was reacted with ethyl 2-bromo-acetate (1.67 g) in dimethylformamide (60 ml), in the presence of anhydrous K2CO3 (1.38 g), under stirring at room temperature for 3 hours. The reaction mixture was diluted with ice water containing NaH2PO4 and the precipitated product was filtered and washed with water: crystallization from CH2Cl2 /methanol gave (3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-acetic acid, ethyl ester, m.p. 152°-154° C. (1.75 g), which was dissolved in dimethylformamide (22 ml) and treated with 2N NaOH (11.5 ml) at room temperature for 2 hours. The reaction mixture was acidified with 2N HCl and then diluted with ice water: the precipitated product was filtered and washed with water until neutral. Crystallization from CHCl3 /ethanol gave 1.4 g of (3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1] benzopyran-6-yloxy)-acetic acid, m.p. 277°-279° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21])=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:40]([C:34]3[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=3[F:32])(=[O:42])=[O:41])[C:3]=2[F:31])[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate (400 mg, 0.862 mmol) in pyridine (50 mL) was added dropwise 2,6-difluorobenzenesulfonyl chloride (238 mg, 1.121 mmol). After 4 h, 2,6-difluorobenzenesulfonyl chloride (0.20 g) was added to the reaction mixture and stirred at rt overnight. The reaction mixture was concentrated. The residue was purified via chromatography on silica gel to obtain the title compound (330 mg 59% yield). MS (ESI): 639.9 [M+H]+
Reaction SMILES: CO[C:3]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)=[O:4].CO.[CH2:13]([NH2:16])[CH2:14][NH2:15].Cl>O>[NH2:15][CH2:14][CH2:13][NH:16][C:3]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C#N)CCC1
Reactant: NCCN
Agent: Cl
Solvent: O
Solvent: CO
Product: N#CC1(C(=O)NCCN)CCC1
Yield: 60.6 %

Procedure:
8.74 g (0.063 mol) of 4 and 50 mL of methanol were mixed, after which the mixture was added dropwisely into 3.77 g (4.25 mL) of ethylene diamine to form a reaction solution. The reaction solution was subjected to reaction at room temperature for 15 hours, followed by evaporation to obtain yellow oil. The yellow oil was stirred with water and was mixed with HCl to adjust pH to 2 to obtain a crude product. The crude product was purified by placing in a column (3×20 cm) filled with 100 mL of AG 50 W×8 cationic exchange resin and elutriating with water and HCl solution having gradient concentrations, collecting an eluent fraction of a gradient concentration from 0.5 N to 1.0 N, and followed by evaporating the eluent fraction to obtain 6.37 g (0.038 mol, 60.49%) of 5.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH3:22][C:23]([O:26][C:27]([N:29]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:30]([C:38]1[C:43]([F:44])=[C:42](Cl)[N:41]=[C:40]([Cl:46])[N:39]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:28])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:25][C:23]([O:26][C:27]([N:29]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:30]([C:38]1[C:43]([F:44])=[C:42]([N:6]2[CH2:7][C:4]([CH3:3])([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:5]2)[N:41]=[C:40]([Cl:46])[N:39]=1)[C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[O:28])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CC1(N2CCCC2)CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CC(C)(N3CCCC3)C2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a stirred solution of 1-(3-methyl-3-azetidinyl)pyrrolidine dihydrochloride (0.128 g, 86% pure, 0.52 mmol) in DMF (8 mL) at 0° C. was added DIPEA (0.34 mL, 1.94 mmol) followed immediately by tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.24, 0.49 mmol). The reaction was warmed up to rt and stirred overnight. The mixture was purified by RP-HPLC to provide tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.225 g, 77%). LCMS: (M+H)+: 601.2.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.S(Cl)([Cl:24])=O>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:24])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: O=S(Cl)Cl
Product: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O

Procedure:
2-(5-Oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride is obtained by heating 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionic acid (28 g.) in thionyl chloride (280 cc.) for 1 hour. After cooling, the thionyl chloride is evaporated at 60°C. under reduced pressure (20 mm.Hg). 2-(5-Oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (28.8 g.) is thus obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8](C(OC(C)(C)C)=O)[N:9]=[CH:10][C:5]2=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.CNC>CO.O>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]=12
Reactant: CC(C)(C)OC(=O)n1ncc2c(-c3ccco3)nc(N)nc21
Agent: CNC
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Yield: 69.4 %

Procedure:
A solution of tert-butyl 6-amino-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate (204 mg, 0.68 mmol) in MeOH (2 mL) was treated with dimethylamine in water (0.5 mL, 40%), refluxed for 1 h, cooled and the resulting solid filtered and washed with water to give the title compound (95 mg, 70%) as a cream solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([CH3:38])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]([N:26]([C:34](=[O:36])[CH3:35])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:18][CH:17]2[CH3:37])=[O:15])=[CH:10][CH:9]=1.[OH-].[Li+]>CO.C1COCC1>[C:34]([N:26]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C@H:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][C@H:4]([CH3:38])[C:3]([OH:39])=[O:2])=[CH:13][CH:12]=2)=[O:15])[CH:17]([CH3:37])[CH2:18]1)(=[O:36])[CH3:35]
Reactant: COC(=O)[C@@H](C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)CC2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1CC(C)N(C(=O)c2ccc(OCC[C@H](C)C(=O)O)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2-methyl-butyric acid methyl ester (100 mg) was dissolved in methanol/THF, and lithium hydroxide (1.0N, 2 mL) was added. After 1 hour, the reaction was acidified and extracted with methylene chloride. The organic layer was dried, filtered, and concentrated. The crude residue was purified by silica gel chromatography ethyl acetate—5% MeOH/ethyl acetate gradient) to afford the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl.O>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 82.4 %

Procedure:
To a stirred mixture of 2-amino-5-chloro-3-nitrobenzotrifluoride (250 mg, 1.043 mmol) in ethanol (4 mL) was added SnCl2.2 H2O (1.174 g, 5.217 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h. The solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried (Mg2SO4) and evaporated to give 181 mg (83%) of 2,3-diamino-5-chlorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ 3.515 (s, 2H); 3.878 (s, 2H); 6.845 (s, 1H); 6.988 (s, 1H).