Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][N:12]=2)[CH:7]=[CH:6]1.Cl[C:15](=[O:20])[C:16]([O:18][CH3:19])=[O:17].CO>C(Cl)Cl>[O:20]=[C:15]([C:7]1[C:8]2[C:13](=[N:12][CH:11]=[CH:10][CH:9]=2)[NH:5][CH:6]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: c1cnc2[nH]ccc2c1
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(=O)c1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a suspension of aluminum chloride (56.4 g, 423 mmol, 5 equiv.) in DCM (50 mL) was added 7-azaindole (10.0 g, 85 mmol). After 1 h at room temperature the resulting mixture was cooled to 0° C. and methyl chlorooxoacetate (51.9 g, 423 mmol, 5 equiv.) was added dropwise. After a period of 18 h at room temperature the reaction mixture was cooled to 0° C. and methanol (300 mL) was added. After a period of 0.5 h at room temperature, the solvents were evaporated. DCM (500 mL) and saturated NaHCO3 (600 mL) were added. The organic layer was separated and the water extracted with DCM (250 mL). The organic phases were combined and stirred for 18 h with a solution of potassium sodium tartrate (166 g in 500 mL of water). The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography with 50% ethyl acetate in hexane to provide 13 g of the title compound.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.Cl.Cl.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(=O)(O)[O-].[Na+]>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc(Cl)cc2)CC1)O3
Temperature: 75 °C
Yield: 49.6 %

Procedure:
To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (577 mg, 1.28 mmol) and 4-chlorophenylpiperazine dihydrochloride (1.03 g, 3.81 mmol) in anhydrous DMSO (10 mL) was added N,N-diisopropylethylamine (1.33 mL, 3.81 mmol). The reaction mixture was heated at 75° C. overnight. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (50% hexanes/EtOAc) afforded 260 mg (15%) of the title compound as a tan solid: MS EI m/z 410.09 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([NH:14][C:15]([C:17]1[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=1[C:28]([F:31])([F:30])[F:29])=O)[CH2:7][CH2:6]2.P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1[O:13][C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])=[N:14][C:8]=1[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(NC(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Yield: 97 %

Procedure:
A solution of N-(6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide (Preparation 43A, 135.6 mg, 0.315 mmol) and phosphorous oxychloride (1.468 mL, 15.75 mmol) in anhydrous dichloroethane (5 mL) was heated under an argon atmosphere at 85° C. for 13 hrs. The solvent and excess phosphorous oxychloride were evaporated off and the residue was purified by Combiflash (12 g silica gel) eluting with 2:8 ethyl acetate-hexane to give the desired 7-methoxy-2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazole (126 mg, 97% yield) as an oil. 1H NMR (400 MHz, MeOD) δ ppm 7.62-7.66 (2H, m), 7.53-7.60 (3H, m), 7.48 (1H, d, J=8.14 Hz), 6.94 (1H, d, J=2.20 Hz), 6.89-6.93 (1H, m), 3.84 (3H, s), 3.18 (2H, t, J=8.03 Hz), 2.95-3.01 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[N:13]=[N:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.[H-].[Na+].C(OC1C=C(OC2N(C)N=C([C:37](F)([F:39])[F:38])C=2)N=NC=1)C>CN(C=O)C>[F:38][CH:37]([F:39])[O:14][C:10]1[CH:9]=[C:8]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:16])[F:17])[CH:5]=2)[N:13]=[N:12][CH:11]=1
Reactant: CCOc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(O)cnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(OC(F)F)cnn1
Temperature: 0 °C
Yield: 12 %

Procedure:
6-[[1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]-4-pyridazinol (Compound No. 12, 1.0 g, 0.0038 mole) and NaH (1.15 g of 80% NaH in oil, 0.0384 mole) were heated to 80° C. in DMF (20 mL) while CF2ClH was continuously bubbled through the solution for 6.5 h. The mixture was cooled to 0° C. and quenched by dropwise addition of water under an N2 sweep. After H2 ceased to evolve the mixture was poured into water/ethyl acetate and made acidic with excess ammonium chloride and then extracted 3×100 mL with ethyl acetate. The organic layers were extracted with brine, dried (MgSO4), filtered through silica gel with ethyl acetate, and evaporated in vacuo. Two compounds were present as evidenced by TLC. The mixture was separated by reverse phase chroma-tography to give 5-(difluoromethoxy)-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (0.144 g, 12% yield) as a yellow solid (mp= 86 -88° C.) and 5-ethoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (0.058 g, 5% yield as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:31][CH:32]1[CH2:37][CH2:36][N:35](C(OCC)=O)[CH2:34][CH2:33]1)=[O:17].C(OCC)(=O)C>Br.O.[OH-].[NH4+]>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:31][CH:32]1[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CCOC(=O)N1CCC(Nc2cc(N3CCN(C)CC3)ccc2C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)CC1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCNCC3)c2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
ethyl 4-{[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}piperidine-1-carboxylate (198 mg, 0.313 mmol) were dissolved in 62% aqueous HBr (4 mL) in a screw cap pirex tube and stirred at 70° C. for 1 hour. The mixture was then diluted with water and 30% ammonium hydroxide and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated to dryness. After purification by chromatography on silica gel (DCM/MeOH/NH3 7% in MeOH, 80:10:10) 127 mg of pure product were obtained (72% yield). The product was slurried with ethyl acetate, filtered, washed with n-hexane and dried at 45° C. under high vacuum for 3 hours to give 88 mg of title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.I[C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[N:30]([C@H:38]2[CH2:43][CH2:42][C@@H:41]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)[CH2:40][CH2:39]3)[N:29]=[C:28]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:26]=[CH:25][C:5]=5[N:6]=4)=[CH:15][CH:14]=3)[C:36]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccc(Cl)cc6s5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 90 °C
Yield: 25.8 %

Procedure:
Procedure for Suzuki coupling: A mixture of N-(6-chloro-1,3-benzothiazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.116 g, 0.30 mmol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.106 g, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.014 g, 0.012 mmol) in ethylene glycol dimethyl ether (3.0 mL), sodium carbonate (0.064 g, 0.60 mmol), and water (1.5 mL) in a sealed Schlenk flask were heated at 90° C. for 24 h. The mixture was cooled, diluted with water (10 mL) and extracted with methanol/dichloromethane (1:19, 3×20 mL). The combined organic fractions were dried (magnesium sulfate), filtered, concentrated and purified by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 7.8-10.0 min) to afford cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-6-chloro-1,3-benzothiazol-2-amine as a yellow powder (0.036 g, 0.062 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.42 min;
Reaction SMILES: Cl.[C:2]([CH2:4][CH:5]1[CH2:13][CH:12]2[CH:8]([CH2:9][NH:10][CH2:11]2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH2:6]1)#[N:3].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[C:2]([CH2:4][CH:5]1[CH2:13][CH:12]2[CH:8]([CH2:9][N:10]([C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:11]2)[C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([OH:14])[CH2:6]1)#[N:3]
Reactant: N#CCC1CC2CNCC2C(O)(c2ccccc2)C1
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Product: COc1ccccc1CC(=O)N1CC2CC(CC#N)CC(O)(c3ccccc3)C2C1
Yield: 64.3 %

Procedure:
The procedure is as described in Example 14 beloW, starting from 0.63 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-phenylperhydroisoindol-4-ol hydrochloride and 0.39 g of 2-methoxyphenylacetic acid, and gives 0.56 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-phenyl-2-(2-methoxyphenylacetyl)perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1c2n(c3cc(Br)c(F)cc3c1=O)CCS2
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3CCS2)CC1
Yield: 22 %

Procedure:
A mixture of 500 mg (1.45 mmol) of 8-bromo-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a) quinoline-4-carboxylic acid, 730 mg (7.25 mmol) of N-methylpiperazine and 10 ml of pyridine was heated to reflux for twelve hours on an oil bath. The conent was then concentrated under reduced pressure, water was added to the residue, insoluble matters were collected by filtration, washed with water, dried, and the resulting powder was recrystallized from dimethyl formamide to give 116 mg (22.0 percent) of the title compound. Melting point was 267° to 271° C. (decomposition).
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)C.[NH2:14][C:15]1[C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][NH:17][N:16]=1>C1(C)C(C)=CC=CC=1>[C:22]1([C:20]([C:19]2[CH:18]=[N:17][N:16]3[C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)=[CH:5][CH:4]=[N:14][C:15]=23)=[O:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC=CC(=O)c1cccnc1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.02 mole of 3-ethoxy-1-(3-pyridinyl)-2-propen-1-one, 0.02 mole of (3-amino-1H-pyrazol-4-yl)phenyl-methanone and 100 ml of xylene was refluxed for 12 hours. The solvent was removed and the residue dissolved in dichloromethane. This solution was dried over sodium sulfate and the product isolated as described in Example 1, as crystals, mp 202°-203° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O.C(=O)([O-])O.[Na+]>C(O)CC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:15]=[C:12]3[CH:11]=[CH:10][C:9]([B:4]4[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]4)=[CH:14][N:13]3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: CC1(C)OB(c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)OC1(C)C
Temperature: 80 °C
Yield: 135.8 %

Procedure:
5.0 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine and 5.30 g of 2-bromo-1-(4-chlorophenyl)ethanone are placed in 150 ml of n-propanol in a round-bottomed flask. 2.67 g of sodium hydrogencarbonate are added. The mixture is heated at 80° C. for 16 h. After cooling, the reaction mixture is concentrated under reduced pressure. 10.93 g of compound are obtained, which compound is used as is in the following stages.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4](Cl)[N:3]=1.C1CCN2C(=NCCC2)CC1.[OH:28][C:29]([CH3:38])([CH3:37])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CS(C)=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:29]([OH:28])([CH3:37])[CH3:38])[CH2:32][CH2:33]2)[N:3]=1
Reactant: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Reactant: CC(C)(O)CN1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CC(C)(O)CN1CCN(c2cc3nc(-c4ccco4)nn3c(N)n2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
Into 7 mL of DMSO, 500 mg (2.12 mmol) of Compound E was dissolved, and then 0.95 mL (6.36 mmol) of DBU and 1.50 g (9.50 mmol) of 1-(2-hydroxy-2-methylpropyl)piperazine were added thereto, followed by stirring at 140° C. for about 2 hours. After completion of the reaction, the reaction mixture was extracted by adding chloroform and water, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (3% methanol-chloroform) and then recrystallized from a mixed solvent of hexane-ethyl acetate to obtain 250 mg of Compound 1 as a white solid (yield: 33%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[CH:11][C:10]=1[CH3:21])C1C=CC=CC=1>C(O)C.O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[C:12]1[C:13]([CH3:15])=[CH:14][C:9]([NH2:8])=[C:10]([CH3:21])[CH:11]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Solvent: CCO
Solvent: O
Product: Cc1cc(C2OCCO2)c(C)cc1N
Reaction time: 8 h
Yield: 92 %

Procedure:
The crude dibenzyl-(4-[1,3]dioxolan-2-yl-2,5-dimethyl-phenyl)amine was dissolved in a 2:1 mixture of ethanol and water (150 mL total) and the resulting mixture was purged with dry nitrogen for 5 minutes. Palladium on carbon (2.3 g, 10 wt. % containing about 50% water) and solid sodium bicarbonate (1.0 g) were added and the resulting mixture was hydrogenated at about 1 atm of hydrogen at 25° C. to 30° C. for about 8 hours. The mixture was then filtered through Celite and the filtrate was concentrated on a rotary evaporator to provide crude 4-[1,3]dioxolan-2-yl-2,5-dimethylphenylamine (5.6 g, 92% yield) as a thick oil. 1H NMR (300 MHz, DMSO-d6) δ 2.05 (s, 3H), 2.22 (s, 3H), 3.7-3.9 (m, 4H), 3.95 (s, 4H), 5.59 (s, 1H), 6.72 (s, 1H), 7.0-7.25 (m, 11H).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:21]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:23]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[N:7]=[C:6]([C:38]([O:40]C)=[O:39])[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:20][C:21]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:22][N:23]=5)[CH:17]=4)[NH:12][CH:11]=3)[N:7]=[C:6]([C:38]([OH:40])=[O:39])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(C2CC2)nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4nc(C(=O)O)cc(C5CC5)n4)c3c2)o1
Temperature: 100 °C
Yield: 67.1 %

Procedure:
In a 5 mL microwave tube methyl 6-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-4-carboxylate (16 mg, 0.028 mmol) was treated with dioxane (1 mL) and 1N NaOH (0.5 mL) and heated in the microwave at 100° C. for 10 min. The mixture was concentrated and purified with reverse phase HPLC (20-95% 0.1% TFA/AcCN in 0.1% TFA/H2O) affording 6-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)pyrimidine-4-carboxylic acid (7.6 mg, 67%) as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 405.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (1H, d, J=2.3 Hz), 9.04 (1H, s), 8.40 (1H, d, J=2.7 Hz), 7.65-7.72 (2H, m), 7.59-7.64 (1H, m), 7.57 (1H, d, J=7.8 Hz), 3.83 (1H, dd, J=13.8, 6.6 Hz), 2.34 (1H, dt, J=7.9, 3.9 Hz), 1.29-1.36 (2H, m), 1.27 (6H, d, J=6.5 Hz), 1.23 (3H, dt, J=7.9, 3.2 Hz).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].II>C(O)C>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2[nH]1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2[nH]c(SSc3nc4ccccc4[nH]3)nc2c1

Procedure:
A solution prepared from 10.0 g 2-mercaptobenzoimidazole, 88 g ethanol and 6.68 g 40% aqueous NaOH was mixed with a solution of 8.54 g iodine in 79 g of ethanol. The resulting mixture was filtered, and the collected product was washed with ethanol and dried under vacuum at 70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2O.P(Br)(Br)([Br:16])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2nccc(O)c2c1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(Br)c2c1
Yield: 50 %

Procedure:
This was prepared by heating 6-methoxy-quinolin-4-ol (1 g) and phosphorus oxybromide (5 g) in chloroform (40 ml) under reflux for 18 hours. The mixture was cooled, basified with sodium bicarbonate, extracted with 5% methanol-chloroform, and dried (sodium sulfate). The product was chromatographed on silica gel (2-5% methanol-dichloromethane) to afford a solid (0.68 g).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Clc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2nccs2)cc1
Reaction time: 6 h
Yield: 27.8 %

Procedure:
A mixture of 2-chlorothiazole (2.0 g), ethyl 4-hydroxybenzoate (2.8 g), potassium carbonate powder (3.5 g) and dimethylformamide (30 ml) is stirred at 135°-140° C for 6 hours. The reaction mixture is treated in the same manner as in Example 1. From the eluate of 30% ether-benzene, ethyl 4-(2-thiazolyloxy)benzoate (1.16 g) is obtained. IR νmaxCCl 4 1730, 1280 cm-1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1>>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)ccc1C(=O)O
Product: Cc1c(C(=O)O)ccc(Cl)c1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To fuming nitric acid (20.4 mL, 410 mmol) was slowly added dropwise 4-chloro-2-methylbenzoic acid (5.0 g, 29.3 mmol) while maintaining the temperature of the reaction mixture at 5-10° C. The reaction solution was stirred at 0-5° C. for 1 hr, and poured into ice. The precipitated solid was recovered, washed with water, and dried under reduced pressure to give 4-chloro-2-methyl-3-nitrobenzoic acid (6.14 g, purity 33%) as a crudely purified product.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][C@H:11]([C:13]([O:15]CC)=[O:14])[C@H:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>>[CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[C@H:10]([CH2:18][CH3:19])[CH2:9]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)[C@H]1C[C@@H](NS(=O)(=O)C2CC2)C[C@H]1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing (1S,2R,4S)-ethyl 4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylate (11.1 g, 38.4 mmol, Example #15, Step F) was added aqueous NaOH (1 N, 210 mL, 210 mmol). After stirring at ambient temperature for about 8 h, the reaction was acidified to about pH 1 using 6 N aqueous HCl and extracted with DCM (3×150 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give (1S,2R,4S)-4-(cyclopropanesulfonamido)-2-ethylcyclopentanecarboxylic acid with 25 mol % DCM as an excipient (10.7 g, 99%): LC/MS (Table 2, Method a) Rt=1.71 min; MS m/z: 260 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26].C>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:28]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCCN=C=O
Solvent: CC#N
Product: CCCCNC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Yield: 46.7 %

Procedure:
A mixture of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (1.56 g.) and n-butyl isocyanate (0.99 g.) in anhydrous acetonitrile (30 cc.) is heated at the reflux temperature for 2 hours. The solution obtained is treated with decolourising charcoal at the reflux temperature, filtered hot, after which it is cooled to a temperature of about 20° C. The product which crystallises is filtered off and washed with acetonitrile (4 cc.). After drying, 2-(7-chloro-1,8 naphtyridin-2-yl)-3-n-butylaminocarbonyloxy-isoindolin-1-one (0.96 g.), melting at 152° C. and then at 174° C., is obtained.