Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH3:23])[CH2:20][C:21]#[CH:22].O>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:22][C:21]#[C:20][N:19]([CH3:23])[CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(I)ccc21
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: O
Product: CN(C)C#CCc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 89.8 %

Procedure:
1-(tert-Butoxycarbonyl)-5-iodoindole (1.00 g, 2.91 mmol) was dissolved in diethylamine (20 mL), and the solution was added with bis(triphenylphosphine)dichloropalladium (163 mg, 0.233 mmol), cuprous iodide (44.4 mg, 0.233 mmol) and 1-dimethylamino-2-propyne (0.628 mL, 5.82 mmol), followed by stirring at 80° C. for 7.0 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=19/1) to obtain 1-(tert-butoxycarbonyl)-5-(3-dimethylamino-2-propyn-1-yl)indole (0.78 g, yield 90%).
Reaction SMILES: [S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6](Cl)=[O:7])([OH:4])(=[O:3])=[O:2].[NH2:18][CH:19]1[C:25](=[O:26])[N:24]2[CH:20]1[S:21][C:22]([CH3:31])([CH3:30])[CH:23]2[C:27]([OH:29])=[O:28].O>CCOCC.C(=O)(O)[O-].[Na+]>[S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([NH:18][CH:19]1[C:25](=[O:26])[N:24]2[CH:20]1[S:21][C:22]([CH3:31])([CH3:30])[CH:23]2[C:27]([OH:29])=[O:28])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Reactant: O=C(Cl)C(c1ccc2c(c1)CCO2)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)SC2C(NC(=O)C(c3ccc4c(c3)CCO4)S(=O)(=O)O)C(=O)N2C1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride (5 mmole) in 10 ml of ether is added to 5 mmole of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid dissolved in 10 ml of water containing 10 mmole of sodium bicarbonate. The temperature is maintained at about 0° C. during the addition. The reaction mixture is stirred for about 30 minutes at 0° C. The organic phase is separated from the aqueous phase. The pH of the aqueous phase is adjusted to 6.5 to 7.0. The aqueous phase is extracted with ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:19][C:20]([OH:22])=O)[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)O.[NH2:39][C:40]([NH2:42])=[NH:41].C(N(CC)CC)C>CN(C=O)C>[NH2:41][C:40](=[NH:39])[NH:42][C:20](=[O:22])[CH2:19][N:9]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=[C:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a stirred solution of (2-benzyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (155 mg, 0.53 mmol) in DMF (1.0 ml) was added 1,1′-carbonyldiimidazole (172 mg, 1.06 mmol) at room temperature. After 1 h stirring, the reaction mixture was treated with a solution of guanidine carbonate (286 mg, 1.59 mmol) in DMF (2.0 ml) and triethylamine (0.22 ml, 1.59 mmol). After stirring for 18 h, the reaction mixture was quenched with H2O (10 ml). The aqueous was extracted with EtOAc (3×30 ml). The combined organic extracts were washed with H2O (2×30 ml), brine (30 ml), dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/2M NH3 in MeOH: 97/3) to give the titled compound (130 mg, 74%) as a solid: mp 155-158° C.; MS (+) ES, 333 (M+H)+.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC.C1C=CC=CC=1>[C:11]1([C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=C1CCCCC1
Reactant: c1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCOCC
Product: C1=C(c2cccs2)CCCC1
Reaction time: 16 h

Procedure:
n-Butyllithium (40.7 ml, 1.5 M) was added dropwise to a stirred solution of thiophene (5 g) in dry ether (50 ml) and the mixture heated under reflux for 30 min. After cooling to -78°, cyclohexanone (6.21 ml) in dry ether (30 ml) was added dropwise and the temperature allowed to rise to ambient. After 1h 2N hydrochloric acid (80 ml) was added and stirring continued for 16h. The organic layer was separated and the aqueous layer extracted with ether (2×40 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to give an oil, which was dissolved in benzene (50 ml) and heated under reflux in the presence of PTSA for 0.75h. the cooled solution was washed twice with 8% NaHCO3 solution and the aqueous solution extracted with ether (2×40 ml), dried (MgSO4) filteed and evaporated to give the title compound as an oil (9.83 g). TLC(F) Rf 0.73
Reaction SMILES: [CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:18]2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:59][CH2:60][CH3:61]>C1COCC1>[CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17]([CH2:59][CH2:60][CH3:61])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:18]2)=[CH:13][CH:12]=1)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)OC(C(=O)OCC)CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)OC(CCC)(C(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To a 2 ml THF solution of ethyl 7-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate (Example 1, Step B) (100 mg, 0.204 mmol) were added hexamethylphosphoramide (0.046 ml, 0.26 mmol) and sodium bis(trimethylsilyl)amide (1.0M THF solution) (0.265 ml, 0.265 mmol) upon cooling in a dry ice-acetone bath. After stirring at that temperature for 30min, to it was added iodopropane (0.06 ml, 6.2 mmol). The cooling bath was removed and the reaction mixture was gradually warmed to rt overnight. The solvent was removed under reduced pressure, diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 5% AcOEt/hexanes gave the title compound as a clear oil 33 mg (30%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+].CN(C)C=O.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O>[N:1]1([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C
Yield: 61.5 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1H-pyrazole (422 mg, 6.21 mmol, 1.50 equiv), sodium hydroxide (248 mg, 6.20 mmol, 1.50 equiv), and N,N-dimethylformamide (20 mL). The mixture was stirred and heated to 80° C. for 30 min, then to this was added 4-fluorobenzonitrile (500 mg, 4.13 mmol, 1.00 equiv). The resulting solution was stirred for 3 h at 110° C. in an oil bath. The resulting solution was diluted with 50 mL of H2O. The solids were collected by filtration and dried in an oven. The product was obtained as 0.43 g (62%) of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:26]1([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[CH2:30][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:37])[O:27]1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:26]2([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=3)=[O:39])[CH2:30][CH:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28](=[O:37])[O:27]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Reactant: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC(c3ccccc3)C(=O)O2)C1=O)OCc1ccccc1
Yield: 68.9 %

Procedure:
Production of Compound(64): In 6 ml of dichloromethane was suspended 280 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the suspension were added, under ice-cooling and stirring, 0.36 ml of triethylamine and 490 mg of the Compound (63) obtained in Example 63 dissolved in 1 ml of dichloromethane. The reaction was solution stirred at room temperature for 30 minutes, which was washed with water and dried (MgSO4). The solvent was evaporated off, and the residue was chromatographed on silica gel, followed by elution with hexane-ethylacetate (3:1) to give 470 mg of the subject Compound (64) as colorless oily product. The IR and NMR spectra of this product were in agreement with those of the Compound (64) obtained in Example 64.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.CN(C)C=O.[CH2:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:31][C@H:30]3[O:32][CH2:33][CH2:34][O:35][C@@H:29]3[CH2:28]2)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([C:21]1[C:26]([I:1])=[CH:25][CH:24]=[C:23]([N:27]2[CH2:28][C@H:29]3[O:35][CH2:34][CH2:33][O:32][C@@H:30]3[CH2:31]2)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(Cc2cccc(N3C[C@H]4OCCO[C@@H]4C3)n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccc(N2C[C@H]3OCCO[C@@H]3C2)nc1Cc1ccccc1

Procedure:
4.04 g of N-iodosuccinimide was added little by little to a solution of 40 ml of N,N-dimethylformamide containing 4.84 g of 2-benzyl-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]pyridine under stirring in an ice bath, followed by stirring overnight as it was. The reaction solution was poured into water, and extracted with ethyl acetate. The organic phase was successively washed with an aqueous sodium sulfite solution, water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to filtration using silica gel and crystallized from hexane/ethyl acetate, to give 5.12 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13]>C(O)CCCC.CCOCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: CCCCCO
Product: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Yield: 101 %

Procedure:
2,6-Dichloro-9H-purine (650 mg, 3.44 mmol) and 3-nitroaniline (1.9 g, 13.76 mmol) were stirred in 1-pentanol (5 mL) at 100° C. for 2 h under N2. The mixture was cooled and diluted with Et2O (40 mL). The precipitate was filtered and washed successively on a sinter with Et2O, PriOH, H2O, 10% aq Na2CO3, H2O, PriOH, and Et2O (2×20 mL each). It was then dried in vacuo to afford the title compound as a lemon-yellow powder (1.01 g, quant.). TLC (9:1 CH2Cl2/MeOH): RF=0.35.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:13][C:14]1[CH:15]([OH:25])[CH2:16][C:17](=[CH2:24])[C:18]=1[CH2:19][C:20]([F:23])([F:22])[F:21].N1C=CC=CC=1.N>CN(C)C1C=CN=CC=1.O1CCCC1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7]([O:25][CH:15]2[CH2:16][C:17](=[CH2:24])[C:18]([CH2:19][C:20]([F:21])([F:22])[F:23])=[C:14]2[CH3:13])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: C=C1CC(O)C(C)=C1CC(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C1CC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C(C)=C1CC(F)(F)F
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Under ice-water cooling, 350 mg of (1R)-trans-3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride was added dropwise to the mixed solution of 300 mg of (RS)-2-methyl-4-methylidene-3(2,2,2-trifluoroethyl)cyclopent-2-en-1-ol, 5 mg of 2,6-di-tert-butyl-4-methylphenol, 185 mg of pyridine and 5 mg of 4-dimethylaminopyridine in 10 ml of dry terahydrofuran and then the resultant reaction mixture was allowed to react further 6 hours at room temperature. Then 10 ml of 10% aqueous ammonia solution was added to the solution and vigorously stirred for 2 hours. The reaction mixture was extracted three times with diethyl ether and the ether layers were combined. The combined layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the drying agent, the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography to afford 280 mg of the desired (RS)-2-methyl-4-methylidene-3-(2,2,2-trifluoroethyl)cyclopent-2-en-1-yl (1R)-trans-3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No.15). Yield 52%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[N-:13]=[N+]=[N-].[Na+].CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:13][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a mixture of 6-Methoxy-1-indanone (15 g, 92.6 mmol), sodium azide (26.7 g, 277.8 mmol), in CHCl3 was added methane sulfonic acid (60 g, 926 mmol) via addition funnel at 0° C. Reaction mixture was warm to room temperature. Stirring was continued for 3 hr, then poured into cold water. The organics were extracted with methylene chloride and washed with water, sat. NaCl and dried over Na2SO4. Organic solution was concentrated in vacuo and the residue was purified with silica gel eluting with 20% EtOAc/Hexane to give the title compound as a yellow solid (10.5 g, 63%). MS (ES) m/z 178.1.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[N:48]1([CH2:47][CH2:46][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropyl azodicarboxylate (1.1 eq) was added dropwise to a stirred solution of 4-amino-3-nitrophenol (1.0 eq), triphenylphosphine (1.1 eq), and an alcohol, e.g. N-(2-hydroxyethyl)morpholine (1.0 eq), in tetrahydrofuran at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, and the product was purified by silica gel chromatography (98:2 CH2Cl2:methanol) to yield 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine as a dark reddish-brown oil. LC/MS m/z 268. 0 (MH+), Rt 1.01 minutes. The nitroamine was reduced as in Method 1 to give the crude product which was used without further purification. LC/MS m/z 238.3 (MH+), Rt 0.295 minutes.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O>O>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[N:3]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2cc(Cl)ncc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: O
Product: COc1ccc2cc(-c3ccc(C(=O)O)cc3)ncc2c1

Procedure:
Followed the procedure described in Compound IV-8 step 1, starting with 3-chloro-7-methoxyisoquinoline (Intermediate 12) and 4-boronobenzoic acid with an alternative isolation procedure: After reaction was complete, the reaction mixture was diluted with H2O (10 mL). The aqueous layer was extracted with EtOAc/MeOH (v/v=10:1, 30 mL×2). Then the aqueous layer was acidified with 2M HCl to pH=6. The precipitate was collected by filtration and washed with MeOH (10 mL), dried under high vacuum to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]1)=[O:4].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]([CH:7]1[CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][C:9]2([O:18][CH2:17][CH2:16][O:11]2)[CH2:8]1)=[O:13]
Reactant: OCCO
Reactant: COC(=O)C1CC(=O)CC(C(=O)OC)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(C(=O)OC)CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-oxocyclohexane-1,3-dicarboxylic acid dimethyl ester (22.8 g, 106.4 mmol), ethylene glycol (13.3 g, 215 mmol) and p-toluenesulfonic acid monohydrate (0.22 g, 1.3 mmol) in toluene (230 mL), in a flask fitted with Dean-Stark trap was heated under reflux for 5 h. The reaction was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. Organic layer was separated, washed with NaHCO3 solution and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give an oil, which was triturated with hexane and left in the fridge overnight. The precipitated solid was filtered and dried under vacuum to provide 17.1 (63%) g of the title compound, 1,4-Dioxa-spiro[4.5]decane-7,9-dicarboxylic acid dimethyl ester as a white solid. 1HNMR (400 MHz, CDCl3), δ: 3.95 (m, 4H), 3.7 (s, 6H), 2.72-2.62 (m, 3H), 2.32-2.22 (m, 1H), 2.02-1.96 (m, 2H), 1.6-1.4 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([NH:10][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: COc1ccc(NC(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: COc1ccc(NC(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 74 %

Procedure:
Prepared according to the procedure described for Example 78 using 1-(4-methoxy-3-aminophenyl)-3-phenyl-urea from Example 24, Step C (0.390 g, 1.52 mmol) and 3,5-dichlorophenyl isothiocyanate (0.311 g, 1.52 mmol). Filtration without trituration afforded the product (0.5187 g); m.p. 218-219° C.
Reaction SMILES: NCC1C=CC(F)=C(C2CCN(C(C3C4C(=C(F)C=CC=4OC(F)(F)F)N(CCOC)C=3)=O)CC2)C=1.[C:37]([OH:46])(=[O:45])[C@@H:38]([C@H:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]>C(#N)C.O>[C:37]([OH:46])(=[O:45])[CH:38]([CH:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COCCn1cc(C(=O)N2CCC(c3cc(CN)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Solvent: O
Solvent: CC#N
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 60 °C

Procedure:
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indol-3-yl]-methanone (0.250 g, 0.554 mmol) was weighed in a 20 ml glass vial. A solution of L-(+)-tartaric acid at 2.66 mmol/ml in 5:1 (v/v) acetonitrile/water was prepared, and 0.2084 ml of this solution was added to the weighed solid with stirring and heating to ˜60° C. giving a clear solution. The solution was then evaporated in vacuo on a rotary evaporator leaving a glassy solid which was recrystallized in hot isopropyl acetate to which a minimum amount of isopropanol was added to give a clear solution. Upon cooling the crystalline product was isolated by filtration and dried in vacuo at room temperature.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.[NH2:27][C:28]1[C:33]([S:34]([N:37]2[CH2:41][CH2:40][C@@H:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38]2)(=[O:36])=[O:35])=[CH:32][C:31](Br)=[CH:30][N:29]=1>>[NH2:42][C@@H:39]1[CH2:40][CH2:41][N:37]([S:34]([C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[C:31]([C:20]3[CH:21]=[CH:22][C:16]4[O:15][CH2:14][CH2:13][N:12]([C:5]5[C:4]6[CH2:3][C:2]([CH3:1])([CH3:26])[CH:11]=[CH:10][C:9]=6[N:8]=[CH:7][N:6]=5)[CH2:18][C:17]=4[CH:19]=3)[CH:32]=2)(=[O:35])=[O:36])[CH2:38]1
Reactant: CC1(C)C=Cc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Product: CC1(C)C=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)N6CC[C@@H](N)C6)c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using [4-(6,6-dimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) and 1,1-dimethylethyl {(3R)-1-[(2-amino-5-bromopyridin-3-yl)sulfonyl]pyrrolidin-3-yl}carbamate (reagent preparation 25) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.57 (d, 1H), 8.41 (s, 1H), 8.02 (d, 1H), 7.58 (d, 1H), 7.47 (dd, 1H), 7.02 (d, 1H), 6.75 (brs, 2H), 6.26 (dd, 2H), 4.63 (s, 2H), 4.33 (m, 2H), 3.84 (m, 2H), 3.37 (m, 2H), 3.27 (m, 2H), 2.89 (m, 1H), 2.71 (s, 2H), 1.86 (m, 3H), 1.53 (m, 1H), 0.95 (s, 6H); MS (EI) for C28H33N7O3S: 548 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=S)[CH2:25][C:26](=O)[CH3:27])=[O:4].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][NH2:39])=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:37][CH:36]=2)[N:39]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 266 c) was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as yellow solid. MS (ESI): m/z=580.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1(CC#N)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: N#CCc1ccccc1
Product: N#Cc1cccc(OS(N)(=O)=O)c1
Yield: 85 %

Procedure:
Using the procedure described in Example 75, the title compound was prepared in 85% yield from 10.3 g (0.086 mole) of 3-cyanophenol and 8.3 ml (0.086 mole) of chlorosulfonyl isocyanate in 75 ml of toluene as a white solid, mp 101°-104° C. (benzene-acetonitrile).