Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[C:5]1([CH2:18][OH:19])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH3:3])[CH3:2].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1.C(N(CC)CC)C>[C:33](=[O:34])([O:19][CH2:18][C:5]1([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:25])[CH3:24])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)C1(CO)c2ccccc2-c2ccccc21
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C(C)C)(C(C)C)C1(COC(=O)Nc2ccccc2)c2ccccc2-c2ccccc21
Temperature: 82 °C
Yield: 100 %

Procedure:
To a mixture of 1.0 g of 9-triisopropylsilyl-9-fluorenemethanol and 0.3 mL of phenyl isocyanate in 10 mL of dry benzene was added 2 drops of triethylamine. The mixture was heated in an oil bath at 82° C. for one hour and cooled to room temperature. The solvent was evaporated in vacuo to give 1.30 g (100%) of the crude urethane as a yellow solid. Recrystallization from Skelly B gave 1.12 g (86.02%) of the pure urethane as colorless crystals, m.p. 152.5°-154° C.; IR (KBr): 3240 (NH), 1690 (C=O) cm-1 ; 1H NMR (CDCl3); δ 0.87 (d, 18H, Si-C-Me2), 1.18-1.44 (hept, 3H, C-Si-CH), 5.33 (s, 2H, CH2), 6.02 (b, 1H, NH), 6.70-7.95 (m, 13H, aryl).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=4)[NH:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:27]([Sn](CCCC)(CCCC)CCCC)=[N+:28]=[N-:29]>C1(C)C=CC=CC=1>[NH:27]1[C:25]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)=[N:26][N:29]=[N:28]1
Reactant: N#Cc1ccc2[nH]nc(-c3ccc(OCCN4CCOCC4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: c1cc(-c2n[nH]c3ccc(-c4nnn[nH]4)cc23)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
A mixture of 3-[4-(2-morpholin-4-ylethoxy)phenyl]-1H-indazole-5-carbonitrile (290 mg, 0.832 mmol), azidotributyltin (Bu3SnN3, 1.56 g, 4.70 mmol, 5.65 equiv.), and 9.0 mL toluene was refluxed for 17.5 h and concentrated to an oil. To the oil was added 6.5 mL of dioxane and 6.5 mL of 6.0 N aq. HCl. The mixture was stirred at room temperature for 4 h and then added to 25 mL of 6.0 N aq. NaOH. The mixture was extracted with 3× hexanes, and 3×Et2O. The aqueous layer was filtered to remove particulates. The pH was adjusted with 6.0 N aq. HCl to give maximum visual turbidity (approximately pH 5.0–5.5) and then the mixture was extracted with 2×EtOAc. The combined organics were dried (Na2SO4), filtered, and concentrated. The product was triturated in 5% EtOAc in hexanes. Filtration and drying of the solid afforded the title compound (29.0 mg, 8.90% yield): 1H NMR (CDCl3/CD3OD) δ 8.75 (s, 1H), 8.08 (d, 1H), 7.95 (d, 2H), 7.70 (m, 1H), 7.13 (d, 2H), 4.30 (t, 2H), 3.85–3.79 (m, 4H), 3.07 (t, 2H), 2.89–2.80 (m, 4H); ES-MS (m/z) 392 [M+1]+.
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10]N1C(=O)CCC1=O.BrC1C=CC=CC=1>>[Br:10][CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccccc1
Solvent: Brc1ccccc1
Product: C=C(CBr)c1ccccc1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A mixture of 2-phenylpropene (22.4 g, 190 mmoles), N-bromosuccinimide (23.7 g, 133 mmoles) and bromobenzene (76 ml) was heated in a 160° C. oil bath until the N-bromosuccinimide dissolved. The reaction mixture was allowed to cool to room temperature. The precipitate was subsequently removed using filtration and was washed using chloroform. The filtrate was distilled under reduced pressure to purify it (b.p. 80° C. to 85° C./3 mmHg), and 3-bromo-2-phenylpropene (12.1 g) was obtained. 1H NMR (CDCl3) δ ═4.39 (s, 2H), 5.49 (s, 1H), 5.56 (s, 1H), 7.33-7.51 (m, 5H); 13C NMR (CDCl3) δ=34.2, 117.2, 126.1, 128.3, 128.5, 137.6, 144.2.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][OH:16].O[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC1C(F)=C(CCCCC)C=CC=1C1N=CC(OC[C@H](F)CCCCCC)=CN=1>C1COCC1>[F:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][O:16][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Oc1ncccn1
Reactant: CCCCCC[C@@H](F)CO
Agent: CCCCCC[C@@H](F)COc1cnc(-c2ccc(CCCCC)c(F)c2F)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCC(F)COc1ncccn1
Yield: 140.5 %

Procedure:
(R)-(31)-2-[2',3'-difluoro-4'-(trans-4"-pentylcyclohexylethyl)phenyl]-5-(2-fluorooctyloxy)pyrimidine 49.-Quantities: DEAD (448 mg, 2.58 mmol) in THF (3 ml), (R)-(+)-2-fluorooctanol (379 mg, 2.58 mmol), hydroxypyrimidine 48 (1.0 g, 2.58 mmol), triphenylphosphine (676 mg, 2.58 mmol). The experimental procedure was as described for compound 34. The crude product was purified by flash chromatography (5 to 7% ethyl acetate-light petroleum) to give the 2-fluorooctyloxypyrimidine 49 (820 mg, 61%) (from EtOH), transitions/° C. K 102.2 N* 128.3 I; [α]D26 -2.4° (c 2.0 in CHCl3); νmax /cm-1 (KBr) 2920, 2845, 1540, 1460, 1435s, 1285 1080, and 900; δ 0.80-1.03 (10 H, m), 1.06-1.45 (16H, m), 1.55 (4H, m), 1.82 (6 H, m), 2.71 (2 H, t J 8, ArCH2), 4.22 (2 H, dd, 3JHF 22 and J 4, OCH2), 4.86 (1 H, d of sext, 2JHF 48 and J 4, CHF), 7.01 (1 H, ddd, J 7.5, 7 and 1.5, 5'-H), 7.67 (1 H, ddd, J 7.5, 7 and 1.5, 5'-H), and 8.53 (2 H, s, 4- and 6-H); m/z 518 (M+), 489, 475, 461, 447, 365 and 353.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([CH:8]([CH2:37][CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])[CH2:9][CH:10]([O:33][C:34](=[O:36])[CH3:35])[CH:11]([NH:20][C:21]([C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=O.C([O-])(=O)C.[NH4+:49].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:19][C:15]1[CH:14]=[C:13]([CH2:12][CH:11]([CH:10]([O:33][C:34](=[O:36])[CH3:35])[CH2:9][CH:8]([C:6]2[NH:5][CH:4]=[CH:3][N:49]=2)[CH2:37][CH2:38][C:39]([OH:42])([CH3:40])[CH3:41])[NH:20][C:21]([C:23]2[CH:32]=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(CNC(=O)C(CCC(C)(C)O)CC(OC(C)=O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(CC(CCC(C)(C)O)c1ncc[nH]1)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1
Temperature: 115 °C
Yield: 16.8 %

Procedure:
To a solution of acetic acid 3-(2,2-dimethoxy-ethylcarbamoyl)-1-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-6-hydroxy-6-methyl-heptyl ester (150 mg, 0.245 mmol) in acetic acid (2 mL) was added ammonium acetate (1.5 g 19.5 mmol). The resulting mixture was heated to 115° C. for 3 hours, cooled to ambient temperature and diluted with ethyl acetate. The solution was then neutralized with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel gave the title compound (22.5 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9].F[B-](F)(F)F.[CH2:22]([O+](CC)CC)[CH3:23]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH:12]([O:16][CH2:22][CH3:23])[CH2:11]1)=[O:9]
Reactant: CC[O+](CC)CC
Reactant: O=C1CN(C(=O)c2ccccc2Cl)CCN1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1CN(C(=O)c2ccccc2Cl)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(2-chlorophenyl)carbonyl]-2-piperazinone (I4) (676 mg, 2.83 mmol) was dissolved in dichloromethane (DCM) (10 mL) and was treated with triethyloxonium tetrafluoroborate (628 mg, 3.31 mmol). The solution was stirred at 25° C. for 16 hr and the solution partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL), combined extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated to a crude oil in 816 mg that was used in the subsequent step without further purification. Compound was not characterised but used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]([C:36]([NH:38][NH2:39])=[O:37])=[CH:34][CH:35]=1)=[O:30]>CS(C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]([C:36]([NH:38][N:39]=[C:18]([C:3]2[C:2]([OH:1])=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:5]([CH3:17])[N:4]=2)[CH3:19])=[O:37])=[CH:34][CH:35]=1)=[O:30]
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccccn2)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccccn2)s1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 80.9 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (50 mg, 0.18 mmol) in dimethyl sulfoxide (1.0 mL) was heated with 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-picolylamide (58 mg, 0.21 mmol) prepared in Reference Synthetic Example 2 at 110° C. for 21 hours. The solvent was evaporated, and the residue was washed with water and chloroform to give 79 mg of the desired product (yield 83%).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[NH:14][C:10]=2[N:9]=[CH:8]1.[Li+].[OH-]>C1COCC1.CO>[CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[NH:14][C:10]=2[N:9]=[CH:8]1
Reactant: CCOC(=O)c1cc2c(ncn2COCC[Si](C)(C)C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc2[nH]c(C(=O)O)cc21
Temperature: 60 °C
Yield: 153.9 %

Procedure:
Ethyl 1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (0.088 g, 0.284 mmol) was dissolved in THF and MeOH. LiOH (1 mL, 1 mmol) was added to the solution and the reaction was heated to 60° C. When starting material was no longer evident by TLC the reaction was evaporated to afford the title compound (0.123 g, 77%) a white solid. This was used with no further purification. LCMS: m/z=280.0 (M−1).
Reaction SMILES: C([O:8][C:9](=[O:35])[C@@H:10]([NH:31][C:32](=[O:34])[CH3:33])[CH2:11][NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:16]1)=[O:14])C1C=CC=CC=1>C(O)C.Cl.C(OCC)(=O)C.O=[Pt]=O>[NH:27]1[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C:13]([NH:12][CH2:11][C@H:10]([NH:31][C:32](=[O:34])[CH3:33])[C:9]([OH:35])=[O:8])=[O:14])[CH2:16]2)=[O:30])[CH2:25][CH2:26]1
Reactant: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)C=Cc2ccncc2)C1)C(=O)OCc1ccccc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O
Reaction time: 3.5 h
Yield: 79.8 %

Procedure:
A mixture of N-[(R)-1-[3-(4-pyridyl)-2-propenoyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl ester (233 mg), PtO2 (60 mg) in ethanol (10 ml), 4N HCl in ethyl acetate (121 μl) and PtO2 (50% wet, 1.2 g) was stirred vigorously under hydrogen (1 atm) atmosphere. After 3.5 hours, the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in water (10 ml). The solution was adjusted to pH 6.5 with aqueous NaHCO3, then evaporated in vacuo. The residue was purified by ODS-chromatography (Disogel SP-120®) eluting with 4% CH3CN/water. The eluent was concentrated in vacuo and freeze-dried to give N-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine (154 mg) as a white powder, which is the compound obtained in Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][CH2:26][C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCc1cccs1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCc1cccs1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and Thiophene-2-ethylamine (41 mg, 0.32 mmol). The title compound was obtained as a solid (35 mg, 27% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.00 (1H, m), 8.99 (2H, m), 8.41 (1H, s), 7.33 (1H, m), 6.94 (2H, m), 3.44 (2H, m), 3.02 (2H, m). MS m/z: 458.00, 459.99 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.O>[Br:24][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH2:9][CH2:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCC(N2CCc3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(N2CCc3cc(Br)ccc32)CC1
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of compound 2 (1.12 g, 5.176 mmol) in dry DMF (10 mL) was treated with NBS (0.92 g, 5.176 mmol) in dry DMF (5 mL) at 0° C. over a period of 5 min. and stirring was continued at same temperature for 3 h. The reaction was diluted with water (100 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 3:97) to obtain compound 3 (1.15 g, 76%) as a syrup. 1H NMR (DMSO-d6) δ 7.14-7.06 (m, 2H), 6.37 (d, 1H, J=8.4 Hz), 3.35-3.24 (m, 3H, merged with water peak), 2.93-2.80 (m, 4H), 2.16 (s, 3H), 2.00-1.88 (m, 2H), 1.64-1.55 (m, 4H); EI-MS (m/z, %): 293, 295 (M+, bromine isotope, 47), 98 (59), 97 (100), 71 (47).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[C:12]1([C:7]2[C:6]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:10]=3[OH:9])=[N:20][NH:21][CH:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1ccc(-c2n[nH]cc2-c2ccccc2)c(O)c1
Temperature: 60 °C
Yield: 80.3 %

Procedure:
7-Hydroxy-3-phenyl-chromen-4-one (0.2 g, 0.84 mmol) was dissolved in ethanol (5 ml) and heated to ˜60° C. Hydrazine hydrate (5 ml) was added, and the solution refluxed until no starting material was visible by TLC (45 mins). After this time the majority of the ethanol was remove under vacuum and the residue quenched with cold water. The residue was extracted into ethyl acetate, washed (water), and the solvent removed under vacuum to give 4-(4-Phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as a white solid (0.17 g, 80.3%); Rf 0.65 ethyl acetate/hexane (70/30)].
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].[H-].[Na+].I[CH3:30]>CN(C=O)C.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:30])[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:17]=1)#[N:2]
Reactant: CI
Reactant: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N(C)S(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) is treated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for 10 min. Iodomethane (0.03 mL, 0.53 mmol) is added, and the mixture is stirred at room temperature for 18 h. The reaction mixture is then diluted with H2O, and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Purification by flash chromatography over silica gel (EtOAc/CH2Cl2, 0-1%) gives 60 mg (45%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methyl methanesulfonamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:11][S:12](O)(=[O:14])=[O:13].O=S(=O)=O>>[OH:1][C:2]1[N:10]=[CH:9][C:8]([S:12]([OH:14])(=[O:13])=[O:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1O
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(S(=O)(=O)O)cnc1O
Temperature: 140 °C
Yield: 82.9 %

Procedure:
2-Hydroxynicotinic acid (27 Kg, 194.2 mol) was added portionwise to 30% oleum (58.1 Kg) at 50° C. over 1 hr. This caused an exotherm to 82° C. The reaction mixture was heated further to 140° C. After maintaining this temperature for 12 hrs the reactor contents were cooled to 15C and filtered. The filter cake was then re-slurried with acetone (33 Kg) at room temperature, filtered and dried to afford the title compound (35.3 Kg, 83%) as a white solid. Decomposition pt 273° C. δ (DMSOd6): 7.93 (1H, d), 8.42 (1H, d). m/z (Found: 220 [M+H]+, 100%. C6H6NO6S requires 220.17).
Reaction SMILES: [Cl:1]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O[CH2:23][CH:24]1[C:28]2=[C:29]3[C:33](=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=[C:27]2[N:26]([C:43]([C:45]2[NH:46][C:47]4[C:52]([CH:53]=2)=[CH:51][C:50]([O:54][CH3:55])=[C:49]([O:56][CH3:57])[C:48]=4[O:58][CH3:59])=[O:44])[CH2:25]1)[NH:32][C:31]([C:39]([O:41][CH3:42])=[O:40])=[CH:30]3.O>N1C=CC=CC=1>[Cl:1][CH2:23][CH:24]1[C:28]2=[C:29]3[C:33](=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=[C:27]2[N:26]([C:43]([C:45]2[NH:46][C:47]4[C:52]([CH:53]=2)=[CH:51][C:50]([O:54][CH3:55])=[C:49]([O:56][CH3:57])[C:48]=4[O:58][CH3:59])=[O:44])[CH2:25]1)[NH:32][C:31]([C:39]([O:41][CH3:42])=[O:40])=[CH:30]3
Reactant: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1)CC3CO
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1)CC3CCl
Temperature: 20 °C
Yield: 63.6 %

Procedure:
Dichlorotriphenylphosphorane (1.65 g, 5.1 mmol) was added to a solution of 56 (1.34 g, 2.55 mmol) in pyridine (75 mL) and the solution stirred at 20° C. After 10 min more dichlorotriphenylphosphorane (2.06 g, 6.4 mmol) was added, and after a further 10 min the solution was poured into H2O and the mixture stirred for 5 min. The precipitated solid was filtered off, washed with H2O, and redissolved in CH2Cl2 (400 mL). This solution was filtered through Celite, eluting with CH2Cl2, and the filtrate was dried (Na2SO4) and evaporated. The resulting orange solid was recrystallized from CH2Cl2 giving methyl 1-(chloromethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (31) as an orange powder (0.88 g, 64%), mp 246-247.5° C. The mother liquor was evaporated onto silica and purified by chromatography (50% EtOAc-petroleum ether) to give further 31 (0.50 g, 36%). 1H NMR (CDCl3) δ 10.39 (s, 1 H, NH), 9.42 (s, 1 H, NH), 9.39 (s, 1 H, H-4), 7.31 (d, J=2.2 Hz, 1 H, H-8), 6.97 (d, J=2.4 Hz, 1 H, H-3'), 6.86 (s, 1 H, H-4'), 4.80 (t, J=10.0 Hz, 1 H, H-2), 4.69 (dd, J=10.8, 4.4 Hz, 1 H, H-2), 4.32-42.3 (m, 1 H, H-1). 4.09 (s, 3 H, OMe), 4.05 (dd, J=11.4, 3.9 Hz, 1 H, CH2Cl), 4.02 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 3.91 (s, 3 H, OMe), 3.77 (dd, J=11.4, 8.8 Hz, 1 H, CH2Cl); 13C NMR [(CD3)2SO] δ 160.5, 160.0, 149.2, 140.0, 139.0, 137.5, 133.6, 132.1, 131.3, 130.2, 127.7, 126.1, 125.5, 123.2, 111.3, 107.5, 106.4, 97.9, 61.1, 60.9, 55.9, 54.1, 52.3, 47.0, 42.0. Anal. Calculated for C25H23ClN4O8 : C, 55.3; H, 4.3; N, 10.3. Found: C, 55.4; H, 4.1; N, 10.3%.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCCN1
Reactant: ClCc1ccccc1SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.35 g of potassium-tert-butoxide in 25 mL of dimethylformamide, cooled to 0° C., was added 0.92 mL of 2-pyrrolidinone. As a white precipitate formed, the mixture was stirred for 10 minutes, and 3.0 g of 2-phenylmethylthio chloromethyl benzene was added in one portion. The resulting solution was allowed to warm to room temperature, stirred for 1 hour, poured into water, and extracted with methylene chloride. The organic layer was washed well with water, dried over magnesium sulfate, filtered, and the filtrate evaporated to leave 3.0 g of a yellow oil.
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14](Br)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(O)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14]([C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: O=C(c1nc(Br)cs1)N1C2CCC1COC2
Reactant: OB(O)c1ccc(Cl)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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1C2CCC1COC2
Temperature: 92.5 °C
Yield: 51.9 %

Procedure:
To a solution of 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(4-bromothiazol-2-yl)methanone (Step-1 of compound 68, 0.35 g, 1.15 mmol) in a mixture of toluene:ethanol (2.5 ml: 7.5 ml) were added (4-chlorophenyl) boronic acid (0.2 g, 1.27 mmol) and potassium carbonate (0.34 g, 2.42 mmol) at 25° C. in a tube, nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.06 mmol) under nitrogen, tube was sealed and reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with ethanol (2×20 ml). The filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 51.7%). MS: m/z 335 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.O[C:12]([C:15](O)([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(O)C(C)(C)O
Product: CC1(C)OB(c2cccc(Cl)c2)OC1(C)C
Yield: 75 %

Procedure:
The title compound (75%, oil) was prepared from 3-chlorophenylboronic acid and pinacol.