Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:22]=[C:21]([NH2:23])[N:20]=[CH:19][N:18]=1.O>CO>[C:5]1([C:3]2[N:16]=[C:17]3[CH:22]=[C:21]([NH2:23])[N:20]=[CH:19][N:18]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cc(N)ncn1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
ω-Bromoacetophenone (9.04 g, 45 mmol) and NaHCO3 (4.30 g, 50 mmol) were added to a solution of 4,6-diaminopyrimidine (5.00 g, 0.45 mmol) in methanol (80 ml), and the mixture was heated to reflux (3 h). Upon cooling, water (40 ml) was added, and the suspension was stirred at r.t. (15 min). The precipitated title compound (5.62 g, 59%) was isolated by filtration, washed with small amounts of water and methanol, and dried under vacuum. MS (m/e)=211.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=[O:22])[C:11]=2[CH2:10][CH2:9]1>C1(OC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=[O:22])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccccc1-n1ccc2c(=O)[nH]c3c(C)cccc3c21
Temperature: 25 °C
Yield: 85 %

Procedure:
1-(2-methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetra hydropyrrolo[3,2-c]quinoline (290 mg, 1.0 mmol) was dissolved in 20 ml of diphenyl ether and 40 mg of 5% palladium/carbon was added. The reaction mixture was heated for 4 hours. The reaction mixture was cooled to the room temperature and directly purified by silica gel chromatography to obtain 245 mg of desired compound as solid in 85% of yield.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][C:11]([CH:19]1[C:20](=[O:21])[O:22][C:15]([CH3:23])([CH3:14])[O:16][C:17]1=[O:18])=[O:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Reaction time: 8 h

Procedure:
Boc-β-alanine (25 g, 132 mmol), Meldrum's acid (20.9 g, 145 mmol) and 4-dimethylaminopyridine (DMAP, 24.2 g, 198 mmol) were dissolved in 700 mL of dry dichloromethane (DCM) at 0° C. under nitrogen atmosphere. To this solution 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 30.4 g, 158 mmol) was added. The resulting solution was allowed to reach room temperature and stirred overnight. The reaction mixture was washed (0.5 L×4) with 5% KHSO4 aqueous solution. The organic layer was dried over anh. Na2SO4, filtered and evaporated under vacuum, affording crude [3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-3-oxo-propyl]-carbamic acid tert-butyl ester that was dissolved in 600 mL of ethylacetate and refluxed for 4 hours. The solvent was reduced to 150 mL under vacuum and the resulting solution was allowed to crystallize at 4° C. overnight. The solid was filtered and washed with cold ethyl acetate affording 18.4 g (65% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[NH4+:12]>>[NH2:12][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(=O)c1ccc(N)nc1
Temperature: 130 °C

Procedure:
2 g (11.57 mmol) of 1-(6-chloropyrid-3-yl)ethanone and 70 mL of ammonium hydroxide are placed in a Parr reactor. The solution is heated at 130° C. overnight. The mixture obtained is evaporated to dryness, and the residue is taken up in ethyl acetate and washed with water and with saturated NaCl solution. The organic phase is dried over sodium sulfate and evaporated to dryness to give 1.14 g of 1-(6-aminopyrid-3-yl)ethanone, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:36][CH:35]=1>>[NH:2]=[C:1]([N:44]1[CH2:45][CH2:46][N:41]([CH2:40][C:37]2[CH:36]=[CH:35][N:34]=[CH:39][CH:38]=2)[CH2:42][CH2:43]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: c1cc(CN2CCNCC2)ccn1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(Cc2ccncc2)CC1
Yield: 11 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of 1-(pyridin-4-ylmethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([CH3:32])([CH3:31])[CH2:9][NH:10][CH:11]([C:14]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:27])[C:17]2=[CH:28][CH:29]=[CH:30][N:16]2[N:15]=1)[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]([CH3:32])([CH3:31])[CH2:9][N:10]([CH:11]([C:14]1[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](=[O:27])[C:17]2=[CH:28][CH:29]=[CH:30][N:16]2[N:15]=1)[CH2:12][CH3:13])[C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([Cl:34])=[CH:36][CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCC(NCC(C)(C)NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
{2-[1-(3-Benzyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (70 mg, 0.15 mmol) and 4-chlorobenzoylchloride (81.0 mg, 0.463 mmol) in CHCl3 (20 mL) was treated with Et3N (20.8 mg, 0.385 mmol). The reaction mixture was stirred at 25° C. for 18 h then concentrated under vacuum. The residue was and purified by preparative HPLC using a YMC S10 ODS 30×100 mm column to afford the desired material (52.2 mg, 57%) as a white powder: 1H NMR (CD3OD, 400 MHz) δ 7.55 (s, 1H), 7.45 (m, 5H), 7.08 (m, 1H), 6.67 (m, 1H), 5.87 (m, 1H), 3.93 (m, 1H), 3.72 (m, 1H), 3.48 (m, 1H), 3.30 (s, 1H), 1.81 (m, 1H), 1.38 (s, 9H), 1.17 (m, 3H), 0.90 (m, 3H), 0.54 (m, 3H); LC/MS (ESI+) 592 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH:11]([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
A solution of 4-bromobenzaldehyde (2 g, 10.8 mmol) in tetrahydrofuran (30 mL) in a two-necked round flask was cooled to −5° C. under nitrogen atmosphere. After 0.5 hour, isobutylmagnesium bromide (8 mL) was added dropwise. And then the mixture was warmed to room temperature. The resultant reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layers were combined, dried over sodium sulfate and concentrated to give a residue. The crude product was purified by silica gel column chromatography (silica gel, petroleum ether/ethyl acetate=8:1) to give 1-(4-bromophenyl)-3-methylbutan-1-ol (0.35 g, 13%). 1H NMR (300 MHz, CDCl3): δ 7.48-7.45 (m, 2H), 7.25-7.21 (m, 2H), 4.74-4.72 (m, 1H), 1.72-1.68 (m, 2H), 1.47-1.46 (m, 1H), 0.95 (d, J=6.0 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH2:26])[CH:18]=[CH:19][C:20]=1[C:21]1[N:22]=[CH:23][S:24][CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:17]2[CH:18]=[CH:19][C:20]([C:21]3[N:22]=[CH:23][S:24][CH:25]=3)=[C:15]([F:14])[CH:16]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: Nc1ccc(-c2cscn2)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)nc1Nc1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (165 mg, 0.746 mmol) and 3-fluoro-4-(thiazol-4-yl)benzenamine (145 mg, 0.747 mmol) in CH3CN (5 mL) at room temperature, DIEA (0.260 mL, 1.49 mmol) was added. The mixture was stirred at room temperature overnight, during which time solids precipitated out. The precipitate was collected, dried on vacuum to give ethyl 2-chloro-4-(3-fluoro-4-(thiazol-4-yl)phenylamino)pyrimidine-5-carboxylate as a solid (186 mg). MS 379.3 and 381.3 (M+H, Cl pattern)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:15])=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:19]([CH3:22])[CH2:20]O>CN(C)C=O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:15])=[N:9][N:10]([CH:19]([CH3:22])[CH3:20])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(Br)CO
Reactant: O=c1[nH]nc(Br)c2ccc([N+](=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc([N+](=O)[O-])cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200.5 %

Procedure:
7-Nitro-4-bromo-2H-phthalazin-1-one (84 g, 0.31 mol) was dissolved in dimethylformamide (DMF) (400 ml). To this was added NaH (60%, 7.5 g, 0.31 mol) as a DMF suspension (200 ml). The mixture was stirred at room temperature for 30 minutes then 2-bromo-propanol (7.7 g, 62 mmol) was added in one portion as a solution in DMF (250 ml). The reaction mixture was stirred for 24 hours whereupon LC-MS showed 40% starting material remaining. To this was added NaH (3.75 g 0.15 mol) and the reaction stirred for a further 24 hours. The DMF was removed under vacuum and the resulting crude material purified by successive column chromatography (elution: 92% heptane to 8% ethyl acetate) to give the title compound (38.8 g, 40% yield) as a light yellow solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C1([N+]([O-])=O)C=CC=CC=1.[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].[Cl:25][C:26]1[CH:27]=[C:28]([O:33][CH3:34])[CH:29]=[C:30]([Cl:32])[CH:31]=1>CCOCC>[Cl:25][C:26]1[CH:27]=[C:28]([O:33][CH3:34])[CH:29]=[C:30]([Cl:32])[C:31]=1[C:17]([C:16]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=1[Cl:14])=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(Cl)c(C(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Anhydrous AlCl3 (4.5 g, 33.9 mmol) was placed in a round bottom flask and PhNO2 (150 mL) was added. At −78° C. 2,4-dichlorobenzoyl chloride (4.7 mL, 33.9 mmol) and 3,5-dichloro anisole (5.0 g, 28.2 mmol) were added. The reaction mixture was kept at the same temperature for 1 h and warmed to rt over 24 h. The reaction mixture was diluted with Et2O (50 mL) at 0° C. and quenched with 1N NaOH (˜30 mL). The reaction mixture was stirred vigorously until a white precipitate had been formed. The precipitates were filtered and washed with CH2Cl2 (50, 30, and 20 mL). The combined organic solvents were dried (Na2SO4), filtered, and concentrated under vacuum at ˜10 mmHg. Purification by silica gel chromatography (4:1, hexanes:CHCl3) to provide (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanone (8.3 g, 85%) as a white powder. 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J=8.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.37 (dd, J=8.1, 2.1 Hz, 1H), 6.95 (s, 2H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 197.6, 163.8, 142.0, 138.3, 137.7, 136.4, 130.3, 129.9, 127.8, 122.9, 118.4, 117.9, 114.6, 56.1; IR (film): 1619 cm−1, 1584, 1553, 1400, 1309; HRMS (FAB): C14H8Cl4O2 (M+Na1) calcd. 370.91761, found 370.91765.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH2:34][CH2:35][CH:36]([OH:43])[CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[OH:43][CH:36]([CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:35][NH:34][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: NCC(O)CN1CCCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC(O)CN1CCCC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 1-amino-3-pyrrolidin-1-yl-propan-2-ol to give the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH2:18]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[C:27](=[C:36](SC)SC)[C:26]1=[O:41])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([OH:35])=[C:27]([C:36]2[NH:1][C:2]3[N:3]=[CH:4][N:5]([CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[S:7](=[O:9])(=[O:8])[N:10]=2)[C:26]1=[O:41])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ncn(Cc2ccccc2)c1S(N)(=O)=O
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(Cc2ccccc2)C1=O
Solvent: Cc1ccccc1
Product: O=c1c(C2=NS(=O)(=O)c3c(ncn3Cc3ccccc3)N2)c(O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
The product of Example 312F (152 mg, 0.602 mmol) was reacted with the product of Example 309B (214 mg, 0.602 mmol) in toluene (8 mL) at 100° C. for 3 hours. The reaction was allowed to cool to 25° C. and diluted with hexanes. The resulting precipitate was collected by filtration. The residue was chromatographed on silica gel, eluting with gradient of 0-2% methanol in dichloromethane to give the title compound (155 mg, 50%). MS (ESI+) m/z 512 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.42 (s, 2H), 5.63 (s, 2H), 7.22-7.44 (m, 11H), 7.53-7.56 (m, 1H), 7.74-7.79 (m, 1H), 8.20-8.23 (dd, J=8.1, 1.5 Hz, 1H), 8.32 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:36][CH:37]=2)(=[O:30])=[O:31])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(O)c2ccccn2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol (3.1 g, 5.3 mmol) in dry dichloromethane (25 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.2 g, 7.54 mmol; Dess-Martin periodinane) and the reaction mixture stirred for 1 hour at room temperature. The reaction mixture was cooled and treated with saturated sodium hydrogen carbonate solution (125 mL) followed by dichloromethane (50 mL). The mixture was stirred for 10 minutes and the phases separated. The aqueous phase was extracted with further dichloromethane (×2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a pale yellow foam (2.20 g). The product was further purified by preparative Hplc (C-18 column eluting with 80% aqueous methanol) to give (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl) methanone as a white solid (1.10 g). LCMS (Method D, ESI): RT 5.61 min, m+H=583.0; 1H NMR (400 MHz, CDCl3): δ 8.62 (ddd, J=4.8, 1.7, 1.0 Hz, 1 H); 7.85-7.86 (m, 1 H); 7.80-7.81 (m, 3 H); 7.70 (d, J=8.3 Hz, 2 H); 7.44-7.45 (m, 3H); 7.27 (s, 1 H); 7.16 (t, J=8.5 Hz, 2 H); 6.49 (d, J=2.2 Hz, 1 H); 5.56 (dd, J=12.3, 2.1 Hz, 1 H); 4.26 (d, J=16.9 Hz, 1 H); 3.86-3.89 (m, 1 H); 2.83-2.84 (m, 3 H); 2.54-2.56 (m, 2 H).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH:15]([C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH2:16]
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1[nH]c2ccccc2c1C(=O)OC
Yield: 156.9 %

Procedure:
Methyl 2-bromo-1H-indole-3-carboxylate (100 mg, 0.19 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (154 mg, 1 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) and cesiumcarbonate (326 mg, 1 mmol) in dioxane/water (20 mL, 5 mL) were stirred at room temperature for 15 hours. Filterated the solid and the solvent was concentrated in vacuum. The resulted residue was purified by silica gel column (ethyl acetate/petroleum ether=1/2) to give methyl 2-vinyl-1H-indole-3-carboxylate as a pale yellow solid (60 mg, 76%) LRMS (M+H+) m/z: calcd 201.1 found 201.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:38][CH:37]([OH:39])[CH:36]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:38][CH:37]([OH:39])[CH:36]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CC(O)C(N2CCCC2)C1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CC(O)C(N4CCCC4)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and Racemic-1′-((2-bromophenyl)sulfonyl)-[1,3′-bipyrrolidin]-4′-ol in Step B. MS (ESI): mass calcd. for C24H26FN5O3S, 483.17; m/z found, 484.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.60-8.57 (m, 1H), 8.15 (d, J=6.8, 1H), 8.11 (d, J=1.5, 1H), 7.97 (m, 1H), 7.61 (dd, J=7.5, 6.1, 1H), 7.55-7.49 (m, 1H), 7.38-7.28 (m, 3H), 4.68 (s, 2H), 4.18-4.12 (m, 1H), 3.30 (dd, J=10.5, 6.2, 1H), 3.23 (dd, J=10.1, 6.8, 1H), 2.95 (dd, J=10.0, 6.4, 1H), 2.88 (dd, J=10.4, 4.4, 1H), 2.63-2.57 (m, 1H), 2.52-2.38 (m, 5H), 1.74-1.67 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]([O:17]CC)=[O:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[OH-].[Li+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([C:15]([OH:17])=[O:16])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To ethyl 4-(4-nitrophenyl)thiazole-2-carboxylate (Intermediate 3, step A, 7.0 g) in THF (70 ml) was added (1 ml) 1N lithium hydroxide monohydrate solution and reaction mixture was stirred for 4 hours at RT. Organic solvent was concentrated, water was added, and the reaction mixture was made acidic by dilute HCl solution. This resulted in precipitation of white solid, which was filtered and washed with water. The solid was dried to obtain the title compound. Yield: 6.2 gm (98%). 1H NMR (DMSO-d6, 300 MHz): δ 8.78 (s, 1H), 8.32 (d, 4H).
Reaction SMILES: [CH3:1][C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(C)C=CC=CC=1>ClCCl.[Cu]I>[CH3:1][C:2]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Reactant: C1CNCCN1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C(=O)c1ccc(N2CCNCC2)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
4.2 g of 2-methyl-1-[4-fluorophenyl]-2-morpholinopropan-1-one (0.0167 moles), 5.75 g of piperazine (0.0669 moles), 0.063 g of copper (I) iodide and 15 ml of toluene were mixed in a three necked flask equipped with a stirrer, nitrogen inlet, condenser, nitrogen outlet and a temperature probe. The mixture was heated to reflux for a total of 24 hours under a constant flow of nitrogen gas. The mixture was then cooled to room temperature, after which it was dissolved in 75 ml of dichloromethane. The mixture was then extracted with 100 ml of a saturated aqueous sodium chloride solution and then with 2×100 ml of water. The dichloromethane layer was then dried using anhydrous magnesium sulphate. The magnesium sulphate was removed by filtration and the organic solvent was then removed on a rotary evaporator to yield the product.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: CC(=O)CC(=O)Nc1cccc(OCc2ccccc2)c1

Procedure:
m-hydroxy-3-methoxy-crotonanilide of formula V may be prepared by reacting diketene with m-benzyloxy-aniline to form m-benzyloxy-acetylacetanilide which is then reacted with methyl orthoformate to form m-benzyloxy-3,3-dimethoxybutyranilide which is converted by hydrogenolysis into m-hydroxy 3,3-dimethoxy-butyranilide which is then heated. Other compounds of formula V may be made in an analogous fashion.