Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1)(=O)[CH3:2].Cl.[NH2:12][OH:13]>N1C=CC=CC=1>[Br:10][C:6]1[N:5]=[C:4](/[C:1](=[N:12]\[OH:13])/[CH3:2])[CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: CC(=O)c1cccc(Br)n1
Agent: Cl
Solvent: c1ccncc1
Product: C/C(=N/O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-acetyl-6-bromopyridine (10.0 g, 0.050 mol) and hydroxylamine hydrochloride (6.90 g, 0.10 mol) in pyridine (50 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate (200 mL), washed with water (100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a 10.75 g of A461.1 as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[O:13]=[C:14]1[C:19]2=[CH:20][NH:21][C:22]([CH:23]=O)=[C:18]2[CH2:17][CH2:16][O:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:23][C:22]1[NH:21][CH:20]=[C:19]2[C:14](=[O:13])[O:15][CH2:16][CH2:17][C:18]=12
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: COc1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
5-Methoxy-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[CH2:13][C:14](OCC)=[O:15]>>[OH:15][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:12]([CH:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[CH:13]=1
Reactant: CCOC(=O)CC(=O)C(C)c1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Product: CC(c1ccccc1)c1cc(O)n(-c2cc(C#N)ccn2)n1
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxo-4-phenylpentanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [C@:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.S([CH2:22][N+:23]#[C-])(C1C=CC(C)=CC=1)(=O)=O>>[CH3:11][C:1]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:2]2[C:22]#[N:23]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Product: CC1(C)C2CCC1(C)C(C#N)C2

Procedure:
(1R)-(+)-Camphor was converted to the nitrile using tosylmethyl isocyanide according to the procedure of O. H. Oldenziel (O. H. Oldenziel, D. van Leusen, and A. M. van Leusen J.Org.Chem. 1977, 42, 3114).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27])=[CH:20]2>CC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:2]4[CH:6]=[CH:5][N:4]=[CH:3]4)=[CH:15][CH:14]=3)[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[CH:20]2
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Agent: Cl
Solvent: CC(C)=O
Product: O=C(c1ccc(-n2ccnc2)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Yield: 60 %

Procedure:
By an analogous method, starting from 4-(1-imidazolyl)benzoic acid hydrochloride and 1-(5-chloroindol-2-ylsulphonyl)piperazine, was prepared 1-(5-chloroindol-2-ylsulphonyl)-4-[4-(1-imidazolyl)benzoyl]piperazine (375 mg, 60% yield) as colourless crystals from acetone; m.p. 155-165° C., 1H NMR (d6DMSO) 3.0-3.2 ppm (broad s, 4H), 3.4-3.8 ppm (broad s, 4H), 7.0 ppm (s, 1H), 7.1 ppm (s, 1H), 7.3 ppm (dd, 1H), 7.5 ppm (m, 3H), 7.7 ppm (d, 2H), 7.8 ppm (m, 2M), 8.3 ppm (s, 1H), 12.4 ppm (broad s, 1H), the spectrum also contained a signal due to acetone, ca 0.05 mol. eq.; MS (M+H)+ 470/472.
Reaction SMILES: [NH2:1][C:2]([CH2:4][NH:5][C:6]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:3]>CO>[C:14]1([C:13]2[N:5]([CH2:4][C:2]([NH2:1])=[O:3])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)CNc1ncccc1NC(=O)c1ccccc1
Solvent: CO
Product: NC(=O)Cn1c(-c2ccccc2)nc2cccnc21
Yield: 45 %

Procedure:
A 7.62-g (0.028 mole) sample of N-[2-[[(aminocarbonyl)methyl]amino]-3-pyridinyl]benzamide was heated in glass in a Wood's metal bath under a flow of nitrogen at 200° C. for 7 minutes. The green solid residue was broken up with a glass rod in methanol and the solid was filtered off. The filtrate was concentrated and the precipitate which formed, was separated by filtering twice. The solids were combined and recrystallized from boiling water to give 3.19 g (45%) of white needles which were dried under high vacuum at room temperature overnight, mp. 226°-7° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:19][NH2:20].O>C(O)C>[CH2:1]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:19][NH2:20])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NN
Reactant: CCCCCCOc1ccc(C(=O)OC)cc1
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(C(=O)NN)cc1
Yield: 98 %

Procedure:
A solution of Methyl 4-n-hexyloxybenzoate (2.00 g) and hydrazine hydrate (4.24 g) in ethanol (10 ml) was refluxed for 6 hours. After cooling, the reaction mixture was poured into water. The precipitate was collected by filtration, washed with water and dried over P2O5 under reduced pressure to give N-(4-n-hexyloxybenzoyl)hydrazine (1.96 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:16][CH2:12][CH2:13][C:14]#[CH:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C#CCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCOc1ccc(Br)cc1[N+](=O)[O-]
Yield: 71.4 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (20.0 g, 90 mmol), 3-butyn-1-ol (7.0 g, 99.8 mmol) and potassium carbonate (13.8 g, 99.8 mmol) in dry DMF (20 mL) was heated with 4 Å molecular sieves for 43 h. The mixture was cooled, diluted with water to approximately 500 mL and extracted three times with ethyl acetate. The combined organic extracts were washed with water and then brine, dried and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 5 to 10% ethyl acetate in cyclohexane) to give 4-Bromo-1-but-3-ynyloxy-2-nitro-benzene as a yellow solid (17.35 g, 71%). NMR showed an impurity (19%) which was not removed at this stage. LCMS: RT=4.41 min, [M+Na]+=292/294.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[C:15](=[O:17])[NH:14][CH2:13][CH2:12]2.C1C(=O)N([Br:25])C(=O)C1>>[Br:25][C:8]1[C:7]([CH3:6])=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][C:15]2=[O:17])=[CH:10][CH:9]=1
Reactant: Cc1cccc2c1C(=O)NCC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc2c1C(=O)NCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
To cooled conc. H2SO4 (10 mL) was added 8-methyl-3,4-dihydroisoquinolin-1(2H)-one (76b, 1 g, 6.21 mmol) and the reaction mixture was stirred for 10 minutes. NBS (1.1 g, 6.21 mmol) was added and the reaction mixture stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and poured into ice-water (30 mL) with stirring. The suspension was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=1:1) to give 7-bromo-8-methyl-3,4-dihydroisoquinolin-1(2H)-one (76c, 0.63 g, 42%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[NH:5][CH2:4]1.[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2>>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[N:5]([C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:26][CH2:25][CH2:24][OH:23])=[CH:35][CH:34]=3)=[O:37])[CH2:4]1
Reactant: O=C(O)c1cc2cc(OCCO)ccc2[nH]1
Reactant: NS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Product: NS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)N(C(=O)c1cc2cc(OCCO)ccc2[nH]1)CC3CCl
Temperature: 0 °C
Yield: 88 %

Procedure:
(Scheme C). The amine 117 was reacted with 5-(2-hydroxyethoxy)-1H-indole-2-carboxylic acid as described in Example 7. The reaction mixture was poured into ice-water and the precipitate was collected to give 28 (88%): mp (EtOAc) 231-234° C.; 1H NMR [(CD3)2SO] δ 11.72 (s, 1H), 9.28 (s, 1H), 8.87 (d, J=1.6 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 7.97 (dd, J=8.9, 1.6 Hz, 1H), 7.63 (s, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.7 z, 1H), 7.17 (d, J=2.2 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 5.00-4.93 (m, 1H), 4.188-4.81 (m, 1H), 4.74-4.70 (m, 1H), 4.69-4.60 (m, 1H), 4.19-4.12 (m, 2H), 4.05-3.98 (m, 2H), 3.79-3.71 (m, 2H), 2.94 (s, 1H), 2.79 (s, 1H), 1.95 (s, 1H); 13C NMR δ 160.6, 153.2, 147.0, 142.6, 142.5, 132.2, 131.9, 130.4, 129.7, 127.4, 125.6, 124.4, 121.3, 120.5, 116.5, 116.1, 113.2, 106.3, 103.1, 69.8, 59.6, 54.8, 47.6, 41.4. Anal. (C24H21ClN4O7S.⅓H2O) C, H, N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]([NH:12][CH2:13][CH2:14][OH:15])[C:6]=1[N+:16]([O-:18])=[O:17].[CH2:19]([CH2:21][NH2:22])[OH:20].Cl>>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([NH:22][CH2:21][CH2:19][OH:20])[CH:8]=[C:7]([NH:12][CH2:13][CH2:14][OH:15])[C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Reactant: NCCO
Agent: Cl
Product: O=[N+]([O-])c1c(NCCO)cc(NCCO)cc1NCCO
Temperature: 0 °C

Procedure:
0.0072 mole (2 g) of 2-(β-hydroxyethyl)amino-6-(β-hydroxyethyl)amino-4-chloronitrobenzene, synthesized in stage 1 of example 2, was heated at 100°-110° C. with 6 ml of ethanolamine for 6 hours. The reaction medium was diluted with ice water then brought to neutrallity by addition of concentrated hydrochloric acid to precipitate out the desired product. After filtering and hot drying under vacuum in the presence of P2O5, it was recrystallized from 96° ethanol. It melted at 200° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of compound 1D (0.630 g, 2.56 mmol) in CH2Cl2 (12 mL) at rt was added imidazole (0.350 g, 5.14 mmol), and then tert-butydimethylsilyl chloride (0.430 g, 2.83 mmol). After stirring for 3 h, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield (2S,3R)-3-(tert-butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7A) (0.910 g). LC/MS m/z 360 [M+H]+.
Reaction SMILES: C([O:4][CH:5]([CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1)=[O:7])(=O)C.[OH-].[Na+].O>CO>[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:13][CH:14]=1)(=[O:7])[CH:5]([CH3:23])[OH:4]
Reactant: CC(=O)OC(C)C(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)C(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a stirred solution of 6-[4-(2-acetoxypropionylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.94 g) in methanol (6 ml) was added dropwise 1N sodium hydroxide (3 ml) under ice cooling. The mixture was stirred for 15 minutes after adding water. The resulting precipitates were collected by filtration, washed with water and dried to give 0.61 g of 6-(4-lactoylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][C:16]=2[N+:25]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36]>[Pt].C(O)C>[CH2:35]([O:37][CH2:38][C:39]1[N:14]([CH2:13][C:2]2([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:36]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OCC)CC1
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
A mixture of ethyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate (4.53 g, 12.1 mmol) and 5% platinum on carbon (0.50 g) in ethanol was hydrogenated on a Parr apparatus at 40 psi (2.8×105 Pa) for 2.5 h. The mixture was filtered through CELITE filter agent and the filtrate was concentrated. The residue was concentrated twice from toluene and once from chloroform to remove the ethanol, then was dissolved in dichloromethane (100 mL). To the solution at 0° C. was added triethylamine (1.86 mL, 13.3 mmol) and ethoxyacetyl chloride (88%, 1.77 g, 12.7 mmol). After 1 h at rt, the solution was concentrated to a yellow foam and ethanol (120 mL) and triethylamine (6 mL) were added. The resulting solution was heated at reflux for 16 h and then concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed twice with brine, dried over MgSO4, filtered, and concentrated to a crude yellow oil. The oil was purified by flash chromatography (silica gel, gradient elution with 2-7% methanol/dichloromethane) to provide ethyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate as a yellow foam (3.04 g, 61%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=2)[NH:13][C:12](=[O:24])[C:11]1=[O:25]>C(O)C.P([O-])(O)(O)=O.[K+]>[CH2:1]([O:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=2)[NH:13][C:12](=[O:24])[C:11]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2n(O)c1=O
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Benzyl bromide (72 ml, 0.60 mol) was added to a suspension of 1-hydroxy-7-trifluoromethylquinoxaline-2,3(1H,4H)-dione (49.2 g, 0.20 mol) in 2.5 l of ethanol and 800 ml of 1M potassium dihydrogen phosphate buffer (pH 7.4). The mixture was stirred at room temperature overnight, and filtered. The precipitate was washed with water and dried to give 59.5 g (89%) of the title compound. M.p.>220° C. decomp.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:10][CH:9]=[N:8]1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:33])C(=O)C1>C(#N)C>[I:33][C:10]1[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[C:11]=1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1nccs1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCOCn1ncc(I)c1-c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)thiazole (Compound 2-BA-1) in 50 mL of acetonitrile at rt under nitrogen were added TFA (1 mL) and NIS (10.8 g). The reaction mixture was stirred at rt overnight and an additional amount of NIS (0.5 eq to 1.0 eq) was added as needed. The crude reaction mixture was slowly quenched with ˜30 mL of a saturated aqueous Na2S2O3 solution, and ˜30 mL of a saturated aqueous NaHCO3 solution. The reaction mixture was diluted with 50 mL of EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layer was purified by MPLC (eluted with 0-50% EtOAc/hex) to give 2-(4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)thiazole (Compound 4-BA-1). LCMS: 408.0 m/z (M+H)+.
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.[C:10]1([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]([O:28]CC)(=[O:27])C>O>[C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:10]2[CH:11]=[CH:12][C:13]([C:25]([OH:28])=[O:27])=[CH:14][CH:15]=2)[CH2:21][CH2:20]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CCC(c2ccccc2)CC1
Reactant: CCOC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of aluminum chloride(III) (26 g, 195 mmol) and dichloromethane (200 mL) was stirred at 0° C., and oxalyl chloride (20 mL, 228 mmol) was dripped over 10 minutes. Then a mixture of 1-(4-phenylpiperidin-1-yl)ethanone described in Production Example 1-9 (12.3 g, 60.5 mmol) and dichloromethane (50 mL) was dripped over 30 minutes. The mixture was stirred under nitrogen atmosphere at 25° C. for 14 hours. The reaction liquid was poured onto ice and ethyl acetate (1 L) and water (1 L) were added for separation. The aqueous layer was extracted with ethyl acetate (1 L) twice, then the organic layer was washed with water (1 L) twice and then with a saturated saline solution (500 mL). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. Ethyl acetate was added to the concentrated residue and the product was collected by filteration and washed with ethyl acetate to obtain the title compound (9.09 g, 61%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:18])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:1][C:2]1[C:3]([NH:18][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccccc1COc1ncc(F)c(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1COc1ncc(F)c(NS(=O)(=O)c2ccccc2)n1
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
To a magnetically stirred solution of 5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-amine (500 mg, 2.01 mmol) in dry THF (10 mL) was added 1M LiHMDS solution in THF (3.21 mL, 3.21 mmol) causing a slight exotherm. After stirring for 5 min, benzenesulfonyl chloride (0.346 mL, 2.71 mmol) was added and after 10 min the orange solution turned light orange and turbid. The mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo and the resulting viscous gold oil was diluted in EtOAc (10 mL), poured into a separatory funnel containing EtOAc (100 mL) and washed with 1N HCl aqueous solution (4×50 mL) and brine solution (1×50 mL). The organic extract was dried over Na2SO4, filtered, and evaporated to yield N-(5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-yl)benzenesulfonamide (714 mg, 91% yield) as a light tan solid. MS (ESI) m/z 387.99 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:39]3[CH:40]=[CH:41][C:36]([C:33]4[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=4)=[CH:37][CH:38]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccc(-c4ccccc4)cc3)c3cc(Cl)ccc23)c1
Temperature: 170 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.100 g, 0.3 mmol) was combined with CuO (0.0024 g, 0.03 mmol), potassium carbonate (0.041 g, 0.3 mmol) and 4-bromobiphenyl (0.0699 g, 0.3 mmol) in DMF (150 μL) and the reaction was heated to 170° C. overnight. After cooling the reaction was submitted to standard aqueous workup to give the title compound as a crude mixture that was taken directly to the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28]>CC(C)=O>[C:27](=[O:28])([O:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][C:11]([S:13](=[O:15])(=[O:14])[NH2:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[O:29][CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)COC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(C(=O)c2ccc(O)cc2)s1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)Oc1ccc(C(=O)c2ccc(S(N)(=O)=O)s2)cc1

Procedure:
A solution of 5-(4-hydroxybenzoyl)thiophene-2-sulfonamide (0.00783 mole) in acetone (50 ml) at 0° C. is treated with triethylamine (0.00861 mole) followed by isobutyl chloroformate (0.00861 mole) dropwise, during 30 minutes at 0°-2° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[C:9]2[C:5]=1[C:6]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:7][NH:8]2>O.CO>[Cl:3][C:4]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[C:9]2[C:5]=1[C:6]([CH2:15][C:16]([OH:18])=[O:17])=[CH:7][NH:8]2
Reactant: COC(=O)Cc1c[nH]c2c(Cl)cc(Cl)c(Cl)c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1c[nH]c2c(Cl)cc(Cl)c(Cl)c12
Temperature: 50 °C

Procedure:
An aqueous solution containing 8.4 g (0.15 mole) of potassium hydroxide in 10 ml of water was added to a solution of 4.3 g (0.015 mole) of methyl 4,5,7-trichloroindole-3-acetate in 50 ml of methanol, and the resulting mixture was heated at 50° C. for 10 hours, after which the reaction mixture was concentrated under reduced pressure until it became an aqueous solution. Said aqueous solution was acidified with acetic acid and extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and subsequently the ethyl acetate was removed by distillation under reduced pressure to obtain crude 4,5,7-trichloroindole-3-acetic acid, which was then purified by a column chromatography (silica gel) to obtain 3.3. g of the desired compound represented by the formula: ##STR16##