Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[P:2]([O-:10])([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[S:3].O[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[P:2]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])([O:10][N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)=[S:3]
Reactant: CCOP([O-])(=S)OCC
Reactant: On1cccn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=S)(OCC)On1cccn1
Reaction time: 12 h
Yield: 91 %

Procedure:
112 of diethyl thiophosphate chloride were added to 55 parts of 1-hydroxypyrazole and 50 parts of sodium carbonate in 600 parts of acetonitrile at 25° C., with stirring. Stirring was continued for another 12 hours. The solid product was filtered off with suction and washed with two portions of 50 parts of acetonitrile. The filtrate was concentrated in a rotary evaporator at from 20° to 40° C. under 20 mbar. The residue was dissolved in 300 parts by weight of methylene chloride, the organic phase was extracted with three portions of 50 parts by weight of saturated aqueous NaHCO3 solution, the methylene chloride solution was dried with magnesium sulfate and the solvent was stripped off in a rotary evaporator at from 20° to 40° C. under 20 mbar to give 127.5 parts by weight (91% of theory) of O-pyrazol-1-yl O,O-diethyl thiophosphate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C=O)C>[CH2:18]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH2:3]1)[CH3:19]
Reactant: c1ccc2c(c1)NCCO2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCOc2ccccc21
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (4.0 g, 29.6 mmol) in DMF (20 ml) was added potassium carbonate (10.22 g, 74.0 mmol). After stirring for five min. Iodo-ethane (3.5 ml, 44.4 mmol) was added and heated to 60° C. for overnight. Reaction mixture was cooled to room temperature, quenched by the addition of water (20 ml), extracted with ethyl acetate (3×25 ml). The organic layer was washed with water (30 ml), brine (30 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.7 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:8]2[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:32][CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc(OCc3ccccc3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 77.9 %

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.600 g, 2.001 mmol), [4-(benzyloxy)phenyl]amine (1.415 g, 6.004 mmol) and TEA (0.840 ml, 6.004 mmol) in DMF (5 ml) was heated in a microwave reactor at 140° C. for 25 mins. EtOAc was added to the mixture, and it was washed with brine, evaporated and the residue was purified by flash chromatography using a 5:1 EtOAc/petroleum ether 40-60° C. mixture as eluent to give the title compound (0.721 g, 78%). 1H NMR (500 MHz CDCl3); δ 7.42-7.33 (m, 4H), 7.22-7.17 (m, 1H), 7.15-7.09 (m, 5H), 6.65 (d, 2H), 6.61 (d, 2H), 4.96 (s, 2H), 3.79 (t, 2H), 1.92-1.84 (m, 2H), 1.54-1.44 (m, 2H), 1.01 (t, 3H); Mass Spectrum M+H+ 463.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.CS(O[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:21][C:20]=1[CH3:40])(=O)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:26]#[C:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][N:7]4[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[C:20]([CH3:40])[CH:21]=3)=[N:28][CH:29]=2)=[CH:34][CH:35]=1
Reactant: CC(C)C1CCNCC1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
164 mg (1.0 mmol) 4-isopropyl-piperidine (used as the hydrochloride) are added to a solution of 88 mg (0.2 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl methanesulphonate and 0.34 mL (2 mmol) ethyldiisopropylamine in 1.8 mL DMF and the reaction mixture is stirred for 24 h at RT. It is filtered using an injection filter and the reaction mixture is purified by HPLC.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O1CCCC1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N:17]1([C:1]([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 1 h

Procedure:
A mixture of 12.0 g. of 4-carboxybenzaldehyde, 13.6 g. of N,N'-carbonyldiimidazole and 100 ml. of tetrahydrofuran is allowed to stand for one hour, then 9.4 ml. of piperidine is added. The reaction mixture is allowed to stand for 18 hours, then heated at reflux temperature for one hour. Water is added and the solvent is distilled off. Methylene chloride is added and the solution is washed with 25 ml. of concentrated hydrochloric acid, then with water then is dried over magnesium sulfate. The mother liquor is concentrated to yield p-piperidinocarbonylbenzaldehyde as an oil.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:32][C:33]([F:36])([F:35])[F:34])=[C:17]([NH:19][S:20]([C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH:27]=2)(=[O:22])=[O:21])[CH:18]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:32]([C:33]([F:35])([F:34])[F:36])=[O:9])=[C:17]([NH:19][S:20]([C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH:27]=2)(=[O:21])=[O:22])[CH:18]=1
Reactant: O=S(=O)(Nc1cc(Cl)ccc1SC(F)(F)F)c1cc2ccccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1)C(F)(F)F

Procedure:
Following General Procedure D using 10 equivalents of mCPBA in refluxing CH2Cl2, the title compound was prepared from N-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[N:32]1([C:38]2[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][N:39]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:44][C:41]6[CH:42]=[CH:43][C:38]([N:32]7[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]7)=[N:39][CH:40]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4ccc(N6CCCCC6)nc4)C5)n[nH]c3c2)cc1F

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbaldehyde (88.2 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 16.99% yield, 22 mg.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12]CC)=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:15][CH2:16][C@H:17]([N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1)[CH3:18]>>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([C@H:17]([CH3:18])[CH2:16][NH:15][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: CCOC(=O)c1coc(C(C)(C)O)n1
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@H](CNC(=O)c1coc(C(C)(C)O)n1)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from ethyl 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate (0.5 mmol, 139 mg) and (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (0.5 mmol, 100 mg). Yield 27 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.45 (d, 3H), 1.49 (s, 6H), 3.55-3.61 (m, 1H), 3.66-3.73 (m, 1H), 4.67-4.76 (m, 1H), 5.65 (s, 1H), 7.03 (d, 1H), 7.88 (d, 1H), 7.91 (d, 1H), 8.0 (s, 1H), 8.19 (t, 1H), 8.51 (s, 1H). LC-MS: [M+1]=432.02.
Reaction SMILES: [OH:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]1([CH2:14][O:1][C:2]2[C:12]3[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCOc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCOc2c(OCc3ccccc3)cccc21
Yield: 67.4 %

Procedure:
A mixture of 9-hydroxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (7.46 g, 41.6 mmol), benzyl bromide (Preparation 58) (5.45 ml, 45.8 mmol) and potassium carbonate (17.26 g, 125 mmol) was stirred and heated at 60° C. in DMF (75 ml) for 2 hours. Cooled, diluted with water (300 ml) and extracted with EtOAc (200 ml and 4×75 ml) and the combined organics washed with 3×100 ml of water. Dried (magnesium sulphate), evaporated, triturated with ether and filtered off to give 7.55 g of white solid. MS (ES): C16H15NO3 requires 269; found 270 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.C(N(CC)CC)C.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>CC(C)=O>[C:26]([CH2:25][CH2:24][C:23]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:29])([OH:28])=[O:27]
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(O)CCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a stirred solution of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (4.5 g) and triethylamine (4.0 g) in acetone (100 ml), succinic anhydride (2.0 g) was added at room temperature, and stirred for 3 hours at the same temperature. The reaction mixture was concentrated in vacuo, and acidified with dilute hydrochloric acid. The separated oil was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 4.9 g (75%) of the titled compound: mp 190°-191° C. (dec.) (ethyl acetate-methanol); [α]D27 +181.6° (c=1.0, methanol). IR (nujol, cm-1): 3210 (OH), 1720 (COOH), 1618 (CON), 1602 (aromatic), 1245, 1173, 940, 763. NMR (DMSO-6, δ): 2.0-2.7 (4H, m, --CH2CH2 --), 3.03 (1H, ABq (A part), d, J=11.0, 10.0 Hz, C5 --HA), 3.36 (1H, ABq (B part), d, J=11.0, 7.0 Hz, C5 --HB), 4.61 and 5.07 (1H, dd, J=10.0, 7.0 Hz and m, C4 --H), 6.36 (1H, s, C2 --H), 6.5-8.0 (4H, arom. H). TLC: Rf value* 0.35.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH3:18])=[N:9][C:10]([N:13]=CN(C)C)=[N:11][CH:12]=1)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[N:31]=[C:5]([C:7]3[C:8]([CH3:18])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=3)[CH:4]=[CH:3][N:30]=2)=[CH:26][CH:27]=1
Reactant: N=C(N)Nc1ccc(F)cc1
Reactant: Cc1nc(N=CN(C)C)ncc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)ncc1-c1ccnc(Nc2ccc(F)cc2)n1
Yield: 80 %

Procedure:
A solution of N′-{5-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-methylpyrimidin-2-yl}-N,N-dimethylimidoformamide (27) (50 mg, 0.191 mmol), 1-(4-fluorophenyl)guanidine hydrochloride (102 mg, 0.383 mmol), and K2CO3 (106 mg, 0.765 mmol) in DMF (1018 μl) was heated at 120° C. for 2 d. The crude product was filtered through a syringe filter, then the crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] to obtain ˜80% pure desired product. The product was taken up in 10% MeOH/DCM, then was purified by Biotage™ silica gel chromatography [10 g SNAP column, 2-10% MeOH/DCM] and further purified by trituration with acetone and acetonitrile to obtain the desired product as a pale yellow solid (10.23 mg, 18% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3H) 6.93 (s, 2H) 7.02 (d, J=5.05 Hz, 1H) 7.12 (t, J=8.84 Hz, 2H) 7.77 (dd, J=9.35, 4.80 Hz, 2H) 8.44 (s, 1H) 8.46 (d, J=5.05 Hz, 1H) 9.61 (s, 1H). HRMS (ES+) for C15H13FN6.H+ [MH+]: calcd, 297.1264; found, 297.1274. UV-LC: 98.95/100% UV purity at 214/254 nm; tR=4.30 minutes over 7.75 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[N:7]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[N:7]=1
Reactant: COC(=O)CCc1nc(C=O)ccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COC(=O)CCc1nc(C=O)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 29.3 %

Procedure:
Under the conditions of example 1 D, 510 mg of 3-(6-formyl-3-hydroxy-2-pyridyl)-propionic acid methyl ester is reacted with 730 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 284 mg of 3-{6-formyl-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester of melting point 66°-69° C. is obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2([C:26]#N)[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13]1.Cl.C([O:32]C(C)C)(C)C>C1(C)C=CC=CC=1.CO>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2([CH:26]=[O:32])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13]1
Reactant: Cn1cc(C2(C#N)CCCC2)c2ccccc21
Reactant: CC(C)OC(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1cc(C2(C=O)CCCC2)c2ccccc21

Procedure:
The reaction is performed under a dry nitrogen atmosphere. 94.4 cm3 (0.0944 mol) of a 1N toluene solution of diisobutylaluminium hydride are added at -60° C. to a solution of 13.3 g (0.059 mol) of 1-(1-methyl-3-indolyl)-cyclopentanecarbonitrile in 230 cm3 of toluene. The temperature of the mixture is thereafter allowed to rise to room temperature, and the reaction is then stopped by adding 50 cm3 of methanol and then 230 cm3 of 3N hydrochloric acid to the reaction mixture. The mixture is extracted with dichloromethane, the organic extract is washed with water, dried over sodium sulphate and filtered and the filtrate is evaporated. In succession, the residue obtained is taken up with diisopropyl ether, some insoluble matter is removed by filtration, the solvent is evaporated and the residue is crystallised in hexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:32]([CH3:34])[CH3:33])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a solution of 0.20 g (0.468 mmol) of the product of Example 37 dissolved in 5.0 mL of DMF was added 0.26 mL (2.81 mmol) of 2-bromopropane and 1.16 g (8.43 mmol) of potassium carbonate. The reaction mixture was then heated to 80 degrees for 18 h, cooled to room temperature, diluted with ether and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc-Hexanes (1:3) to provide 0.198 g (90%) of the desired product as a colorless oil. Electrospray Mass Spec: 470.3 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)n1ncc2ccccc21

Procedure:
To prepare 1-substituted 1H-indazoles of formula 1 wherein R1 is formyl, alkanoyl, cycloalkylalkanoyl ##STR46## wherein R2', R5, X", p" and q' are as above, a 1-unsubstituted 1H-indazole 8 wherein R is as above, with the proviso that R is not hydrogen, and X, m, n and p are as before, is treated, respectively, with a formyl, alkanoyl or cycloalkylalkanoyl chloride, bromide or iodide, a compound of the formula ##STR47## R2'OCOHal or R5COHal wherein R2', R5, X", p" and q' are as above and Hal is iodo, bromo or chloro, or the corresponding acid anhydrides thereof, at an elevated temperature of about the reflux temperature of the reaction medium. For example, treatment of a 1H-indazole 8 wherein R is methyl with acetic anhydride at the reflux temperature of the reaction mixture affords a 1-acetyl-1H-indazole 14 wherein R2 is methyl, and treatment of a 1H-indazole 8 wherein R is methyl with benzoyl chloride at a reaction temperature of about 100° C. yields a 1-benzoyl-1H-indazole 14 wherein R2 is phenyl.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IN1C(=O)CC[C:26]1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: CC#N
Product: Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 65 °C
Yield: 121.9 %

Procedure:
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) in anhydrous acetonitrile (55 mL) was heated at 65° C. for 4 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2SO3 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.73 (d, 1H, J=7.6 Hz), 7.36 (m, 6H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.28 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0196 (M+H calculated for C19H16NO2FI requires 436.0210). Step 2. Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-methylpyridin-2(1H)-one
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C([O:24][C:25]1[CH:34]=[CH:33][C:28]([O:29][CH2:30][CH2:31]Br)=[CH:27][C:26]=1[F:35])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:24][C:25]1[CH:34]=[CH:33][C:28]([O:29][CH2:30][CH2:31][N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:3]=3[F:2])[CH2:11][CH2:10]2)=[CH:27][C:26]=1[F:35]
Reactant: Cc1ccc(CC2CCNCC2)c(F)c1
Reactant: Fc1cc(OCCBr)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)c(F)c3)CC2)c(F)c1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-methylbenzyl)piperidine hydrochloride (311.7 mg, 1.28 mmol), 2-(4-benzoxy-3-fluorophenoxy)ethyl bromide (411 mg, 1.28 mmol), potassium carbonate (444 mg, 3.2 mmol) in two steps as white-off solid (270 mg), mp 128-130° C. 1H NMR (CD3OD) 1.40 (m, 2 H), 1.704 (m, 3 H), 2.114 (s, 3 H), 2.422 (d, J=6.3 Hz, 2 H), 2.837 (m, 2 H), 3.303 (m, 2 H), 3.430 (d, J=11.4 Hz, 2 H), 4.072 (m, 2 H), 6.50 (m, 1 H), 6.632-6.750 (m, 4 H), 6.90 (m, 1 H). Anal. Calcd for C21H26ClF2NO2.0.4H2O: C, 62.25; H, 6.67; N, 3.46. Found: C, 62.20; H, 6.61; N, 3.22.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=[O:8].B(Br)(Br)Br>ClCCl>[OH:1][C:2]1[C:3]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:10]=[C:11]([C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:8]
Reactant: COc1ccc(C(=CNC(=O)c2sc3ccc(C(F)(F)F)cc3c2O)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NC=C(c1ccc(O)cc1)c1ccc(O)cc1)c1sc2ccc(C(F)(F)F)cc2c1O
Temperature: -50 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 3-hydroxy-N-[2,2-di-(4-methoxyphenyl)ethenyl]-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (200 mg) in dichloromethane (30 ml) cooled to -50° C. was added dropwise with stirring N boron tribromide in dichloromethane (2.9 ml). The reaction mixture was stirred at -50° C. for one hour, then the temperature allowed to rise to 0° C., and the reaction quenched by pouring into ice-saturated sodium hydrogencarbonate solution. The yellow solid that separated out was filtered, washed thoroughly with hexane and dried in vacuo to yield 104 mg (55%) of 3-hydroxy-N-[2,2-di-(4-hydroxyphenyl)ethenyl]-5-trifluoromethylbenzo[b]thiophene-2-carboxamide; m/z 471 (M+).