Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:19][CH3:20])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:21])[N:7]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[Cl:22])[CH2:19][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(C(=O)OC(C)(C)C)c1cnc(-c2cccnc2)s1
Solvent: CC#N
Product: CCN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
To a solution of ethyl-(2-pyridin-3-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (3.0 g, 9.82 mmol) in acetonitrile (58 mL) was added N-chlorosuccinimide (2.62 g, 19.64 mmol) in one portion and the reaction mixture was stirred at 45° C. for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a red oil (2.24 g, 67%): 1H NMR (300 MHz, CDCl3) δ 9.09 (d, J=1.9 Hz, 1H), 8.68 (dd, J=4.8, 1.6 Hz, 1H), 8.19 (dd, J=5.9, 4.2 Hz, 1H), 7.39 (dd, J=7.6, 5.2 Hz, 1H), 3.68 (q, J=7.2 Hz, 2H), 1.45 (s, 9H), 1.22 (t, J=7.0 Hz, 3H); ESIMS m/z 340 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](N)=[C:6]([CH3:11])[CH:5]=1.S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].NC(N)=O>O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[Cu]=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:14])=[C:6]([CH3:11])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=S(=O)(O)O
Agent: O=[Cu]
Agent: [Cu+2]
Agent: NC(N)=O
Solvent: O
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 0 °C
Yield: 42 %

Procedure:
4-Amino-3-methyl-benzoic acid methyl ester (5.25 g, 32.0 mmol) was treated with a 35% solution of sulphuric acid (50 ml) and the mixture was stirred and heated until dissolution then cooled to 0° C. Sodium nitrite (2.82 g, 41.6 mmol) in water (50 ml) was added dropwise and the mixture was stirred for 5 min at 0° C. Urea was added to destroy the excess nitrite. Copper nitrate (121 g, 320 mmol) in water (11) was added then copper oxide (4.25 g, 32.0 mmol). The mixture was warmed up to room temperature over 30 min and extracted with EtOAc (×3). The organics were combined, washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% hexane) to yield the title compound (2.2 g, 42%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C1(C)C=CC=CC=1>[CH:11]1([O:10][N:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH2:3][C:4]2([CH3:18])[CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Reactant: COC(=O)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 48.6 %

Procedure:
A mixture of 10.0 grams (39.3 mmol) of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine, 27.8 grams (236 mmol) of dimethyl oxalate and 100 ml of toluene is heated at reflux. Methanol and toluene are removed from the reaction mixture by fractional distillation. The reaction is then filtered and the filtrate is concentrated to obtain a solid. Fractional crystallization of the solid from 9:1 isopropanol:methylene chloride followed by recrystallization from heptane affords 6.5 grams (48% yield) of the title compound as a white solid melting at 124°-1260° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.[Cl-].[NH4+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([O:10][C:8]([NH:7][N:6]([CH2:5][C@@H:4]([OH:23])[C:3]([OH:2])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:25])[CH:31]=2)=[CH:18][CH:17]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O
Temperature: 90 °C
Reaction time: 18 h

Procedure:
(R)-3-[N-(4-Bromobenzyl)-N′-t-butoxycarbonyl-hydrazino]-2-hydroxy-propionic acid methyl ester (1.0 g, 2.5 mmol), 3-chlorophenylboronic acid (776 mg, 5.0 mmol), and K2CO3 (857 mg, 6.2 mmol) were dissolved in a mixture of THF (18 mL) and water (18 mL). The reaction flask was then purged with nitrogen and tetrakis(triphenylphosphine) palladium(0) (286 mg, 248 μmol) was added. The mixture was stirred at 90° C. overnight (˜18 hours). The mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was collected, dried and concentrated. The product was purified (Interchim reverse phase chromatography column, 10-80% MeCN in water) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19]C2C=CC=CC=2)[N:3]=1.[S-2].[Na+].[Na+].Cl>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([SH:19])[N:3]=1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(S)c(C#N)c1-c1cccc(F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2 g (5.77 mmol) of 2-amino-4-(3-fluorophenyl)-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 37A) were initially charged in 20 ml of DMF. 1.58 g (20.21 mmol) of sodium sulfide were added, and the mixture was stirred at 80° C. for 2 h and stirred further at RT overnight. 10 ml of 1N hydrochloric acid were added to the reaction mixture, and the precipitate was filtered off, washed with water and dried under high vacuum. In addition, more solid precipitated from the filtrate overnight, and this solid was filtered off and washed with water. Once more, this gave the desired solid.
Reaction SMILES: Cl.Cl.[OH:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.CN(C)C=O.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:34])[C:32]=1F)[N:29]([CH2:35][CH2:36][F:37])[CH:28]=[C:27]([C:38]([OH:40])=[O:39])[C:26]2=[O:41]>C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:34])[C:32]=1[N:7]1[CH2:8][CH2:9][N:4]([OH:3])[CH2:5][CH2:6]1)[N:29]([CH2:35][CH2:36][F:37])[CH:28]=[C:27]([C:38]([OH:40])=[O:39])[C:26]2=[O:41]
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reactant: ON1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C(O)c1cn(CCF)c2c(F)c(N3CCN(O)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 169.4 %

Procedure:
1-Hydroxypiperazine dihydrochloride (1.03 g), triethylamine (35.6 g) and dimethylformamide (85 ml) are added to 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (8.5 g), which is prepared by the procedure described in Japanese Patent First Publication No. 30964/1981, and the mixture is stirred for 1.5 hours at 100°-105° C. After cooling to room temperature, the reaction mixture is poured into ice-water (500 ml) and the pH is adjusted to 7.0 with 50% aqueous acetic acid. The resulting precipitate is filtered, washed with water and then recrystallized from dimethylformamide. Ethanol (100 ml) is added to the resulting pale yellow needles and the mixture is refluxed for 1.5 hours. After cooling the mixture to room temperature, the insoluble substance is filtered to yield 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (3.7 g) as pale yellow needles, m.p. 220°-229° C. (decomposition).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>ClCCl>[CH3:35][O:34][C:32]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:15][CH:14]=[C:13]([C:11]([N:1]3[C@@H:10]4[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:4][CH2:3][CH2:2]3)=[O:12])[CH:17]=2)[CH2:23][CH2:22]1)=[O:33]
Reactant: COC(=O)Cl
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 2 h
Yield: 49.1 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.04 g, 0.12 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (0.37 mmol). Methyl chloroformate (0.25 mmol) was added and the mixture stirred for 2 hours and then the solvent removed by evaporation. The residue was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.023 g). LCMS m/z 391.15 min [M+H]+ RT=11.55 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.6 (m, 1H), 4.3 (m, 2H), 3.8 (m, 1H), 3.7 (s, 3H), 3.1-2.7 (m, 4H), 2.1-1.1 (m, 17H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].[Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[N+:35]([CH:38]=[CH:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)([O-:37])=[O:36]>C1COCC1.CCCCCCC.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH:39]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH2:38][N+:35]([O-:37])=[O:36])[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])C=Cc1cccnc1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(C[N+](=O)[O-])c2cccnc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -40 °C

Procedure:
To a cooled (−78° C.) solution of ethyl-1-BOC-3-piperidinecarboxylate (1.53 g, 10.20 mmol) in THF (15 ml) was added dropwise 2M LDA in heptane, THF, and ethylbenzene (5.34 ml, 10.69 mmol) and the resulting mixture was allowed to warm to −40° C. over 1 h and then cooled back to −78° C. A solution of 3-(2-nitroethenyl)pyridine (1.53 g, 10.20 mmol) in DMF (5 ml) was added dropwise and the reaction mixture was allowed to warm to RT over 1 h. The reaction was quenched with NH4Cl saturated aqueous solution (50 ml) and extracted with EtOAc (200 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-10% MeOH in DCM afforded the title compounds as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>O>[N:10]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: COc1cccc(Cl)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cccc(N2CCNCC2)n1
Reaction time: 24 h

Procedure:
A mixture of 2-chloro-6-methoxypyridine (20 g) and piperazine (32.9 g) with potassium carbonate (20.1 g) in water (50 ml) is stirred at 100° for 24 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is dissolved in ether. The organic phase is extracted with hydrochloric acid (10%). The aqueous phase is washed with ether, neutralized with sodium hydroxide (10%) and extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated to give 2-piperazino-6-methoxypyridine. This material is stirred in acetonitrile (100 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (3.01 g) and potassium carbonate (1.3 g) at 20°-25°for 16 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed over silica gel (2% methanol in methylene chloride to 4%) to give the free base of the title compound which is 92% pure by HPLC. This material is dissolved in ethyl acetate and treated with methane sulfonic acid (0.606 g) . The salt is filtered and recrystallized from methanol and ethyl acetate to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[S:32]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:37][C:34]2[CH:35]=[CH:36][S:32][CH:33]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: BrCc1ccsc1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccsc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.193 g, 0.44 mmol), prepared as described in EXAMPLE 43, part A, and thiophen-3-ylmethyl bromide (0.30 g, 1.68 mmol). The crude product is triturated with hexane/ether and used without further purification (0.25 g, 0.48 mmol).
Reaction SMILES: P(=O)(O)(O)O.C([C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:9](=[O:12])[CH2:10][CH3:11])#N.Br>C(O)(=O)C>[CH3:17][C:15]1([CH3:16])[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]([C:9](=[O:12])[CH2:10][CH3:11])[CH2:13][CH2:14]1
Reactant: CCC(=O)C(C#N)(CC=C(C)C)c1ccccc1
Agent: Br
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CCC(=O)C1CCC(C)(C)c2ccccc21
Temperature: 105 °C
Reaction time: 12 h
Yield: 23.8 %

Procedure:
In a 3-liter flask provided with a thermometer and stirrer 200 g of phosphorus pentoxide are added while cooling to 500 g of 85% phosphoric acid and subsequently 150 g of 4-cyano-7-methyl-4-phenyl-oct-6-en-3-one are added at ca.50° C. The mixture is stirred at 105° C. until starting material is no longer present (gas chromatography/thin-layer). 1000 g of 48% hydrobromic acid and 500 g of glacial acetic acid are then added. After 12 hours, a further 200 g of 48% hydrobromic acid and 100 g of glacial acetic acid are added and the temperature is raised to 110° C. After a total reaction time of 30 hours, the mixture is cooled, ice is added and the mixture is extracted with ether, washed neutral with water, with 10% sodium hydroxide and again with water, dried over sodium sulphate and evaporated. Vacuum distillation gives 32 g of 1,1-dimethyl-4-propionyl-tetralin of boiling point 75° C./0.05 mmHg; nD20 =1.5263; yield 24%. Odour: see (3).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0352 g, 0.0716 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (aminopropyl silica was used, chloroform/methanol) to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0213 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](Br)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[Na+].[CH3:32][S:33]([O-:35])=[O:34].[Na+].N1CCC[C@H]1C([O-])=O>CS(C)=O.O.[Cu]I>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CS(=O)[O-]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: O=C([O-])[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 150 °C
Yield: 51 %

Procedure:
[(R)-4-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (118.0 mg, 0.20 mmol), methanesulfinic acid sodium salt (24.5 mg, 0.24 mmol), copper(I) iodide (4.0 mg, 0.02 mmol) and L-proline sodium salt (3.2 mg, 0.04 mmol) were dissolved in dimethyl sulfoxide (1.5 mL) and water (0.3 mL). The mixture was heated in a microwave oven at 150° C. for 30 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [(R)-4-(3-methanesulfonyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (52.0 mg, 51.1%) as a white solid. MS calcd. for C19H22F3N3O6S2 509, obsd. (ESI+) [(M+H)+] 510.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:11])=[CH2:10]>C(Cl)Cl.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10]
Reactant: C=C(C)c1cc(F)ccc1Br
Agent: [Rh]
Solvent: ClCCl
Product: CC(C)c1cc(F)ccc1Br
Reaction time: 18 h

Procedure:
To a solution of 1-bromo-4-fluoro-2-(prop-1-en-2-yl)benzene (200 mg, 0.930 mmol) in DCM (5 mL) was added 5% Rhodium on Alumina (30 mg, 0.015 mmol). The resulting mixture was stirred under hydrogen atmosphere (50 psi) for 18 h after which time the reaction was filtered through Celite™ and concentrated in vacuo to afford 1-bromo-4-fluoro-2-isopropylbenzene. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.48 (dd, J=8.6, 5.7 Hz, 1H), 7.01 (dd. J=10.3, 3.1 Hz, 1H), 6.82-6.75 (m, 1H), 3.38-3.25 (m, 1H), 1.21 (d, J=6.9 Hz, 6H).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][C@H:6]([C:10]([O:12]C)=[O:11])[CH2:5][C:4]=2[CH:3]=[N:2]1.O.O.[OH-].[Li+]>CO>[NH:1]1[C:9]2[CH2:8][CH2:7][C@H:6]([C:10]([OH:12])=[O:11])[CH2:5][C:4]=2[CH:3]=[N:2]1
Reactant: COC(=O)[C@H]1CCc2[nH]ncc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H]1CCc2[nH]ncc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of (S)-methyl 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (500 mg, 2.80 mmol) in methanol (20 mL) were added water (10 mL) and lithium hydroxide hydrate (234 mg, 5.57 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h and then concentrated to remove most of methanol. The remaining mixture was acidified with diluted aqueous HCl to pH=4 and then concentrated. The residue was dried under vacuum to afford (S)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid (380 mg, 81% yield) as a colorless solid, which was used directly without further purification. (R)-methyl 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate was synthesized in a similar manner.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:13])[CH:5]1[CH2:15][O:16][CH:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:25][CH:24]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1.C(N(CC)CC)C.[C:57]1([CH3:67])[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:13][C:6]1([CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:3][CH2:2][O:1][S:63]([C:60]2[CH:61]=[CH:62][C:57]([CH3:67])=[CH:58][CH:59]=2)(=[O:65])=[O:64])[CH:5]1[CH2:15][O:16][CH:17]1[CH:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:27][CH:28]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2N(CCO)c3ccccc3C2(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2N(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 0.457 g of tert-butyl 3-[1-(2-hydroxyethyl)-3,3-dimethyl-2,3-dihydro-1H-indol-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.274 ml of triethylamine and 0.008 g of 4-dimethylaminopyridine in 10 ml of dichloromethane is admixed with stirring at 0° C. with 0.301 g of p-toluenesulphonyl chloride and stirred at room temperature over 18 hours. The reaction mixture is admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:1 EtOAc-heptane); Rt=6.46.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC(C)=O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[CH:12]=[N:11]2)=[CH:4][C:5]=1[O:9][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Cn1c(=O)cnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(-n2ncc(=O)n(C)c2=O)c(Cl)cc1Cl
Yield: 75.7 %

Procedure:
In a manner similar to Example II, Step C, the reaction of 0.86 g (0.0030 mole) of 2-(2,4-dichloro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (Compound 9, Example III H) with 0.62 g (0.0045 mole) of potassium carbonate and 0.75 g (0.0045 mole) of ethyl bromoacetate in 10 mL of acetone produced an oil. The oil crystallized upon treatment with heptane to yield 0.85 g of ethyl 2,4-dichloro-5-[4-methyl-1,2,4-triazine-3,5(2H,4H)-dione-2-yl]phenoxyacetate (mp 115°-117° C.), Compound 22 in the tables.