Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])O.C(O)(=O)/C=C\C(O)=O.OO>O[W](O)(=O)=O>[C@@H:4]1([C:6]([OH:8])=[O:7])[O:5][C@@H:2]1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=[W](=O)(O)O
Agent: O=C(O)/C=C\C(=O)O
Agent: OO
Product: O=C(O)[C@H]1O[C@H]1C(=O)O

Procedure:
M. Church and R. Blumberg (Ind. Engng. Chem. 43 (1951), 1780) have described a method of producing tartaric acid from maleic acid and hydrogen peroxide. The maleic acid is epoxidised with hydrogen peroxide in the presence of tungstic acid and the cis-epoxysuccinic acid formed is hydrolysed into tartaric acid which is crystallised by cooling the reaction solution and filtered off, the mother liquor being recycled to the epoxidation stage. The reaction takes place in accordance with the following reaction scheme: ##STR1##
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([NH:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH2:25][CH3:26])[N:24]=2)[CH2:17]1)=O)(C)(C)C.CO>O1CCOCC1>[NH2:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH2:25][CH3:26])[N:24]=2)[CH2:17]1
Reactant: CCc1nc(N2CC(NC(=O)OC(C)(C)C)C2)sc1C(=O)OC
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc(N2CC(N)C2)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 95 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (1.02 mL, 4.07 mmol) was added to a solution of methyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-4-ethyl-1,3-thiazole-5-carboxylate obtained in Example (222a) (139 mg, 0.41 mmol) in 1,4-dioxane (4 mL) at room temperature, and the mixture was stirred at room temperature for 13 hours. Then, methanol (2 mL) was added, and the mixture was further stirred for 5.5 hours. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution was added to the resulting residue. Thereafter, the mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure to obtain 94 mg of the title compound as a pale yellow oily substance (96%).
Reaction SMILES: CS(O)(=O)=O.O[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:28]2[CH2:29][CH2:30][N:31]([CH2:7][CH2:8][CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[CH2:32][CH2:33]2)=[CH:39][CH:38]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCO
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 2.7 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 2.88 parts of 1-[bis(p-fluorophenyl)methyl]piperazine, 2.66 parts of sodium carbonate and 100 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 197.3° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][CH2:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:28](=[O:27])[CH2:29][CH2:30][OH:31])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)CCO
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CCO)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (31 mg, 31%), MS (ISP) m/z=401.5 [(M+H)+], mp 158° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-hydroxy-propionic acid.
Reaction SMILES: C[C@H:2]1[C@:19](O)([C:20](CO)=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:29])[CH2:6]3)[CH2:3]1.I(O)(=O)(=O)=[O:31]>CO.O>[F:29][C@@H:7]1[C:8]2[C@:14]([CH3:28])([CH:13]=[CH:12][C:10](=[O:11])[CH:9]=2)[C@:15]2([F:27])[C@H:5]([C@H:4]3[C@@:18]([CH2:17][C@@H:16]2[OH:26])([CH3:25])[C@@H:19]([C:20]([OH:21])=[O:31])[CH2:2][CH2:3]3)[CH2:6]1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](C[C@H](F)C4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reaction time: 3 h

Procedure:
6α-Fluoro-dexamethasone (2 g) dissolved in methanol (100 ml) was treated with stirring overnight at room temperature with 1.5 g periodic acid in water (25 ml). The mixture was evaporated to small bulk in a rotary evaporator at 50° C. and refrigerated for 3 hours. The acid was collected by filtration and washed 3 times with small volumes of water.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:14][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:12]1)#[N:9].[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH:53]([NH2:55])[CH3:54])[CH2:49][CH2:48]1>>[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:12][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:55][CH:53]([CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH3:54])=[O:21])=[CH:17][CH:16]=2)[CH2:14]1)#[N:9]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5)C4)c3)ncnc21
Reactant: CC(N)C1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1)C1CCN(C)CC1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 19, Step 3 started from 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}benzoic acid and 1-(1-methylpiperidin-4-yl)ethanamine (ChemBridge: Cat. #4019769). LCMS (M+H)+: m/z=524.3.
Reaction SMILES: C(OC(=O)C)(=O)C.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[N+:21]([C:15]1[CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]2[O:11][CH2:10][CH2:9][O:8][C:13]=2[CH:14]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1OCCO2
Yield: 27 %

Procedure:
160 ml of acetic acid, 160 ml of acetic anhydride and 100 g of 1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated and a solution of 40 ml of nitric acid in 40 ml of acetic acid was added. The mixture was agitated at 40°-45° C. and then cooled. The crystals were dried off, washed and dried. 34 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 246° C.; yield: 27%).
Reaction SMILES: [ClH:1].C1C2C(=CC=CC=2)CCN1CC[CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[C:23]=2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30].BrCC[CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[C:47](=O)[C:46]2C=CC=[C:44]3[C:45]=2[C:40](=[CH:41][CH:42]=[CH:43]3)[C:39]1=O.BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[CH2:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46][CH2:47][N:38]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]3[C:23]=2[C:18](=[CH:19][CH:20]=[CH:21]3)[C:17]1=[O:30]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCc2ccccc2C1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CCc2ccccc2C1

Procedure:
Following the procedure of part (b) of example 39 but substituting 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione, one obtains 2-[6-(3,4-dihydro-2(1H)-isoquinolinyl)-hexyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:1).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([Mg]Br)[CH3:16]>>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([CH:11]([OH:12])[CH2:15][CH3:16])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Reactant: CC[Mg]Br
Product: CCC(O)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43b (313 mg, 1.71 mmol) and ethylmagnesium bromide (3.42 mL, 3.42 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Light yellow solid. Yield: 298 mg, 82%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.90-0.95 (m, 3H) 1.71-1.88 (m, 2H) 4.62 (t, J=6.62 Hz, 1H) 7.38-7.43 (m, 1H) 7.43-7.49 (m, 2H) 7.64-7.67 (m, 1H) 7.69-7.73 (m, 1H) 7.92-7.96 (m, 2H) 8.54 (d, J=2.21 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=9.9, 31.7, 73.2, 120.3, 126.8, 128.7, 128.8, 134.5, 138.3, 139.0, 147.7, 156.5; MS (ESI): m/z=214.28 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[CH2:11][O:12][CH2:13][CH3:14])=[O:5])C.O.[OH-].[Li+].[OH-].[Na+]>CO.O>[C:15]([N:9]1[C:10]([CH2:11][O:12][CH2:13][CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOCc1c(C(=O)OCC)cnn1C(C)(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOCc1c(C(=O)O)cnn1C(C)(C)C
Temperature: 100 °C
Yield: 87.8 %

Procedure:
A solution of 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (99.8 mg, 0.39 mmol) in methanol (0.5 mL) and water (0.5 mL) at 25° C. was treated with lithium hydroxide monohydrate (20.2 mg, 0.48 mmol). The reaction mixture was fitted with a reflux condenser and was then heated to 100° C. for 2 h. At this time, the reaction was concentrated in vacuo. The resulting residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. A cloudy mixture resulted. The material was brought to a basic pH by treatment with a 1N aqueous sodium hydroxide solution. This solution was extracted with ethyl acetate (1×10 mL). These organics were discarded. The aqueous layer was re-acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (2×10 mL). These organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-tert-butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid (77.5 mg, 87%) as a yellow solid. The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:12])[C:4](=[O:11])[C:5]([C:7]([F:10])([F:9])[F:8])=[CH2:6].C[Si](C)(C)[O:15][C:16]([CH:18]=[CH2:19])=[CH2:17].Cl>C1COCC1>[CH3:1][O:2][N:3]([CH3:12])[C:4]([C:5]1([C:7]([F:10])([F:8])[F:9])[CH2:19][CH2:18][C:16](=[O:15])[CH2:17][CH2:6]1)=[O:11]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=C(C(=O)N(C)OC)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1(C(F)(F)F)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.8 g (119 mmol) of N-Methoxy-N-methyl-2-trifluoromethyl-acrylamide (67) and 36.1 ml (29.6 mmol) of 2-(trimethylsiloxy)-1,3-butadiene were mixed and divided into 3 portions. Each portion was treated at 120° C. under microwave irradiation for 2 h. The combined reaction products were then diluted using 150 ml of THF, 100 ml of a 5% aqueous solution of HCl was added and stirred for 1 h at ambient temperature. Afterwards, the mixture was extracted three times using 200 ml of ethyl acetate each, dried using MgSOt and evaporated to yield 18.0 g, used without further purification. Rt=0.72 min (Method P).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7]CCOC.[CH3:12][C:13]1[N:14]([CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])[C:15]([CH3:18])=[CH:16][CH:17]=1.[OH-].[Na+]>O.CN(C)C=O>[CH:6]([C:16]1[CH:17]=[C:13]([CH3:12])[N:14]([CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])[C:15]=1[CH3:18])=[O:7]
Reactant: COCCOC
Reactant: CC(=O)NCCn1c(C)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)NCCn1c(C)cc(C=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
123 ml (1.34 mol) of phosphoryl chloride are added dropwise in the course of 30 minutes at 0° C. to 750 ml of 1,2-dimethoxyethane and 109 ml of dimethyl formamide. The mixture is stirred for a further 30 minutes at 0° C., and, in the course of 45 minutes at 0° C., 180 g (1 mol) of N-(2-(2,5-dimethyl-1H-pyrrolyl)ethyl)acetamide are introduced. After 10 minutes at 0° C., the mixture is allowed to warm to 10° C., stirred for 1 h at 10° C. and hydrolysed by pouring in a solution of 250 g of sodium hydroxide in 920 ml of water in the course of 2 h at 20° C. to the reaction mixture. The resulting reaction mixture is filtered, the organic phase is isolated and the water phase is extracted twice, each time with 370 ml of 1,2-dimethoxyethane. The organic phases are combined and substantially concentrated in vacuum. After addition of 250 ml of toluene, the mixture is concentrated to dehydrate it, 1 l of ethyl acetate is added and the mixture is filtered over silica gel and charcoal, crystallised and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)ccc1Cc1ccc(F)cc1
Yield: 78.8 %

Procedure:
A solution of methyl 3-nitro-6-(4-fluorobenzyl)benzoate (10 g, 36.9 mmol) in ethyl acetate (740 ml) was treated with stannous chloride dihydrate (41.6 g, 184.5 mmol). The mixture was refluxed for 17 hours, evaporated to 300 ml and aqueous ammonia (S.G. 0.88) added to pH 10. The resulting suspension filtered, washed with ethyl acetate and evaporated to give a yellow oil which was purified by flash chromatography (ethyl acetate/ iso-hexane: 1/1) to give methyl 3-amino-6-(4-fluorobenzyl)benzoate (7.54 g; 85%)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]([C:19]([C:21]1[S:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[O:20])C(C1SC(C)=CC=1)=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][C:3]2[NH:10][C:19](=[O:20])[C:21]3[S:22][C:23]([CH3:26])=[CH:24][C:25]=3[C:4]=2[CH:5]=1
Reactant: COc1ccc(N(C(=O)c2ccc(C)s2)C(=O)c2ccc(C)s2)c(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Product: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1
Yield: 481.8 %

Procedure:
Following Step 3 from General Procedure A, N-(2-bromo-4-methoxyphenyl)-5-methyl-N-(5-methylthiophene-2-carbonyl)thiophene-2-carboxamide (500 mg, 1.1 mmol) was reacted with bis(tri-tert-butylphosphine)palladium (45 mg, 0.089 mmol) to afford the desired product (1.3 g, 48%) as a green solid: ESI MS m/z 246 [C13H11NO2S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=13.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[CH:4]1[CH:9]3[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CN1CCc2ccc(F)c3c4c(n(c23)CC1)CCCC4
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2ccc(F)c3c2N(CC1)C1CCCCC31
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.7 %

Procedure:
To a solution of 8-fluoro-3-methyl-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.12 g, 0.44 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (0.12 g, 1.76 mmole) and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% methanol in methylene chloride) provided 60.0 mg of the title compound as a colorless oil. The oil was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 168-170° C. MS (ESI) m/z 275 ([M+H]+).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[C:21]([O-:24])(=[S:23])[CH3:22].[K+]>CN(C)C=O>[C:21]([S:23][CH:14]1[CH2:13][N:12]([C:9]2[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[N:8]=2)[CH2:15]1)(=[O:24])[CH3:22]
Reactant: C=CCOC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 10 h
Yield: 63.4 %

Procedure:
To a solution of 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (2.70 g, 8.51 mmol) (obtained as described in Reference Example 41(3)) in dimethylformamide (135 ml) was added potassium thioacetate (5.83 g, 51.1 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 10 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 3-acetylthio-1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)azetidine (1.61 g, yield 63%) as a pale brown solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@@H:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: N[C@H](CO)c1ccccc1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@H](CO)c3ccccc3)cc2c1=O
Yield: 76 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) -methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (S)-2-amino-2-phenyl-ethanol according to the GPA affording 25.8 mg (76%) of a red powder. Rt=4.10 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:22].[OH-].[Na+].Cl>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:22]
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)cc(C)n3C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc2cc(Cn3cc(C(=O)O)cn3)ccc2n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Ethyl 1-((1,2-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxylate (88%, 122 mg, 0.361 mmol) and 2 N NaOH (0.9 ml, 1.8 mmol) in dioxane (1 ml) was stirred at rt for 16 hours. The reaction mixture was acidified with 1 N HCl to pH 2 and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford crude 1-((1,2-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxylic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH:12]1[C:19]1[C:20]([O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[NH:24][C:23]=2[CH:33]=1)(=O)C>CO>[C:16]([N:13]1[CH2:14][CH2:15][CH:11]([OH:10])[CH:12]1[C:19]1[C:20]([O:34][C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)=[CH:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[NH:24][C:23]=2[CH:33]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC1CCN(C(C)=O)C1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N1CCC(O)C1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mg of potassium carbonate was added to a methanol (2 ml) solution of 14 mg of (1-acetyl-2-(5-(4-(methanesulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazol-6-yl)pyrrolidin-3-yl acetate diastereomer A obtained in Example 468, and the reaction liquid was stirred overnight at room temperature. The solvent was evaporated away, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=15/1) to obtain the entitled compound as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:16]=[C:17]([C:21]([NH:23][C:24]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[O:22])[CH:18]=[CH:19][CH:20]=1.[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](B(O)O)=[CH:37][N:36]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:24]([NH:23][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:38]3[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:35]=[N:36][CH:37]=3)[CH:16]=2)=[O:22])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(Br)c1
Reactant: OB(O)c1cncc2ccccc12
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: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2cncc3ccccc23)c1
Temperature: 90 °C
Reaction time: 7 h
Yield: 63.5 %

Procedure:
Under an Ar atmosphere, 10 mL of toluene, 2.5 mL of methanol, and 2.5 mL of 2M aqueous sodium carbonate solution were added to 500 mg (1.36 mmol) of methyl 2-{[(3-bromophenyl)carbonyl]amino}-5-chlorobenzoate obtained in Example 8-(i) and 352 mg (2.03 mmol) of isoquinolin-4-ylboronic acid, and the mixture was degassed. Further, 100 mg (0.087 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was heated under stirring at 90° C. for 7 hours. The mixture was cooled to room temperature, and then water and ethyl acetate were added, followed by collection by filtration, water-washing, and drying. Thereafter, the resultant was dissolved in chloroform and filtered. The filtrate was condensed, thereby giving 360 mg of methyl 5-chloro-2-({[3-(isoquinolin-4-yl)phenyl]carbonyl}amino)benzoate (yield: 63%).