Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH2:16][CH3:17])[N:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([CH2:36][O:37][CH3:38])[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=1)[C:8]2=[O:39].[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>N1C=CC=CC=1>[C:40]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH2:16][CH3:17])[N:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([CH2:36][O:37][CH3:38])[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=1)[C:8]2=[O:39])(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCCc1nc2ccc(OCCO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2ccc(OCCOC(=O)c3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of 6-(2-hydroxyethyloxy)-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-2-propyl-4(3H)-quinazolinone (0.09 g) in pyridine (2 ml) was added benzoyl chloride (0.08 ml) and the reaction solution was stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate-water and the organic layer was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give a colorless oil (0.1 g, 93%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([O:18]C)[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].O>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(O)C(OS(C)(=O)=O)C1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
11.5 g (0.1 mole) of methanesulfonyl chloride were added dropwise, whilst ice-cooling to a solution of 13.0 g (0.06 mole) of 1-t-butoxycarbonyl-3-hydroxy-4-methoxypyrrolidine [prepared as described in Step (c) above] in 100 ml of pyridine, and the mixture was stirred overnight whilst ice-cooling. The reaction mixture was then poured into 800 ml of water and extracted with diethyl ether. The extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to afford 12.9 g of 1-t-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxypyrrolidine as a brown oily substance. The whole of this oily substance was placed in a 100 ml stainless steel autoclave, and 50 ml of liquid ammonia was added thereto. The mixture was then heated with stirring at 140° C. under pressure for 8 hours. At the end of this time, the excess ammonia was removed by evaporation, and the residue was subjected to silica gel column chromatography eluted with ethanol, to afford 8.0 of cis-3-amino-1-t-butoxycarbonyl-4-methoxypyrrolidine as a brown oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[CH:14][CH:15]=2)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: Cn1c(CO)cnc1[N+](=O)[O-]
Reactant: Nc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(N)cc2)cnc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A suspension of 30 g of 1-methyl-2-nitroimidazole-5-methanol, 22 g of 4-aminophenol and 55 g of triphenylphosphane in 600 ml of anhydrous tetrahydrofuran was treated dropwise with vigorous stirring within 20 minutes with a solution of 42.5 g of diisopropyl azodicarboxylate in 300 ml of anhydrous tetrahydrofuran. The mixture was maintained at a temperature of 20°-24° C. by external cooling. After 2 hours, the clear solution obtained was evaporated under reduced pressure and the residue was boiled briefly with a mixture of 125 ml of methylene chloride and 125 ml of ethyl acetate to yield 24.4 g (52%) of crystalline α-(1-methyl-2-nitroimidazol-5-yl)-p-anisidine, m.p. 168°-170° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[N:2]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[N:2]=1
Reactant: O=C1CCC(Oc2cccnn2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3cccnn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(pyridazin-3-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][C:36]([CH:39]([CH3:40])[CH3:41])=[CH:37][CH:38]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C(C)C)nc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (193 mg, 0.75 mmol) and 3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K22) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (160 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[H-].[Na+].[F:13][C:14]([F:44])([F:43])[C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][N:22]2[C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])=[CH:17][CH:16]=1.O>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:31]([N:22]2[CH2:23][CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:21]2[C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:43])([F:13])[F:44])=[CH:16][CH:17]=2)=[O:32])=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)ccc1N
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)ccc1NC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 4-amino-3-methylbenzonitrile (30 mg, 226 μmol) in THF (2 mL) was added sodium hydride, 60% dispersion in mineral oil (15 μL, 339 pimp. The resulting mixture was then stirred at RT for 2 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, 26 mg of NaH (60% dispersion in mineral oil) was added and the mixture was stirred at RT for overnight. Then, H2O (0.2 mL) was added and the solvents were removed. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 1.0 mL). The solution was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was then washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 436 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:20])[CH:6]=[C:7]([S:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:8]2=[O:13]>C(Cl)(Cl)Cl.CC(O)=O.C([O-])(=O)C.[Ag+]>[C:16]([O:18][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:20])[CH:6]=[C:7]([S:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:8]2=[O:13])(=[O:17])[CH3:15]
Reactant: CC(SC1=CC(=O)c2c(CBr)cccc2C1=O)C(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OCc1cccc2c1C(=O)C=C(SC(C)C(=O)O)C2=O
Reaction time: 8 h

Procedure:
A mixture of the brominated acid 1b (6 mmol) and silver acetate (2.2 g, 13.2 mmol) is combined in 20 mL of CHCl3 and 40 mL of AcOH, heated at 95° to 100° C. with vigorous stirring overnight. The solvent was evaporated in vacuo, and the residue was poured onto ice water saturated with NaCl. The crude product and AgCl were collected by filtration and washed with water. The solid was then added to a CHCl3, and the insoluble AgCl was removed by filtration. The AgCl was washed with CHCl3 until the washings were colorless. The combined CHCl3 solutions were dried with Na2SO4, concentrated and chromatographed on a silica gel column (C6H6 -CHCl3, 1:1, v/v). To yield (5-acetoxymethyl-1,4-naphthoquinonyl thio)-propionic acid, designated 1c.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:23][C:24]([F:32])([F:31])[CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([C:9]2[CH:14]=[C:13]([S:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]([CH3:21])=[CH:11][C:10]=2[F:22])[C:6]=1[NH:7][CH3:8].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:23][C:24]([F:31])([F:32])[CH:25]([F:30])[C:26]([F:27])([F:28])[F:29])=[N:4][N:5]([C:9]2[CH:14]=[C:13]([S:15]([CH2:16][C:17]([F:20])([F:19])[F:18])=[O:41])[C:12]([CH3:21])=[CH:11][C:10]=2[F:22])[C:6]=1[NH:7][CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1c(Cl)c(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CNc1c(Cl)c(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 97 %

Procedure:
0.24 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-methylaminopyrazole was dissolved in 10 mL of chloroform, and 120 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.24 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-methylaminopyrazole.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2>N1C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2)=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCOC(=O)c1ccc2ccc(C)nc2c1O
Solvent: c1ccncc1
Product: CCCCOC(=O)c1ccc2ccc(C)nc2c1OC(=O)C(C)(C)C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
10.4 ml (84 mmol) of pivaloyl chloride are added, at 0° C., to a solution of the preceding ester 2 (step 1) (11.0 g, 42 mmol) in pyridine (45 ml). After 1 hour at 20° C., the pyridine is distilled under reduced pressure, and then 20 ml of water and 50 ml of dichloromethane are added. The phases are separated and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on a silica column, eluting with a 2/1 cyclohexane/ethyl acetate mixture so as to give 11.7 g (82%) of n-butyl 8-(2,2-dimethylpropionyloxy)-2-methylquinoline-7-carboxylate 3 in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:19]([OH:21])[N:17]=[C:15]([OH:16])[C:3]=3[N:4]=2)=[CH:13][CH:12]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1nc(-c2ccc(F)cc2)ccc1N
Solvent: C1COCCO1
Product: Oc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1

Procedure:
A solution of 3-amino-6-(4-fluorophenyl)picolinamide (2.48 g) and triphosgene in 1,4-dioxane (50 mL) was heated to 100° C. for 1 hour. Cooling and filtration provided 2.2 g of 6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine-2,4-diol which was characterized by its mass spectrum as follows: MS (m/z) 258 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(I)cc1
Reactant: OB(O)c1ccc(Br)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Yield: 71 %

Procedure:
In accordance with Example 11-(1), but using ethyl 4-iodophenylacetate instead of 4-bromobenzyl bromide, and (4-bromophenyl)boronic acid instead of [3-(hydroxymethyl)phenyl]boronic acid, ethyl (4′-bromobiphenyl-4-yl)acetate (yield 71%) was afforded as a white solid.
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:37])[C@@H:8]([CH:34]([CH3:36])[CH3:35])[N:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(C)(C)C>ClCCl>[ClH:1].[Br:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:23]2[CH:22]=[CH:21][C:20]([S:17]([N:9]([CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[C@@H:8]([C:7]([OH:37])=[O:6])[CH:34]([CH3:36])[CH3:35])(=[O:19])=[O:18])=[CH:25][CH:24]=2)=[CH:32][CH:31]=1
Reactant: CC(C)[C@H](C(=O)OC(C)(C)C)N(Cc1cccnc1)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@H](C(=O)O)N(Cc1cccnc1)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry hydrogen chloride was bubbled through a −20° C. solution of N-[4-(4-bromophenoxy)benzenesulfonyl]-N-(pyridin-3-yl)methyl-D-valine t-butyl ester (920 mg, 1.6 mol) in 20 mL of dichloromethane for 10 min, and the reaction was sealed and stirred at room temperature overnight. The reaction was vented, nitrogen was bubbled through the solution for 20 min, and the solution was concentrated to give N-[4-(4-bromophenoxy)benzenesulfonyl]-N-(pyridin-3-yl)methyl-D-valine hydrochloride that was used without further purification in the next step. The above acid was dissolved in 8 mL of dichloromethane, treated with O-t-butyl hydroxylamine hydrochloride (600 mg, 4.8 mol), N-methylmorpholine (0.92 mL, 8.3 mol), and EDC (613 mg, 3.2 mol), and stirred at room temperature overnight. The reaction was partitioned between water and dichloromethane, and the organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica, eluting with 5% methanol in dichloromethane, to give 750 mg (79%) of 2(R)-N-(tert-butoxy)-2-[4-(4-bromophenoxy)benzenesulfonyl][(pyridin-3-yl)methyl]amino-3-methylbutanamide as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>CO.C(O)C>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:11][C:9]2[NH:8][C:7]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[N:10]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc2[nH]c(S)nc2c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(CSc2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Yield: 40.8 %

Procedure:
A mixture of 5-nitro-1H-benzoimidazol-2-thiol (1.95 g, 0.01 mol), 4-bromomethyl-benzoic acid methyl ester (2.29 g, 0.01 mol), triethylamine (2 mL), and ethanol (100 mL) was heated at reflux for a period of 4.5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. The organic phase was evaporated. The residue was crystallized from ethyl acetate/hexane. The solid obtained was dissolved in methanol and the solution was saturated with hydrogen chloride. The methanol was evaporated. The residue was treated with ethyl acetate. The solid was collected to give the title compound (1.4 g, 41%) as a mono-hydrochloride, white solid, m.p. 228°-230° (dec.). Anal. Calcd. for C16H13N3O4S.HCl: C, 50.60; H, 3.72; N, 11.06. Found: C, 50.82; H, 3.68; N, 10.92. Mass spectrum (+FAB; [M+H]+) 344. 1H-NMR (DMSO-d6 ; 400 MHz) δ 8.32 (s, 1H), 8.06 (d, 1H), 7.88 (d, 2H), 7.62 (m, 3H), 5.0-7.4 f(br s, 4H), 4.67 (s, 2H), and 3.81 ppm (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[C:2][CH2:3][CH3:4].[N+:11]([CH:14](C(OC)=O)[C:15]([O:17][CH3:18])=[O:16])([O-])=[O:12]>C1(C)C=C(C)C=C(C)C=1>[CH2:3]([C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[N:11][O:12][C:1]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCC#Cc1ccccc1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Solvent: Cc1cc(C)cc(C)c1
Product: CCc1c(C(=O)OC)noc1-c1ccccc1
Yield: 29.7 %

Procedure:
A solution of but-1-ynylbenzene (404 mg, 3.11 mmol) and dimethyl nitromalonate (0.381 mL, 2.82 mmol) in mesitylene (5 mL) was heated to 150° C. for 24 h. The reaction mixture was concentrated, and the residue purified on silica gel column with hexanes/ethyl acetate (10/1) to afford methyl 4-ethyl-5-phenylisoxazole-3-carboxylate (194 mg). The compound had an HPLC ret. time=3.25 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO; Start % B=0; Final % B=100. LC-MS: M+1=232+.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:10][C:9]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[O:13][CH2:14][C:8]=2[C:7](=[O:19])[CH:6]=1)=[O:4].[OH-].[K+:21]>CO>[K+:21].[O:19]=[C:7]1[CH:6]=[C:5]([C:3]([O-:4])=[O:2])[O:10][C:9]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[O:13][CH2:14][C:8]1=2
Reactant: COC(=O)c1cc(=O)c2c(o1)-c1ccccc1OC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1cc(=O)c2c(o1)-c1ccccc1OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-2-carboxylic acid methyl ester (0.292 g, 1.1 mmoles, described in Example 6) in methanol (15 ml) containing potassium hydroxide (0.2 g) is stirred at room temperature overnight. The solution is evaporated under reduced pressure and the residue is crystallized from methanol to give 4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-2-carboxylic acid potassium salt; m.p. >280° C, νmaxnujol 1650 cm-1. The latter compound is dissolved in water and the resulting solution is added to dilute hydrochloric acid. The precipitate is collected and crystallized from methanol to give the title compound; m.p. 253°-254° C (dec.), νmaxnujol 2500, 1735 and 1650 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
100 mg (72%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(4-chlorophenyl)piperazine (73 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cccn3)nc3sc4c(c23)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:45])[C@@H:5]([NH:37]C(OC(C)(C)C)=O)[CH2:6][CH2:7][C:8](=[O:36])[NH:9][C:10]1[C:15]([C:16]2[O:20][N:19]=[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:24][CH:23]=3)[CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:45])[C@@H:5]([NH2:37])[CH2:6][CH2:7][C:8](=[O:36])[NH:9][C:10]1[C:15]([C:16]2[O:20][N:19]=[C:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:26][CH:27]=3)[CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H](N)CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-4-(3-{3-[4-(pyridin-2-yloxymethyl)-benzyl]-isoxazol-5-yl}-pyridin-2-ylcarbamoyl)-butyric acid ethyl ester (40 mg, 0.065 mmol) described in Manufacturing Example 4-2 and dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) at room temperature, which was stirred overnight at the same temperature. The solvent was evaporated from the reaction mixture under a reduced pressure, and the residue thus obtained was washed with diethyl ether, so as to obtain the titled compound (30 mg) as the trifluoroacetic acid salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3C=CC=C(OC)C=3)=[CH:29][CH:28]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[F:41][C:42]1[C:43](=O)[NH:44][C:45]2[C:50]([CH:51]=1)=[CH:49][C:48](B1OC(C)(C)C(C)(C)O1)=[CH:47][CH:46]=2>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:48]3[CH:49]=[C:50]4[C:45](=[CH:46][CH:47]=3)[N:44]=[CH:43][C:42]([F:41])=[CH:51]4)=[CH:33][C:28]=2[CH3:29])[C:23]([F:24])([F:25])[F:26])[N:3]=1
Reactant: COc1cccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)cc2)c1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)c(F)cc3c2)OC1(C)C
Product: Cc1cc(-c2ccc3ncc(F)cc3c2)ccc1[C@@H](Oc1cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)nc(N)n1)C(F)(F)F

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 55an) Steps 4-5. 3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolone was used as the Suzuki coupling partner (CAS#1251731-31-3).