Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O.CO.[OH-].[Na+]>[C:26]1([S:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=3[CH3:15])=[CH:21][CH:20]=2)(=[O:25])=[O:24])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c1C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(NS(=O)(=O)c2ccccc2)cc1
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of [4-(4-benzenesulfonylamino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (38 mg, 0.08 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (10 mg, 0.25 mmol) in water (1 mL) and methanol (1 mL) plus sodium hydroxide solution (1 ml, 1.0 N) at room temperature. The resulting clear solution was stirred for 4 h and then the solvents were removed under vacuum. The residue was diluted with water (10 mL). The mixture was acidified with 1.0 N hydrochloric acid and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum provided the desired [4-(4-benzenesulfonylamino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (34 mg, 92%) as a light brown foam. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.43 (br. s, 1 H), 10.44 (s, 1 H), 7.88-8.02 (m, 1 H), 7.76-7.87 (m, 3 H), 7.50-7.71 (m, 3 H), 7.33 (t, J=7.7 Hz, 1 H), 7.24 (d, J=8.0 Hz, 2 H), 7.09 (d, J=8.0 Hz, 2 H), 6.58 (d, J=11.2 Hz, 1 H), 3.80 (br. s, 2 H), 2.00 (s, 3 H). HRMS calcd. for C25H19FNO4S [(M−H)−] 448.1024, obsd. 448.1022.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.N1C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:31]([O:33][C:34](=[O:35])[C:26]=12)=[O:32].O.C1COCC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:34]([C:26]2[N:25]=[CH:30][CH:29]=[CH:28][C:27]=2[C:31]([OH:33])=[O:32])=[O:35])=[N:2]1.[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:31]([C:27]2[C:26]([C:34]([OH:35])=[O:33])=[N:25][CH:30]=[CH:29][CH:28]=2)=[O:32])=[N:2]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ncccc21
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1cccnc1C(=O)O
Product: O=C(O)c1cccnc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
To a solution of Compound 2 (0.10 g, 0.43 mmol) in THF (2.0 mL), pyridine (0.10 μL, 1.3 mmol) and 2,3-pyridinedicarboxylic anhydride (76 mg, 0.51 mmol) were added and stirred at room temperature for 1.5 hours. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10), crystallized from ethyl acetate to obtain (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}nicotinic acid or (E)-3-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}pyridine-2-carboxylic acid (63 mg, 39%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N+](=[CH2:15])=[N-]>O1CCCC1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:15])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc2[nH]ncc2c1
Reaction time: 1 h

Procedure:
Under ice-cooling, to a solution of 910 mg of 1H-5-indazolecarboxylic acid in 60 ml tetrahydrofuran was added an excess amount of a solution of diazomethane in diethyl ether, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, the residue was added with 50 ml of ethyl acetate, sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 923 mg of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N+:13]([CH3:16])([O-:15])=[O:14].C[O-].[Na+]>CO>[OH:1][C:2]1([CH2:16][N+:13]([O-:15])=[O:14])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(O)(C[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a stirred and cooled mixture of 85.5 parts of ethyl 4-oxo-1-piperidinecarboxylate, 33.6 parts of nitromethane and 240 parts of methanol were added dropwise 10 parts of a sodium methoxide solution 30% at 10°~15° C. Upon completion, stirring was continued first for 2 hours at about 10° C. and further overnight at room temperature. The reaction mixture was evaporated at room temperature, crushed ice was added to the oily residue and the whole was acidified with acetic acid. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The oily residue was solidified on triturating in petroleum ether. The product was filtered off and dried, yielding 73 parts of ethyl 4-hydroxy-4-(nitromethyl)-1-piperidinecarboxylate (intermediate 3).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[C:21]2[C:16](=[N:17][C:18]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[N:20]=2)[N:15]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[C:21]2[C:16](=[N:17][C:18]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[N:20]=2)[N:15]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:14][CH2:13]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3=O)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of oxalyl chloride (0.085 ml, 0.973 mmol) in DCM (20 ml) at −78° C. under nitrogen was added a dropwise solution of DMSO (0.168 ml, 2.373 mmol) in DCM (10 ml). After stirring at −78° C. for two hours, a solution of tert-butyl 8-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 1) (200 mg, 0.463 mmol) in DCM (5 ml) was added dropwise and the mixture was left to stir for 15 minutes at −78° C. under an atmosphere of nitrogen. Triethylamine (0.331 ml, 2.373 mmol) was added and after 5 minutes the reaction mixture allowed to warm to 18° C. under an atmosphere of nitrogen overnight. The reaction mixture was diluted with DCM (30 ml) and was sequentially washed with 2M NaOH (30 ml), water (30 ml) and brine (30 ml). The organic layer was separated and dried using a hydrophobic frit and the solvent evaporated to afford the titled compound as a yellow solid;
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.[C:39]([C:46](OCC)=[O:47])#[C:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(O)C>[CH2:44]([O:43][C:41]([C:40]1[N:15]2[CH2:14][C@@H:13]([CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)[O:17][C:16]2=[N:18][C:46](=[O:47])[CH:39]=1)=[O:42])[CH3:45]
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2CCCCC2)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol), prepared in accordance with the procedures described in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, in ethanol (10 mL) was added diethyl acetylenedicarboxylate (0.39 g, 2.29 mmol). The reaction mixture was heated at reflux for 14 hours and then stored in a freezer overnight. The reaction mixture was warmed to room temperature. The resulting crystalline solid was isolated by centrifugation and dried under vacuum at 60° C. to afford 427 mg of (S)-2-(4-cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidine-5-carboxylic acid ethyl ester. [α]D25 −16.15 (c 0.52, CHCl3).
Reaction SMILES: COC(=O)COC1C=C(Cl)C(SC#N)=CC=1C.C[O:19][C:20](=[O:49])[CH2:21][O:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)=[CH:25][C:24]=1[CH3:48]>>[Cl:29][C:27]1[C:26]([S:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:42][CH:43]=3)=[CH:36][CH:37]=2)=[CH:25][C:24]([CH3:48])=[C:23]([CH:28]=1)[O:22][CH2:21][C:20]([OH:49])=[O:19]
Reactant: COC(=O)COc1cc(Cl)c(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: COC(=O)COc1cc(Cl)c(SC#N)cc1C
Product: Cc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(Cl)cc1OCC(=O)O

Procedure:
The title compound was prepared from (5-chloro-2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester in a manner analogous to Example 1D. 400 MHz 1H NMR (DMSO-d6) δ 7.27 (s, 1H), 6.97 (s, 1H), 5.31 (s, 1H), 4.79 (s, 2H), 3.64 (s, 3H), 2.07 (s, 3H). Step 4. Preparation of [5-Chloro-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (Compound 20D)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:7][C:6]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[C:4](=O)[CH2:3]1.[CH2:17]([NH2:19])[CH3:18].[BH4-].[Na+]>O1CCCC1.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:17]([NH:19][CH:4]1[CH2:3][C:2]([CH3:16])([CH3:1])[S:7][C:6]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:5]1=2)[CH3:18]
Reactant: CCN
Reactant: CC1(C)CC(=O)c2cc(S(N)(=O)=O)sc2S1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCNC1CC(C)(C)Sc2sc(S(N)(=O)=O)cc21
Yield: 77.1 %

Procedure:
A solution of 5,6-dihydro-6,6-dimethyl-4H-thieno[2,3-b]thiopyran-4-one-2-sulfonamide (3.00 g, 0.011 mol) in dry tetrahydrofuran (40 ml) and benzene (40 ml) was cooled to -10° C. and condensed ethylamine (15 ml, 10.8 g, 0.24 mol) was added rapidly with stirring. Titanium tetrachloride 1.14 g, 0.006 mol) was added over 20 minutes while maintaining the temperature below 0° C. The mixture was stirred at ambient temperature for 2.5 hours, filtered, and the solid was washed with tetrahydrofuran. The combined filtrate and washings were evaporated in vacuo and the residue was suspended in absolute methanol (105 ml). With stirring under nitrogen, sodium borohydride (0.53 g, 0.014 mol) was added portionwise over 15 minutes and the mixture was stirred at ambient temperature for 21 hours. After acidification with concentrated hydrochloric acid, the mixture was concentrated in vacuo. The residue was distributed between water (100 ml) and ethyl acetate (100 ml), and the aqueous layer was separated and extracted with ethyl acetate (2×50 ml). The water layer then was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×250 ml). The combined extracts were washed with water (3x), dried over sodium sulfate, and evaporated in vacuo. The residue was crystallized as the hydrochloride salt from ethanolic hydrogen chloride to afford 2.60 g (69%) of pure product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[N:39]=[CH:40][CH:41]=[C:42]2[C:47](=[O:48])[C:46](I)=[C:45]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:44][C:43]=12>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:46]3[C:47](=[O:48])[C:42]4[C:43]([O:44][C:45]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:38]([Cl:37])[N:39]=[CH:40][CH:41]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(Cl)nccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Yield: 20 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-chloro-3-iodo-2-phenyl-pyrano[2,3-c]pyridin-4-one was reacted to give the title compound (30 mg, 20%) as a white solid. LCMS (Method A): RT=4.88 min, [M+Na]+=525/527.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.CN1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:16])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:24])([F:23])[F:25])[O:11][N:10]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46820.8 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (50 mg, 0.0001 mmol), Morpholine (9 mg, 0.0001 mmol), HOBt (14 mg, 0.0001 mmol) and EDCI (19 mg 0.00012 mmol) were dissolved in 1 mL dry DMF. N-Methylmorpholine (100 NL, 0.001 mmol) was added and the reaction mixture was stirred at room temperature overnight. Morpholine, HOBt, EDCI and N-Methylmorpholine were added again in the aforementioned ratios. The mixture was stirred at room temperature for 24 h. DMF was removed by evaporation. An aqueous solution of 5% citric acid was added. The precipitate was filtered and dried. The product (example B-35) was purified by pTLC (PE/EE 5/5) to give 26 mg of a yellow oil (yield 45%). Result of LC/MS MH+: 554.7; 1H NMR (CDCl3): 8.15 (1H, s, CH-pyraz.), 7.35-7.6 (6H, m, CH-arom), 7.15 (1H, t, CH-arom), 3.6 (4H, m, CH2-morpholine), 3.18 (4H, m, CH2-morpholine).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F-].[K+].Br[CH:15]([F:21])[C:16](OCC)=[O:17]>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:15]1[C:16](=[O:17])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(=O)C(F)Br
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2OC1F
Temperature: 60 °C
Reaction time: 44 h
Yield: 41.8 %

Procedure:
To a suspension of 2-amino-5-nitrophenol (1.98 g) and potassium fluoride (2.24 g) in N,N-dimethylformamide (40 mL) was added ethyl bromofluoroacetate (2.85 g), and the mixture was stirred at 60° C. for 44 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=19/1→1/1) and triturated with n-hexane/diisopropylether to give 2-fluoro-7-nitro-2H-1,4-benzoxazin-3(4H)-one (1.14 g) as a yellow powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@H:6]([C:10]([OH:12])=[O:11])[C@@H:7]([CH3:9])[OH:8].[CH3:13]O>>[ClH:3].[CH3:13][O:11][C:10](=[O:12])[C@H:6]([C@@H:7]([CH3:9])[OH:8])[NH2:5]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Product: COC(=O)[C@@H](N)[C@@H](C)O
Product: Cl

Procedure:
Thionyl chloride (39.0 ml, 0.542 mole) was added dropwise with stirring to 150 ml of dry methanol at -10° C. Then, 17.85 g. (0.15 mole) of D(+) threonine was added, cooling was discontinued and the reaction mixture was kept at about 22° C. for sixteen hours. The mixture was evaporated in vacuo to remove the solvent plus excess thionyl chloride, leaving crude D(+) threonine methyl ester HCl in essentially quantitative yield. The ester was dissolved in 375 ml saturated aqueous sodium bicarbonate, and the solution was stirred vigorously at about 22° C. while benzyl chloroformate (25.0 ml, 0.18 mole) was added dropwise over 5 minutes. The product separated as an oil which spontaneously crystallized after about 16 hours. This product was extracted into ether and after drying over anhydrous magnesium sulfate and evaporation, 42.8 g of white solid was obtained. Recrystallization from ethyl acetate/hexane gave two crops of product: (a) 30.91 g, m.p. 89.5°-91.5° C. and (b) 3.43 g, m.p. 87°-89° C.; total yield was 71%. Analysis calculated for C13H17NO5 : C=58.42%; H=6.41%; N=5.24%. Found: C=58.50%; H=6.45%; N=5.21%.
Reaction SMILES: [C:1]([C:3]([CH3:29])([CH3:28])[C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10](=[O:25])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)#[N:2].C1(C)C=CC=CC=1.C[Si]([N:41]=[N+:42]=[N-:43])(C)C.C[Sn](=O)C>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:9][CH2:8][C:7]2[CH:26]=[CH:27][C:4]([C:3]([CH3:29])([C:1]3[NH:43][N:42]=[N:41][N:2]=3)[CH3:28])=[CH:5][CH:6]=2)=[O:25])=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C#N)c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Agent: C[Sn](C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1)c1nnn[nH]1
Temperature: 95 °C

Procedure:
N-[4-(Cyano-dimethyl-methyl)-benzyl]-2-(4-fluoro-phenoxy)-nicotinamide (12.22 g) was placed in a sealable tube with anyhdrous toluene (10 mL). Trimethylsilyl azide (8.0 mL) and dimethyltin oxide (1.29 g) were then added. The reaction mixture was heated to 95° C. for 17 h, then allowed to cool to ambient temperature. Excess methanol was added and the mixture was concentrated to dryness in vacuo. Methanol was again added and evaporated. To the crude product were added ethyl acetate (200 mL) and and saturated aqueous sodium bicarbonate (100 mL) and water (100 mL). The aqueous layer was collected, and the organic layer extracted with 50% sodium bicarbonate twice (100 mL). The combined aqueous portions were separated and brought to pH 3 with conc. hydrochloric acid. The aqueous solution was then re-extracted with ethyl acetate (5×300 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by recrystallization (ethanol) to yield the title compound (5.36 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8]([NH:11][CH3:12])(=[O:10])=[O:9].S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8]([NH:11][CH3:12])(=[O:10])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CNS(=O)(=O)c1sccc1CO
Product: CNS(=O)(=O)c1sccc1CCl

Procedure:
7.5 g (36.1 mmol) of 3-hydroxymethyl-2-N-methylthiophenesulfonamide are boiled under reflux with 50 ml of thionyl chloride for 15 minutes. Thereafter, the mixture is evaporated to dryness in a water-jet vacuum. The residue is taken up in 150 ml of methylene chloride and stirred with saturated sodium bicarbonate solution until the aqueous phase has an alkaline reaction. The phases are separated. The aqueous phase is extracted with two 50 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to give an oil which crystallizes out in the cold. There is obtained 3-chloromethyl-2-N-methylthiophenesulfonamide of melting point 52°-53° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)#[N:2].[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[N:8]=[C:4]([CH2:3][C:1]#[N:2])[S:5][CH:6]=3)=[O:11])[CH3:29])[N:16]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: N#CCc1nc(C(=O)O)cs1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CC#N)n1
Yield: 1 %

Procedure:
2-(Cyanomethyl)thiazole-4-carboxylic acid (280 mg, 0.10 mmol) was coupled with (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-100% EtOAc in heptane; 2nd column: C-18 silica, eluent: 0-100% MeCN in water) to obtain 4.9 mg (1%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 4.13 (s, 2H), 4.31 (dd, 1H), 4.43 (dd, 1H), 4.55-4.67 (m, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.70 (d, 1H), 7.79 (dd, 1H), 7.84 (d, 1H), 7.97 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:25]=2[CH3:26])[CH2:22][N:21](CC2C=CC(OC)=CC=2)[CH:20]=[CH:19]3)=O)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=[O:39]>>[CH3:26][C:25]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][NH:21][C:22]2=[O:39])=[CH:17][C:16]=1[O:15][CH2:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COc1ccc(CN2C=Cc3cc(OC(=O)[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c(C)cc3C2)cc1
Reactant: O=C(O)C(F)(F)F
Product: Cc1cc2c(=O)[nH]ccc2cc1OC[C@@H]1CCNC1
Temperature: 150 °C
Yield: 38.7 %

Procedure:
0.53 g (1.1 mmol) (R)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester were dissolved in 2.5 g (22 mmol) trifluoroacetic acid. After 1 h at room temperature the mixture was heated for 2 h in a microwave oven at 150° C. Then the excess trifluoroacetic acid was distilled off in vacuo and the residue was diluted with 10 ml 1 M hydrochloric acid. The aqueous phase was washed with methylene chloride twice and then it was freeze dried to give 0.11 g 7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-one as the hydrochloride. Rt=0.82 min (Method B). Detected mass: 259.1 (M+H+).
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:7])[C:4]([O-:6])=[O:5].[C:8]1([CH:14]([NH3+])C)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[F:1][CH2:2][CH:3]([OH:7])[C:4]([O:6][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C([O-])C(O)CF
Reactant: CC([NH3+])c1ccccc1
Agent: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C(O)CF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-phenylethanaminium 3-fluoro-2-hydroxypropanoate (11-1) (0.14 g, 0.61 mmol) in DMF (1 mL) was added benzyl bromide (0.087 mL, 0.73 mmol). The mixture was stirred at room temperature overnight, diluted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexanes) to provide 11-2. HRMS: 198.0688 found, 198.0692 required (M+).