Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)=O.S(=O)(=O)(O)[OH:37].OO.[OH-].[Na+]>CO.O>[OH:37][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 15.5 %

Procedure:
Step 3 A suspension of 7-formyl-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (30 mg, 0.052 mmol) in methanol (1 mL) was treated with sulfuric acid (4.2 mL, 0.078 mmol) followed by 30% aqueous hydrogen peroxide (0.032 mL, 0.313 mmol), and stirred at rt for 23 h, The mixture was treated with 1 M aqueous sodium hydroxide (200 mL) and stirred for 1 h. The mixture was diluted with water and the precipitate was collected by filtration, washed with water and dried. The residue was purified by preparative HPLC to provide 7-hydroxy-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a tan powder (3.6 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.90 (1H, d, J=7.5 Hz), 7.86 (1H, d, J=7.9 Hz), 7.65-7.76 (2H, m), 7.48-7.63 (3H, m), 7.42 (1H, d, J=6.6 Hz), 7.03 (1H, d, J=7.9 Hz), 6.98 (1H, s), 6.92 (1H, d, J=8.8 Hz), 6.54 (1H, d, J=9.0 Hz), 4.97 (2H, s), 1.94 (3H, s). Mass spectrum m/z 448.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:5]1[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncccc1C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-amino-3-trifluoromethylpyridine (0.980 g, 5.92 mmol) is dissolved in CHCl3 (7 ml) and AcOH (5 ml). The reaction mixture is cooled to 0-10° C. (ice-bath) and bromine (0.424 ml, 8.3 mmol) dissolved in CHCl3 is slowly added drop wise. The reaction mixture is stirred at this temperature for 1 hour then allowed to warm room temperature. The solvents are removed in vacuo and the residue is dissolved in EtOAc washing with saturated NaHCO3. The organic portion is dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O1CCCC1.C(OCC)(=O)C>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cn1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cn1
Yield: 17.3 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg) was dissolved in absolute tetrahydrofuran (20 mL), and sodium hydride (60% in oil, 200 mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (1.01 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Methoxypyridin-3-ylsulfonyl chloride (623 mg) was added, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as an oil (yield 59 mg, 17%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:1]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Tetrapropylammonium perruthenate (9.4 mg, 0.027 mmol) was added to a mixture of (1S, 4R)-4-(tert-butyldimethylsilanyloxy)cyclopent-2-enol prepared, according to Tetrahedron Letters, Vol. 37, No. 18, 1996, pp. 3083-6, (118.6 mg, 0.54 mmol), 4-methylmorpholine N-oxide (94.9 mg, 0.81 mmol) and crushed 4 Å sieves (270 mg) in CH2Cl2 (10 mL). The mixture was stirred for 30 min and was passed through a plug of silica gel with CH2Cl2. The filtrate was concentrated in vacuo to give 100 mg (86%) of the above titled compound.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[O:35][C:14]2[CH2:15][N:16]([C:19](=[O:34])[C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[CH2:17][CH2:18][C:13]=2[CH:12]=1)C)=O)(C)(C)C.[ClH:36]>CO>[ClH:36].[CH3:6][NH:8][CH2:10][C:11]1[O:35][C:14]2[CH2:15][N:16]([C:19](=[O:34])[C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=3)[CH2:17][CH2:18][C:13]=2[CH:12]=1
Reactant: CN(Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Reaction time: 0.5 h

Procedure:
N-tert-Butoxycarbonyl-N-methyl-[6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-ylmethyl]amine 0.127 g (0.268 mmol) was dissolved in 5 ml of methanol; 1 ml of concentrated hydrochloric acid was added, followed by stirring for 30 minutes. This solution was concentrated to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[NH:22][CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:10][CH:8]([C:6]1[C:5]([O:18][CH3:19])=[C:4]([CH:20]2[CH2:21][NH:22][C:23](=[O:25])[CH2:24]2)[C:3]([CH3:26])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CNC(=O)C1
Reaction time: 0.5 h

Procedure:
Solutions of the individual diastereoisomers of tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate (75 mg, 0.20 mmol [peak 1 from step 3]; 75 mg, 0.20 mmol [peak 2 from step 3]) in separate reaction flasks in methylene chloride (1 mL) were each treated individually with trifluoroacetic acid (1 mL) dropwise and stirred for 30 minutes. The reaction mixtures were individually concentrated to residues, diluted with saturated sodium bicarbonate, and extracted several times with dichloromethane to give diastereoisomer from peak 1 (60 mg, quantitative) and diastereoisomer from peak 2 (55 mg, quantitative) as colorless residues that were used without further purification. Peak 1: LCMS for C14H17ClNO2 (M−NH2)+: m/z=266.1. Found: 266.1. Peak 2: LCMS for C14H20ClN2O2 (M+H)+: m/z=283.1. Found: 283.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24](C4C=NC=CC=4)[CH:25]=3)[NH:20][CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.FC1C(O)=CC=C(F)C=1C(C1[C:53]2[C:48](=[N:49][CH:50]=[C:51](Cl)[CH:52]=2)NC=1)=O>>[F:33][C:10]1[C:9]([O:8][CH2:1][C:53]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[CH:14][CH:13]=[C:12]([F:15])[C:11]=1[C:16]([C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:17]
Reactant: O=C(c1c(F)ccc(OCc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Reactant: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ncc(Cl)cc12
Product: O=C(c1c(F)ccc(OCc2cccnc2)c1F)c1c[nH]c2ncccc12

Procedure:
Additional compounds were prepared following the protocol of Scheme 28, replacing pyridin-3-yl-methanol 90 with an appropriate alcohol and optionally replacing (2,6-difluoro-3-hydroxy-phenyl)-(1H-pyrrolo[2,3-b]pyridine-3-yl)-methanone 89 with (2,6-difluoro-3-hydroxy-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)-methanone (prepared as described in Example 11, 3 and 4 of Scheme 8, replacing pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 20 with 5-chloro-1H-pyrrolo[2,3-b]pyridine 4 (see Example 4) in Step 3). The following compounds were made following this procedure:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].Cl.[NH2:13][N:14]=[CH:15]N1C=CC=N1>O1CCOCC1>[NH2:13][N:14]=[CH:15][NH:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: NCC(=O)NC1CCCCC1
Reactant: NN=Cn1cccn1
Agent: Cl
Solvent: C1COCCO1
Product: NN=CNCC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A round-bottomed flask is charged with 15 g of 2-amino-N-(cyclohexyl)-acetamide, 14,6 g 1-aminoiminomehtylpyrazole hydrochloride and 100 ml of dioxane. After 18 h stirring at reflux, the reaction medium is cooled to room temperature and precipitate which has formed is filtered off with suction. 16 g of a white solid are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:16][CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].O>CN(C)C=O>[N:27]([CH2:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12](=[NH:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15][CH2:16]1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC1CCN(C(=N)NC(=O)OCc2ccccc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCC1CCN(C(=N)NC(=O)OCc2ccccc2)CC1
Temperature: 100 °C

Procedure:
In 100 ml of dimethylformamide was dissolved 4.4 g (0.0115 mol) of crude 1-benzyloxycarbonylamidino-4-mesyloxyethyl piperidine and 4.5 g (0.069 mol) of sodium azide was added. The mixture was heated at 100° C. for 2.5 h. It was then poured into water and extracted with ethyl acetate three times. The combined organic phase was washed with water, dried (Na2SO4) and evaporated. The residue was flash chromatographed on silica gel using ethyl acetate/heptane 1/1 as eluent. Yield: 3.0 g (79%).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>C1C=CC=CC=1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 60 %

Procedure:
A mixture of 1.5 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, 200 ml of benzene, 1.5 g of anhydrous potassium carbonate and 1.4 g of 4-tert.-butyl-benzyl chloride was subjected to reaction at a reflux temperature for 6 hours. Then, procedure similar to that in Synthesis Example 5 was conducted to obtain white crystals (yield: 60%).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[CH2:30]1[C@H:33]([C:34]([OH:36])=[O:35])[NH:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:32]1[CH2:31][CH2:30][C@@H:33]1[C:34]([OH:36])=[O:35]
Reactant: O=C(O)[C@H]1CCN1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC[C@@H]4C(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and D-Azetidine-2-carboxylic acid (20.03 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 16 mg of (2R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) azetidine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (2H, dd, J=8.57, 2.86 Hz), 7.82 (2H, dd, J=8.02, 1.65 Hz), 7.58-7.70 (5H, m), 5.16-5.29 (1H, m), 4.89-5.10 (1H, m), 3.84-4.05 (2H, m), 3.18-3.41 (2H, m), 2.96-3.03 (2H, m), 2.51-2.61 (1H, m), 1.63-1.76 (2H, m), 0.97 (3H, t, K=7.25 Hz). MS (m+1)=475. HPLC Peak RT=3.5 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([S:32](=[O:38])(=[O:37])[NH:33][CH:34]2[CH2:36][CH2:35]2)=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[O:27])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([S:32]([NH:33][CH:34]2[CH2:36][CH2:35]2)(=[O:38])=[O:37])=[CH:28][C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2cc(S(=O)(=O)NC3CC3)ccc2Cl)nn1-c1ccc(C(F)(F)F)cc1
Yield: 60.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.050 g, 0.18 mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (step-4 of Intermediate-40, 0.108 g, 0.36 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.050 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 0.40-0.42 (m, 2H), 0.50-0.54 (m, 2H), 2.17-2.21 (m, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.92-7.98 (m, 2H), 8.15-8.21 (m, 4H), 12.84 (s, 1H); MS (m/z): 457.15 (M+H+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:17][C@@H:16]2[CH3:33])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.[C:46](Cl)(=[O:48])[CH3:47]>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1)[C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:18]([N:25]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:46](=[O:48])[CH3:47])[CH2:17][C@@H:16]1[CH3:33])=[O:14]
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of (3,5-bis(trifluoromethyl)phenyl)((2S,4R)-4-(4-chlorophenylamino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)methanone (19.44 g, 0.037 mol) in acetyl chloride (5 mL) was cooled to 0° C. and triethylamine (6.59 mL, 0.037 mol) was added dropwise over 30 min, a precipitate forms during this time. An additional 250 mL of methylene chloride was added to completely dissolve all the precipitate. The reaction was allowed to stir overnight at room temperature. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate and 1N sodium hydroxide while cooled to 0° C. The aqueous layer was extracted 3 times with ethyl acetate washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-((2S,4R)-1-(3,5-bis(trifluoromethyl)benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-(4-chlorophenyl)acetamide (H-31) (18.2 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 4-ethynylbenzonitrile (Aldrich, 38 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ8.00 (s, 1H), 8.09 (s, 4H), 8.45 (t, J=2.1 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 9.09 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 282 (M+H)+, 284 (M+H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH:24]2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]3[O:49][CH2:48][CH2:47][N:46]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]=3[CH:55]=2)=[CH:19][CH:18]=1.[CH2:56]([O:58][C:59](=[O:68])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[C:63](O)[CH:62]=1)[CH3:57].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:56]([O:58][C:59]([CH2:60][C:61]1[CH:62]=[C:63]([CH:64]=[CH:65][CH:66]=1)[O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:25][CH:24]2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]3[O:49][CH2:48][CH2:47][N:46]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]=3[CH:55]=2)=[CH:21][CH:22]=1)=[O:68])[CH3:57]
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OCc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3OCc3ccc4c(c3)N(CCCOC)CCO4)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.1122 g of diisopropyl azodicarboxylate is added dropwise to a solution of 0.246 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270c), 0.1061 g of ethyl(3-hydroxyphenyl)acetate, 0.1396 g of triphenylphosphine and 5 ml of tetrahydrofuran. The solution is stirred at room temperature for 1 hour and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.28 (1:1 EtOAc-heptane); Rt=5.91.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(CBr)ccc1Cl
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a stirred solution of 2-chloro-5-methyl-benzoic acid (25 g) in chloroform (500 ml) at 50° C. was added N-bromosuccinimide (27.40 g). The flask was purged with nitrogen and azobisisobutyronitrile (0.10 g) added in one portion. The solution was heated at reflux for 1 h. Further azobisisobutyronitrile (0.10 g) was added and the mixture heated a further 3 h. The solution was concentrated in vacuo, redissolved in diethyl ether and filtered to remove insoluble succinimide. The ether solution was washed with 2N aqueous hydrochloric acid solution followed by brine then dried over magnesium sulphate. The solution was concentrated to a volume of 150 ml then diluted with isohexane. After further partial concentration crystallization started. The mixture was allowed to stand in an ice-bath for 1 h. The resulting crystals were filtered, washed with isohexane and dried in vacuo to give the subtitled compound (17 g).
Reaction SMILES: C([CH:3]([C:5]1[N:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[S:8][C:9]=1[CH3:10])O)C.Cl.[NH2:16][CH2:17][CH2:18][SH:19].Br>>[CH3:14][N:12]([CH2:11][C:7]1[S:8][C:9]([CH3:10])=[C:5]([CH2:3][S:19][CH2:18][CH2:17][NH2:16])[N:6]=1)[CH3:13]
Reactant: NCCS
Reactant: CCC(O)c1nc(CN(C)C)sc1C
Agent: Br
Agent: Cl
Product: Cc1sc(CN(C)C)nc1CSCCN

Procedure:
Following the procedure of Example 3, a reaction mixture consisting of 6.4 g. of ethyl 2-dimethylaminomethyl-5-methyl-4-thiazolemethanol, 4.2 g. of cysteamine hydrochloride and 30 ml. of 48% aqueous hydrobromic acid was maintained at a temperature of about 100° C. under a nitrogen atmosphere for about 4 hours. The reaction mixture was cooled and the volatile constituents removed in vacuo. The resulting dark residue was twice trituated with ethanol and the ethanol removed by evaporation to remove residual HBr. The residue was then treated with 50 ml. of 5 N aqueous sodium hydroxide. The alkaline layer was continuously extracted with ether over an 18 hour period. The ether extract was dried and the ether removed therefrom in vacuo to provide 2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethylamine prepared in the above reaction; yield=1.38 g. The compound was a brown oil having the following physical characteristics:
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][C:31]=1[C:40]#[N:41].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:40]#[N:41])[CH:32]=2)(=[O:37])=[O:38])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc(F)c(C#N)c1
Yield: 92 %

Procedure:
To a solution of (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 in CH2Cl2 (4 mL) was added 4-fluoro-3-cyanobenzenesulfonyl chloride (92 mg, 0.42 mmol) followed by NaHCO3 (40 mg) and satd. NaHCO3 (0.4 mL) and stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water, brine and dried with Na2SO4 and concentrated to furnish crude product (240 mg). The crude product was purified by column chromatography using 1/1 ethyl acetate/hexane to provide 200 mg product (92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: COC(=O)c1ccc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)cc1F

Procedure:
120 mg (0.39 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of methyl 4-amino-2-fluorobenzoate were reacted according to General Method 5A. Yield: 64 mg (36% of theory)