Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(C1C=C(C=CC=1)N[CH:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][CH2:11]1)(=O)=O.[OH-:32].[NH4+].[CH2:34]([OH:36])[CH3:35]>>[O:36]1[C:10]2([CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:23][NH2:24])=[CH:25][CH:26]=3)(=[O:17])=[O:18])[CH2:14][CH2:15]2)[O:32][CH2:35][CH2:34]1
Reactant: [OH-]
Reactant: N#Cc1ccc(S(=O)(=O)N2CCC(Nc3cccc(S(=O)(=O)C(F)(F)F)c3)CC2)cc1
Reactant: CCO
Agent: [NH4+]
Product: NCc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
The catalyst (Aldrich Palladium, 5 wt % (dry basis) on activated carbon as 50 wt % suspension in water (Degussa type E101 NO/W), 3.0 g, 0.70 mmol) was charged to a flask, which was evacuated and purged with nitrogen three times. A solution of nitrile 1a (14.0 g, 45.4 mmol) in ethanol (450 ml) and concentrated aqueous ammonium hydroxide solution (31 wt %, 40 ml, 620 mmol) were added. The flask was evacuated and purged with nitrogen three times then evacuated and filled with hydrogen twice. The reaction was stirred at room temp under hydrogen at balloon pressure and monitored by TLC (5% methanol in DCM) until complete (1-2 days). When complete, the flask was evacuated and purged with nitrogen three times, the catalyst was filtered off through a glass fibre filter paper and washed with hot ethanol (3×100 ml). The reaction was worked up as follows: the filtrate was evaporated to dryness and the residue was purified by column chromatography on silica gel (25 fold weight of silica based on crude product) using a gradient elution with 5-50% methanol in DCM which yielded 90% of [4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)phenyl]methanamine 7b.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:22])([F:21])[C:5]1[N:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)[CH2:12][CH2:13][C:8]2=[N:7][N:6]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>CO>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH2:12][CH2:13][C:8]4[N:9]([C:5]([C:4]([F:22])([F:21])[F:3])=[N:6][N:7]=4)[N:10]=3)[CH2:15][CH:16]=2)=[CH:24]1
Reactant: O=C1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1nnc2n1N=C(N1CC=C(c3c[nH]c4ccccc34)CC1)CC2
Temperature: 65 °C
Reaction time: 20 h
Yield: 39.6 %

Procedure:
Potassium hydroxide (156 mg, 2.79 mmol) was added to 1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (200 mg, 0.70 mmol) and 1H-indole (90 mg, 0.77 mmol) in MeOH (3 mL). The resulting mixture was stirred at 65° C. for 20 hours. The reaction mixture was evaporated to dryness then quenched with saturated aqueous ammonium chloride (0.5 mL), diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated brine (25 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-[4-(1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (107 mg, 40%) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:24]([Li])[CH2:25][CH2:26]C.C(Br)C=C>O1CCCC1>[CH2:1]([C:2]([CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:3])[CH2:26][CH:25]=[CH2:24]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
By reaction of 15.0 g of methylcarbonylmethylenetriphenyl phosphorane in 471 ml of tetrahydrofuran with 31.0 ml of butyllithium and 4.28 ml of allyl bromide analogously to 7, the title compound is obtained as crystallized oil with a melting point of 92°-93° C.
Reaction SMILES: NC[CH:3]1[CH2:11][CH2:10][CH:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4]1([CH3:13])[CH3:12].[CH:14]([N:17](CC)C(C)C)(C)C>C(O)C>[C:14]([CH:11]1[CH2:10][CH:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4]([CH3:12])([CH3:13])[CH2:3]1)#[N:17]
Reactant: CC1(C)C(CN)CCC2CCCN21
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1(C)CC(C#N)CC2CCCN21
Yield: 74.8 %

Procedure:
(±) Equatorial aminomethyl-2,2-dimethylazabicyclo[4.3.0]nonane (0.1 g, 0.0006 mole) was treated with mutilin 14-toluenesulfonyloxyacetate (0.25 g, 0.0005 mole), (K Biedl, J Antibiotics 29 (2), 133, 1976) and N,N-diisopropylethylamine (0.1 ml, 0.0006 mole) in ethanol (20 ml) and heated under reflux for 6 hours. The mixture was then concentrated in vacuo and the residue partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were separated and dried (Na2SO4). Chromatography on silica gel eluting with chloroform/methanol/35% ammonia solution (90:9:1) gave the title compound 0.08 g, (31%); 1H NMR (CDCl3) 0.71 (3H, d, J 6.5 Hz) 0.90 (3H, d, J 6.5 Hz), 0.95 (3H, s), 1.25-2.55 (38H, m), 2.85-2.97 (1H, m), 3.19-3.39 (2H, m), 5.15 (1H, d, J 16.5 Hz), 5.31 (1H, d, J 11.1 Hz), 5.78 (1H, d, J 8.6 Hz), 6.50 (1H, dd, J 15.0 and 11.1 Hz). MS (+ve ion electrospray) m/z 543 (MH+, 100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[C:12](=O)[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:12]2[NH:34][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)CCC(=O)c2ccccn2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)c2ccc(-c3ccccn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 5-[4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydrofuran-3-yl)hexane-1,4-dione (43.5 mg) in acetic acid (0.53 mL) was added ammonium acetate (129 mg), and the mixture was stirred at 110° C. for 2 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (27.4 mg, yield 66%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(OCc2ccccc2)cc1)C1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCCC1

Procedure:
The title compound was prepared by hydrogenation of 3-(4-benzyloxy-phenyl)-1-cyclohexyl-prop-2-en-1-one (25.85 g, 84 mmol; prepared in Example C) as described in General Method 3 using 1.0 g of 5% Pd on BaSO4 in 600 mL of THF at room temperature. The crude product was flash chromatographed using CH2Cl2 :MeOH (99:1 to 98:2) to afford a gummy solid. 1H NMR (CDCl3) δ 1.1-1.9 (m, 10 H), 2.2-2.4 (m, 1 H), 2.68-2.74 (m, 2 H), 2.79-2.85 (m, 2 H), 5.04 (s, 2 H), 6.8-6.9 (d, 2 H), 7.1-7.2 (d, 2 H), 7.3-7.5 (m, 5 H).
Reaction SMILES: [Cl-].[Li+].[Cl-].[Al+3].[Cl-].[Cl-].[C:7]1([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20](Cl)(=[O:22])[CH3:21]>ClC(Cl)C>[CH3:21][C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1)=[O:22]
Reactant: CC(=O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(Oc2ccccc2)cc1
Yield: 90.3 %

Procedure:
To an agitated mixture of lithium chloride (3.18 g., 0.075 mole) and aluminium chloride (20 g., 0.15 mol) in dichloroethane (20 ml) was slowly added diphenyl ether (8.51 g., 0.05 mole) and acetyl chloride (3.93 g., 0.05 mol) in dichloroethane (7 ml) following the procedure of example 9. The 4-phenoxyacetophenone obtained (9.57 g., 90.3% yield, m.p. 43.5°-51° C.) had a IH NMR purity of 90%.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH3:6]CCCCC.[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([C:28](=O)[CH3:29])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:13]([C:14]1[CH:2]=[CH:1][C:17]([CH2:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:6])=[CH2:29])[CH:23]=2)[CH3:20])=[CH:16][CH:15]=1)([CH3:32])([CH3:31])[CH3:12]
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Reactant: CCCCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
Methyl triphenylphosphonium bromide (1.97 g; 5.51 mmol) was suspended in tetrahydrofuran (15 ml). While the suspension was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.68 M: 3.9 ml; 6.60 mmol) was added dropwise. After the reaction mixture turned deep red, the mixture was cooled in an ice bath, and Compound 1 (1.42 g; 4.59 mmol) in tetrohydrofuran (15 ml) was added dropwise thereto. After completion of the addition, the mixture was removed from the ice bath, and stirred for 30 minutes at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.81 g of the target compound as yellow oily matter (yield: 57.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].C([Sn](CCCC)(CCCC)[CH:25]=[CH:26][O:27][CH2:28][CH3:29])CCC>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:26]([O:27][CH2:28][CH3:29])=[CH2:25])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (17.8 g, 46.1 mmol), tetrakis-(triphenylphosphine)-palladium (2.67 g, 2.30 mmol), and tributyl-(ethoxyvinyl)-tin (25.0 g, 69.2 mmol) in dioxane (100 mL) was heated to 110° C. for 20 h under nitrogen. The mixture was allowed to cool to r.t., and then filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (silica gel 60, hexanes/EtOAc 3:1) to give crude 2-acetylamino-5-(1-ethoxy-vinyl)-4-trifluoromethyl-benzoic acid methyl ester as an orange solid, m.p. 65-73° C., ESI-MS: m/z 332 [M+H]+. This crude product was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([Br:11])=[CH:4][CH:3]=1.[NH2:12][C:13](N)=[O:14]>>[Br:11][C:5]1[C:6]([F:10])=[C:7]2[C:2](=[CH:3][CH:4]=1)[N:1]=[C:13]([OH:14])[N:12]=[CH:8]2
Reactant: NC(N)=O
Reactant: Nc1ccc(Br)c(F)c1C=O
Product: Oc1ncc2c(F)c(Br)ccc2n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of 6-amino-3-bromo-2-fluorobenzaldehyde (3.0 g, 13.76 mmol) and urea (12.40 g, 206.40 mmol) was heated to 180° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature. The resulting precipitate was collected, washed with water (3×100 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. The title compound (3.3 g, 99%) was obtained as a yellow solid. MS (ES+) C8H4BrFN2O requires: 242, found: 243, 245 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:19]=[N:20]2)=[CH:15][CH:14]=1>CN(C=O)C>[CH3:1][N:2]([CH2:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:19]=[N:20]2)=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cnc2cc(CBr)ccc2c1
Reactant: CNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2cc(CN(C)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.2 %

Procedure:
In a nitrogen atmosphere, N-methylaniline (383 mg, 3.57 mmol.) was dissolved in DMF (5 mL). Under chilling with ice, 60% sodium hydride (157 mg, 3.93 mmol.) was added to the resulting solution and the mixture was stirred at room temperature for 5 minutes. Under chilling with ice, to this was added dropwise methyl 7-bromomethylquinoline-3-carboxylate (1.0 g, 3.57 mmol.) in dry DMF (10 mL). The resulting mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform after addition of water (20 mL). The organic portion was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1), to give the desired compound as yellow crystalline powder (615 mg, yield: 56%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Br:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Temperature: 50 °C
Reaction time: 20 h
Yield: 84.1 %

Procedure:
A mixture of (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (2.04 g, 7.78 mmol), 3-(4-trifluoromethylphenyl)-2-propenyl piperazine-1-carboxylate (2.69 g, 8.56 mmol) and N,N′-dimethylformamide (10 ml) was stirred at 50° C. for 20 hours. The reaction solution was allowed to return to room temperature, water was added, and the resultant solution was extracted with ethyl acetate (15 ml) twice. The organic phases were combined, washed with water three times, and dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to obtain 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-bromo-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (3.77 g, 84%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[O:26]=[C:27]1[NH:31][C:30](=[O:32])[CH:29]([CH2:33][C:34]2[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](O)=[O:41])=[CH:36][CH:35]=2)[S:28]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:26]=[C:27]1[NH:31][C:30](=[O:32])[CH:29]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:38][CH2:39][C:40]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:41])=[CH:43][CH:44]=2)[S:28]1
Reactant: COc1ccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 93.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-methoxyphenoxy)phenyl]-N-methylcarbamate (2.0 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.0 g), diethyl cyanophosphonate (1.3 g), triethylamine (0.81 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (3.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][C@@H:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:31][C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Yield: 87.3 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (20.6 g, 85.1 mmol) in DMF (100 mL) with triethylamine (35 mL, 0.225 mol) and (R)-(+)-α-methylbenzylamine (13.3 mL, 102 mmol). After the precipitate was isolated by filtration, it was washed with water and diethyl ether to provide 24.35 g of 2-chloro-3-nitro-N-[(1R)-1-phenylethyl]quinolin-4-amine as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2=[N:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:15]2[N:14]=1.O>CN(C)C=O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]2[N:15]3[N:14]=[C:13]([NH:1][C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)[C:22]4[C:17]([C:16]3=[N:23][N:24]=2)=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:27][CH:28]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4ccc(C#N)cc4)nn23)cc1
Yield: 84.7 %

Procedure:
295 mg of 4-amino-benzonitrile and 6 mg of sodium hydride (60%) in 2.5 ml of N,N-dimethylformamide are treated with 100 mg of 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1) at ambient temperature. After 10 min the reaction mixture is added to water, the precipitate is filtered with suction and the solid is recrystallized from N,N-dimethylformamide to yield 107 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[NH2:38][CH2:39]C1C=CC(B(O)O)=CC=1>>[NH2:38][CH2:39][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:33])[F:35])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(CN)cc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (4-(aminomethyl)phenyl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=526, obsd.=526).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[C:30]([F:39])[C:29]=1[F:40].O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)=[C:30]([F:39])[C:29]=2[F:40])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: Fc1c(CBr)ccc(-c2ncco2)c1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Yield: 39.6 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (200 mg, 0.66 mmol), cesium carbonate (257 mg, 0.79 mmol), and 2-(4-(bromomethyl)-2,3-difluorophenyl)oxazole (217 mg, 0.79 mmol)) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (130 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1H), 7.83 (d, J=8.50 Hz, 2H), 7.80 (d, J=7.50 Hz, 1H), 7.64 (d, J=8.00 Hz, 2H), 7.45 (t, J=7.05 Hz, 1H), 4.52 (s, 2H), 3.41-3.52 (m, 1H), 3.29-3.40 (m, 1H), 3.25 (dd, J=10.45, 2.64 Hz, 1H), 2.80 (t, J=9.32 Hz, 1H), 1.95 (br. s., 1H), 1.52-1.60 (m, 2H), 1.38 (br. s., 3H), 1.18 (br. s., 1H), 0.86-1.04 (m, 2H). Analytical HPLC R.T.=23.46 min. MS [M+H]+=497; [M+Na]+=519. HRMS [M+H]+ calc'd 497.1113, found 497.1093.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][S:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])(=[O:20])=[O:19])[CH:11]=1.Br[CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:34][CH2:33][CH2:32][N:17]([S:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:12]=2[CH:11]=1)=[O:30]
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCCO2
Temperature: 60 °C
Yield: 89.9 %

Procedure:
Potassium carbonate (818 mg, 5.92 mmol) was added to a solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1; 1.00 g, 2.69 mmol) and 1,3-dibromopropane (597 mg, 2.96 mmol) in N,N-dimethylformamide (17 mL), and the suspension was heated at 60° C. for 5 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carboxylic acid methyl ester (996 mg, 90%). White solid, MS (ISP)=412.1 (M+H)+.