Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:26]([F:27])=[CH:25][C:6]2[O:7][C:8]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:9]=3[C@H:10]3[C@H:15]([NH:16][C:17](=[O:19])[CH3:18])[CH2:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1)#[N:2].C1C(=O)N([Cl:35])C(=O)C1>>[Cl:35][C:4]1[C:5]2[N:11]3[CH2:12][CH2:13][CH2:14][C@@H:15]([NH:16][C:17](=[O:19])[CH3:18])[C@@H:10]3[C:9]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:8]=3[O:7][C:6]=2[CH:25]=[C:26]([F:27])[C:3]=1[C:1]#[N:2]
Reactant: CC(=O)N[C@@H]1CCCN2c3cc(C#N)c(F)cc3Oc3cccc(F)c3[C@@H]12
Reactant: O=C1CCC(=O)N1Cl
Product: CC(=O)N[C@@H]1CCCN2c3c(cc(F)c(C#N)c3Cl)Oc3cccc(F)c3[C@@H]12
Yield: 62.7 %

Procedure:
Preparation analogous to Example 3 from (−)-(cis)-N-(7-cyano-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamide (0.277 g, 0.75 mmol) and NCS (0.10 g, 0.75 mmol). The crude compound was purified by HPLC to give the title compound (0.19 g, 62%). 1H-NMR (600 MHz, DMSO) 1.46-1.57 (m, 4H), 1.64 (m, 1H), 1.72 (m, 1H), 1.92 (m, 1H), 3.27 (m, 1H), 3.53 ( m, 1H), 4.31 (d, J=11.6, 1H), 4.38 (m, 1H), 7.05 (m, 1H), 7.11 (d, J=8.7, 1H), 7.33 (m, 1H), 7.64 (d, J=9.8, 1H), 7.81 (br-d, J=9.8, 1H). e.e.=100%, Rf=17.8 min. (chiralpak OD-H 25*0.46 cm, heptane:ethanol=9:1). (MIM)=403. [α]D20=−207° (c=1.0025, THF).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH2:22][NH2:23]>CCO>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:22][NH2:23])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccc(F)cc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(C(=O)c2ccc(F)cc2)CC1
Yield: 64 %

Procedure:
Synthesized according to General Procedure C: 51g (3.73 g, 12.7 mmol, 1.0 equiv.), anhydrous hydrazine (1.6 mL, 50.8 mmol, 4.0 equiv.), EtOH (25 mL, 0.5 M). 46g (2.28 g, 64.1%) was obtained as a white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 1H-NMR (500 MHz, CDCl3) δ 8.09 (br s, 1H), 7.37-7.33 (m, 2H), 7.06-7.02 (m, 2H), 3.85 (br s, 2H), 3.70 (br s, 2H), 3.42 (br s, 2H), 3.06 (s, 2H), 2.48 (br s, 4H). 13C-NMR (125 MHz, CDCl3) δ 169.8, 169.5, 163.5 (d, JC-F=249.1 Hz), 131.5 (d, JC-F=2.8 Hz), 129.4 (d, JC-F=9.1 Hz), 115.7 (d, JC-F=22.0 Hz), 60.6, 53.5 (br), 47.7 (br), 42.3 (br). 19F-NMR (470 MHz, CDCl3) δ −113.1. HRMS (ESI): 281.1409 (M+1); calcd. for C13H1sFN4O2: 281.1414.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O.[NH2:15][NH2:16]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:15][NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(N2CCCC2)c(Cl)nn1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCCC2)c(Cl)nn1

Procedure:
3,6-Dichloro-4-(pyrrolidin-1-yl)pyridazine (7.2 g, 33 mmol) and hydrazine hydrate (9.96 g, 0.2 mol) were heated at reflux in dioxan (130 ml) for 6 hours. Upon cooling the desired isomer crystallized from the reaction and was collected by filtration (4.1 g, 58%). 1H NMR (250 MHz , d6-DMSO) 1.79-1.84 (4H, m), 3.25-3.40 (4H, m), 4.12 (2H, br), 6.09 (1H, s), 7.47 (1H, s). MS (ES+) 214 [MH]+, 216 [MH]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([NH2:19])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[CH:7][CH:6]=1)[CH3:2].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.S(Cl)(Cl)(=O)=O>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:19][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CCC(CC)C(N)c1ccnn1Cc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: O=S(=O)(Cl)Cl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Br)cc1)c1ccnn1Cc1ccc(OC)cc1
Yield: 67 %

Procedure:
The compound of example 3 was synthesized from {2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl} amine in a manner similar to that of example 1 but using 4-bromobenzenesulfonyl chloride as the sulfonyl chloride in step 1D. The product was isolated as a white foam in 67% yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=4)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=4)=[N:18][C:17]=3[N:16]=2)=[CH:13][CH:14]=1
Reactant: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 80 °C
Yield: 181.3 %

Procedure:
To a solution of 8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.217 g, 0.24 mmol) in DMF:water (2.5 ml), 10% Pd/C (0.120 g) and ammonium formate (0.431 g, 6.8 mmol) were added and refluxed at 80° C. for 2 hours. The mixture was cooled and filtered through celite bed, solvent was evaporated and the residue was diluted with water (10 ml), acidified with citric acid and extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (2×15 ml). It was dried over Na2SO4 and the solvent was evaporated to obtain off white solid of 8-(4-Hydroxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.237 g, quantitative).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O)[CH3:8].CN(C)C=O.[NH2:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[CH:28]=[N:27][C:26]=1[C:33]([NH2:35])=[O:34]>ClCCl.N1C=CC=CC=1>[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[CH:28]=[N:27][C:26]=1[C:33]([NH2:35])=[O:34])=[O:14])[CH3:8]
Reactant: CCCn1cnc(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCn1cnc(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
Oxalyl chloride (1.74 g, 0.137 mol) was added dropwise to a stirred solution of 2-ethoxybenzoic acid (1.1 g, 0.00663 mol) and dimethylformamide (0.1 ml) in dichloromethane (20 ml) and the resulting mixture stirred at ambient temperature for 4 hours, then evaporated under vacuum. The residue was azeotroped with dichloromethane (2×20 ml), then added dropwise to a stirred solution of 5-amino-1-n-propylimidazole-4-carboxamide (0.9 g, 0.00536 mol) in pyridine (20 ml) The resulting solution was stirred at ambient temperature for 3 days, then evaporated under vacuum. The residue was dissolved in dichloromethane (50 ml), and the solution washed with 1N hydrochloric acid (30 ml), dried (Na2SO4) and evaporated under vacuum. Chromatography of the crude product on silica gel (15 g) using a methanol in dichloromethane elution gradient (2-6% methanol), followed by crystallisation from ethanol, gave the title compound as a colourless solid (1.3 g, 77%), m.p. 182°-184° C. Found: C,60.85; H,6.40; N,18.06. C16H20N4O3 requires C,60.74; H,6.37; N,17.71%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:28]#[N:29])[CH2:25][CH2:24][C:23]3[N:22]=[C:21]([CH3:26])[NH:20][C:19](=[O:27])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:28]([C:16]1([C:6]2[C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25][CH2:24][C:23]2[N:22]=[C:21]([CH3:26])[N:20]=[C:19]([O:27][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:36])[C:18]=2[CH2:17]1)#[N:29]
Reactant: COc1ccc(C2(C#N)CCc3nc(C)[nH]c(=O)c3C2)c2c1oc1ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1nc(C)nc2c1CC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in example 21 (150 mg, 1.76 mmles) in dry DMF (5 ml) was added ethylbromoacetate (322.3 mg, 1.93 mmol) and cesium carbonate (688 mg, 2.11 mmol). The reaction mass was stirred at room temperature for 1 hr, diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine and dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to get both pure compounds.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([CH3:25])[CH2:4][CH2:3]1.[OH-].[K+]>C(O)C.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([CH3:25])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)N(C)CCN3C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C)CCN2C
Yield: 78.3 %

Procedure:
600 mg of this ester were converted into the free acid by reaction with a solution of 1.5 g of potassium hydroxide in 25 ml of ethanol and 10 ml of water at 50° C. during 4 hours. After recrystallization from ethyl acetate/hexane, there were obtained 450 mg of p-[(E)-2-(1,2,3,4-tetrahydro-1,4-dimethyl-6-quinoxalinyl)propenyl]-benzoic acid in the form of orange crystals, melting point 203°-205° C.
Reaction SMILES: [K].[O:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:4][C:3]1=[S:12].[CH2:13](I)[CH3:14]>C(O)C>[CH2:13]([S:12][C:3]1[O:2][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][N:4]=1)[CH3:14]
Reactant: CCI
Reactant: CCOC(=O)c1n[nH]c(=S)o1
Agent: [K]
Solvent: CCO
Product: CCOC(=O)c1nnc(SCC)o1

Procedure:
A mixture of ethyl 1,3,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate (11 g., 0.03 mole) and ethyl iodide (7 g., 0.045 mole) in absolute ethanol (100 ml.) was heated at reflux for 45 minutes and then worked up as described previously in Experiment A to yield the title compound (5.59 g.).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:50])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:51]([CH:54]([CH2:58][CH2:59][CH2:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1)[C:55](O)=[O:56])(=[O:53])[CH3:52]>>[C:51]([CH:54]([CH2:58][CH2:59][CH2:60][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]1)[C:55]([NH:30][CH:31]([C:33]1[C:34](=[O:50])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:56])(=[O:53])[CH3:52]
Reactant: CC(=O)C(CCCC1CCCCC1)C(=O)O
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCC3CCCCC3)C(C)=O)c(=O)[nH]2)cc1OC

Procedure:
The amount of 2-acetyl-5-cyclohexylpentanoic acid in dichloromethane from Example 36A is reacted analogously to Example 39A with 280 mg (2.08 mmol) of 1-hydroxy-1H-benzotriazole, 610 mg (6.00 mmol) of 4-methylmorpholine, 400 mg (2.08 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 600 mg (2.08 mmol) of 6-(1-aminoethyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one to give 2-acetyl-5-cyclohexyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl }pentanamide.
Reaction SMILES: [CH2:1]([CH:3]1[C@H:8]2[C@H:9]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5](=[O:24])[CH2:4]1)[C@:17]1([CH2:18][OH:19])[C:12](=[CH:13][C:14](=O)[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[CH2:25]([Li])CCC.O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:3]1[C@H:8]2[C@H:9]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5](=[O:24])[CH2:4]1)[C@:17]1([CH2:18][OH:19])[C:12](=[CH:13][C:14](=[CH2:25])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: [Li]CCCC
Reactant: CCC1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@H]12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC(CC)[C@@H]34)[C@@]2(CO)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.7 g of 15-alpha-ethyl-19-hydroxy-4-androstene-3,17-dione in 25 ml of tetrahydrofuran is instilled in a suspension of 28.6 of methyl triphenylphosphonium bromide in 200 ml of tetrahydrofuran, which was stirred with 200 ml of butyllithium solution (1.6 m in ether) for 1.5 hours at 20° C., and stirred for one hour at 20° C. Then it is mixed with water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and is freed from the solvent in a vacuum. After chromatographic purification on silica gel with hexane/ethyl acetate, 1.95 g of pure 15-alpha-ethyl-3-methylene-19-hydroxy-4-androsten-17-one is obtained as foam.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:42]=[CH:41][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH:25](C(OCC)=O)[C:26]([O:28]CC)=[O:27])[C:21]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:42]=[CH:41][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:21]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 110 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of diethyl [1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (4.09 g), 1N aqueous sodium hydroxide solution (30 ml), tetrahydrofuran (30 ml), and ethanol (30 ml) was refluxed for 1 hour. After cooling, 1N hydrochloric acid (30 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless oily substance was dissolved in pyridine (50 ml), and the mixture was stirred at 110° C. for 2 hours. After removing pyridine under reduced pressure, ethyl acetate was added to the residue. The resulting solution was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propionic acid (3.25 g, yield: 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 133˜134° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:20](=[O:30])[C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:31][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:20]1=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccccn2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccccn2)C1=O
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(pyridin-2-ylmethyl)azepan-3-ylcarbamate (202 mg, 0.468 mmol) in dichloromethane (4 mL). After 18 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 332.2 (M+1).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@H:11]([CH2:15][OH:16])[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:12](=[O:14])[C@H:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH2:15][OH:16])[CH2:29][CH2:30]1
Reactant: O=C(O)[C@@H](CO)NS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H](CO)NS(=O)(=O)c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, (R)-2-benzenesulfonylamino-3-hydroxy-propionic acid was coupled with 1-(2,5-dimethylphenyl)-piperazine to give N-{(R)-2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-1-hydroxymethyl-2-oxo-ethyl}-benzenesulfonamide.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1([CH3:28])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:24]([F:27])([F:26])[F:25])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]=2F)[CH2:6]1.O>CN(C)C=O>[CH3:4][C:5]1([CH3:28])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:24]([F:27])([F:26])[F:25])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]=2[N:2]([CH3:3])[CH3:1])[CH2:6]1
Reactant: CNC
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2F)=NO1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1c(CSC2=NOC(C)(C)C2)c(C(F)(F)F)nn1-c1ccccc1
Temperature: 100 °C
Reaction time: 9 h
Yield: 80.6 %

Procedure:
0.8 g (6.7 mmoles) of a 40% aqueous dimethylamine solution was added to a solution of 0.5 g (1.3 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 100° C. for 9 hours in a sealed tube. Thereto was added 3.0 g (26.6 mmoles) of a 40% aqueous dimethylamine solution, and the resulting mixture was stirred for 9 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (yield: 80.6%) of 5,5-dimethyl-3-(5-dimethylamino-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: [CH3:1][C@@:2]12[C:8](=[CH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[C-:17]#[N:18].[K+]>CS(C)=O.C(OCC)(=O)C>[C:17]([C@:8]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C@H:6]2[C@:2]1([CH3:1])[CH:3]=[CH:4][CH2:5]2)#[N:18]
Reactant: CC(C)(C)OC(=O)C=C1C[C@@H]2CC=C[C@]12C
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@@]1(C#N)C[C@@H]2CC=C[C@@]21C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
Tert-butyl(±)-[(1S,5R)-5-methyl-bicyclo[3.2.0]hept-3-en-6-ylidene]acetate (300 mg, 1.36 mmol) and potassium cyanide (89 mg, 1.36 mmol) were mixed at room temperature in anhydrous dimethyl sulfoxide (2 mL), and the mixture was stirred for 2 hours and then left overnight. The mixture was further stirred for 10 hours in an oil bath at 100° C. and then left overnight. The reaction solution was diluted with ethyl acetate, then washed with water and saturated saline, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil (128 mg). In this procedure, a by-product tert-butyl(±)-[(1S,5R,6R)-6-cyano-5-methyl-bicyclo[3.2.0]hept-3-en-6-yl]acetate was obtained as a colorless oil (45 mg).
Reaction SMILES: [O:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:3]=[C:2]1[C:13]([O:15]CC)=[O:14].Cl>[OH-].[Na+]>[O:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:3]=[C:2]1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cc2[nH]c3ccccc3c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2[nH]c3ccccc3c2o1
Temperature: 60 °C
Yield: 96.9 %

Procedure:
To ethyl furo[3,2-b]indole-2-carboxylate (10 g), 10% aqueous sodium hydroxide solution (100 ml) was added, then the mixture was stirred for an hour at 60° C. The resulting solution was acidified with hydrochloric acid, and the precipitate formed was collected by filtration to give furo[3,2-b]indole-2-carboxylic acid (8.5 g). To furo[3,2-b]-indole-2-carboxylic acid (8.5 g), thionyl chloride (40 ml) and benzene (50 ml) were added, the resulting solution was refluxed for 5 hours, and the excess amounts of thionyl chloride and the benzene were evaporated to give furo[3,2-b]indole-2-carbonyl chloride (7.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:7]=1.[NH3:17].C(OO)(C)(C)C>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:17])=[N:13]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCC(=S)N1
Reactant: N
Agent: CC(C)(C)OO
Solvent: O
Solvent: CO
Product: C[C@@]1(c2cc(Br)ccc2F)COCC(N)=N1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A pressure tube was charged with a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholine-3-thione (1.93 g, 6.3 mmol) in methanol (195 ml). A solution of ammonia in methanol (7M, 54 ml, 381 mmol) and an aqueous solution of tert-butyl hydroperoxide (70%, 8.17 g, 63.4 mmol) were added. The tube was sealed and the reaction mixture was stirred overnight at room temperature for 21 hours. For the workup, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulphate and evaporated. The crude product was purified by chromatography on an Isolute flash NH2 column using dichloromethane as the eluent. The (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as an off-white gum (1.42 g, 62% of theory). MS (ISP): m/z=287.1 [M+H]+, 289.0 [M+2+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:36]([NH:39][CH2:40][CH2:41][CH3:42])[CH2:37][CH3:38]>O1CCCC1>[CH2:36]([N:39]([CH2:40][CH2:41][CH3:42])[C:19](=[O:21])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:1])[F:22])=[CH:8][CH:7]=1)[CH2:37][CH3:38]
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.21 g, 0.010 mole), and 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), in anhydrous tetrahydrofuran (75 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of dipropylamine (1.31 g, 0.013 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (50 ml) and filtered. The filter cake was washed with water and recrystallized twice from isopropyl ether-petroleum ether, giving 1.26 g (31%) of a white solid, mp 138°-139° C.