Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11](C)[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.F[C:35]1C=CC([N+]([O-])=O)=C(C)C=1>>[NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:19][CH2:20]2)=[CH:11][C:10]=1[CH3:35])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Product: Cc1cc(N2CCN(C(=O)NCCCCC3CCSS3)CC2)ccc1N=C(N)c1cccs1
Yield: 16 %

Procedure:
The experimental protocol used is the same as that described for the compound of Example 6, 5-fluoro-2-nitrotoluene replacing 2-fluoro-5-nitrotoluene. A white solid product is obtained (yield 16%). Melting point: 169.4-170.9° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[CH3:31])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[K].[CH2:33]([O:35][C:36]([CH2:38]C([O-])=O)=[O:37])[CH3:34].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>CN(C)C1C=CN=CC=1.C([Pd]Cl)C=C>[CH2:33]([O:35][C:36](=[O:37])[CH2:38][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[CH3:31])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH3:34]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COC(=O)CCC(c1ccc(C(=O)OC)cc1C)c1c(-c2ccccn2)nn(C)c1Cl
Agent: C=CC[Pd]Cl
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCOC(=O)Cc1c(C(CCC(=O)OC)c2ccc(C(=O)OC)cc2C)c(-c2ccccn2)nn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A flask was charged with methyl 4-(1-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-methoxy-4-oxobutyl)-3-methylbenzoate (2.20 g, 4.98 mmol), potassium; ethoxycarbonyl-acetate (1.70 g, 9.96 mmol), N,N-dimethylpyridin-4-amine (0.608 g, 4.98 mmol), dicyclohexyl-(2′,6′-diisopropoxy-biphenyl-2-yl)-phosphane (0.836 g, 1.79 mmol) and allylpalladium(II) chloride (0.219 g, 0.597 mmol). The flask was evacuated and backfilled with Argon. Mesitylene (13.2 mL) was added then the mixture was stirred at rt for about 10 min under Argon. The mixture was heated at about 120° C. for about 16 h, allowed to cool to rt then filtered. The filter cake was rinsed with EtOAc (20 mL). The filtrate was concentrated in vacuo. The residue was semi-purified by column chromatography (SiO2, 10-30% EtOAc/heptane) to give crude methyl 4-(1-(5-(2-ethoxy-2-oxoethyl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-methoxy-4-oxobutyl)-3-methylbenzoate (1.23 g, 50%). The material was used as such in the next step: LC-MS (Table 1, Method g) Rt=2.44 min, m/z 494 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32]>C(#N)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: COc1cccc(CN)c1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3-methoxybenzylamine and acetonitrile essentially as described above in example 48. Purity by LC/MS (APCI)=93%, [M+H]+=395.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([F:22])=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([O:19]C)=O)[O:14][C:13]3=[O:21])=[CH:11][C:6]=2[O:5][C:4]1=[O:23])[CH3:2].[NH3:24]>CO>[CH2:1]([N:3]1[C:7]2[C:8]([F:22])=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:24])=[O:19])[O:14][C:13]3=[O:21])=[CH:11][C:6]=2[O:5][C:4]1=[O:23])[CH3:2]
Reactant: CCn1c(=O)oc2cc(N3C[C@H](C(=O)OC)OC3=O)cc(F)c21
Reactant: N
Solvent: CO
Product: CCn1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21

Procedure:
Prepared from methyl(5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 4, 0.250 g, 0.771 mmol) and ammonia in methanol (5 ml) according to the method of EXAMPLE 86, Step 10 (0.15 g, 63%); MS for C13H12FN3O5 m/z 310 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.87 (br s, 1H), 7.63 (br s, 1H), 7.52 (d, 1H), 7.44 (dd, 1H), 5.03 (dd, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 3.86 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].CC1C=CC(S(O)(=O)=O)=CC=1.[I-:35].[K+].N([O-])=O.[Na+]>C(#N)C>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:35])=[C:3]([O:22][CH3:23])[CH:4]=2)[N:9]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1N
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 1-(4-amino-3-methoxyphenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one (0.280 g, 0.83 mmol) in acetonitrile (5.0 ml) was added PTSA (0.477 g, 2.51 mmol). The reaction mass was stirred at RT for 1 h followed by addition of potassium iodide (0.347 g, 2.0 mmol) and sodium nitrite (0.115 g, 1.67 mmol) at 0-5° C. and further stirred for 2 h. Excess solvent was removed under vacuum and the residue reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was washed with sodium metabisulphate and concentrated to obtain a crude product, which was further purified by column chromatography on silica gel eluting with 10% EtOAc: pet. ether to afford 0.200 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.85 (s, 3H), 7.40 (d, J=8.7 Hz, 1H), 7.46-7.74 (m, 4H), 7.83 (d, J=8.1 Hz, 1H), 12.71 (br s, 1H); MS (m/z): 445.84 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:10][N:9]2[C@H:4]([CH2:5][C:6](=O)[CH2:7][C:8]2([CH3:12])[CH3:11])[CH2:3]1.[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[F:1][C:2]1([F:14])[CH2:10][N:9]2[C@H:4]([CH2:5][C:6](=[N:23][C@H:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:22])[CH2:7][C:8]2([CH3:12])[CH3:11])[CH2:3]1
Reactant: CC1(C)CC(=O)C[C@@H]2CC(F)(F)CN21
Reactant: C[C@H](N)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](N=C1C[C@@H]2CC(F)(F)CN2C(C)(C)C1)c1ccccc1
Reaction time: 22 h

Procedure:
A toluene (12 ml) solution of (R)-2,2-difluoro-hexahydro-5,5-dimethylindolizin-7(1H)-one (487.8 mg, 2.4 mmol) and (S)-1-phenylethylamine (306 μL, 2.4 mmol) was heated under reflux in a flask equipped with a Dean-Stark distillation receiver. After 22 hours, most solvent was distilled off through Dean-Stark distillation receiver, and remaining solvent was removed in vacuo. Compound (1S)—N—((R)-2,2-difluoro-hexahydro-5,5-dimethylindolizin-7(1H)-ylidene)-1-phenylethanamine was obtained as a brown oil and was used directly in next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24](O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 18 h
Yield: 75.1 %

Procedure:
To 40 ml of tetrahydrofuran were dissolved 1.8 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate, 1.74 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.92 g of triphenylphosphine. At room temperature, 1.94 g of diethyl azodicarboxylate was added to the above solution, and the resulting mixture was stirred for 18 hours. After distilling off the solvent, the residue thus obtained was dissolved in ethyl acetate, and the solution was washed with water, and then dried. Thereafter, the solvent was distilled-off, and the resulting residue was purified by silica gel column chromatography using a toluene/chloroform mixture as an eluant, thereby obtaining 2.53 g of the title compound as a viscous yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:38])[NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][NH2:29])([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14]([NH:29][CH2:28][C@@H:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25][CH2:24][NH:23][C:22]([O:21][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:38])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)CCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.10 g (0.45 mmol) of N-[(benzyloxy)carbonyl]beta-alanine and 0.185 g (0.58 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.112 g (0.58 mmol) of EDC and 0.018 g (0.134 mmol) of HOBt are added. The mixture is warmed slowly to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)([CH3:5])=[CH2:4].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1.[Cl-].[NH4+]>C1COCC1.C(O)(C)C>[C:3]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:8][CH2:7]1)([CH3:5])=[CH2:4]
Reactant: Clc1ncnc2ccccc12
Reactant: C=C(C)[C@H]1CC[C@@H](O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=C(C)[C@H]1CC[C@@H](Oc2ncnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.42 g (17.5 mmol) of NaH (80% pure) was added in portions to a solution of 1.8 g (12.8 mmol) of cis-4isopropenylcyclohexanol in 20 ml of absolute THF. The mixture was then heated at reflux for 3 hours, and a solution of 1.9 g (11.6 mmol) of 4-chloroquinazoline in 10 ml of THF was added dropwise. The reaction mixture was subsequently heated at reflux for 5 hours. After cooling to room temperature, 10 ml of isopropanol were added, the mixture was subsequently stirred for 15 minutes, and the reaction solution was poured into saturated ammonium chloride solution. Extraction was carried out with ether, the combined organic phases were dried over MgSO4 and the solvent was concentrated by evaporation in vacuo. The residue (2.7 g) was purified by flash chromatography over silica gel with petroleum ether/ethyl acetate 3:1. After concentration, 1.8 g (57.6% of theory) were obtained of a colorless oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:26][C:27]([F:44])([F:43])[C@@H:28]([O:30][C:31](=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1)[CH3:29]>>[F:26][C:27]([F:44])([F:43])[C@@H:28]([O:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([C@@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:32])[CH3:29]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@H](OC(=O)N1CCC([C@H]2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 1. LC (method 1): tR=0.86 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]2[NH:6][C:7](=[O:24])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[C:21]([CH2:22]O)=[N:20][CH:19]=[N:18]4)[CH:12]=3)=[N:10][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl-].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:5]2[NH:6][C:7](=[O:24])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[C:21]([CH2:22][NH:39][CH:36]5[CH2:38][CH2:37]5)=[N:20][CH:19]=[N:18]4)[CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC1CC1
Reactant: O=C1CC(c2cccc(-n3ncnc3CO)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1CC(c2cccc(-n3ncnc3CNC3CC3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 7-chloro-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 63) (218 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF as described in Example 47. Obtained as an off-white solid (135 mg, 57%).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)[CH3:2].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCC1.Cl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNC1
Solvent: c1ccncc1
Product: CCc1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Yield: 96.5 %

Procedure:
A solution of 4-ethylbenzaldehyde (26.0 g, 0.2 mol), malonic acid (41.6 g, 0.4 mol), pyrrolidine (3 ml), and pyridine (80 ml) was heated in an 85° C. oil bath for 16 hr. The reaction mixture was poured over crushed ice (800 ml), and then made acidic with 12N HCl (100 ml). The white precipitate was filtered, suspended in 1N HCl, and filtered again. The white precipitate was washed with water and air dried to give 4-ethyl cinnamic acid (34.0 g, 96.6%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[C:11]([N+:23]([O-])=O)[CH:10]=2)=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.C(OCC)(=O)C.[Fe]>[NH2:23][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:8]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:26]
Reactant: O=C(Nc1ncc(Br)s1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)Nc2ncc(Br)s2)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A suspension of the product of Example 202B (414 mg, 0.9153 mmol) and iron powder (204.5 mg, 3.66 mmol) in acetic acid (7 mL) and ethanol (7 mL) was heated at reflux under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature, and the mixture was diluted with water (50 mL) and ethyl acetate (100 mL). The aqueous pH was adjusted to 5 with solid sodium carbonate, the layers were separated, and the organic phase washed with water (2×50 mL) and brine (50 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a yellow solid (315 mg, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([NH:29][CH:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1C(F)(F)F
Yield: 49 %

Procedure:
A solution of 6-chloro-4-trifluoromethyl-nicotinic acid methyl ester (2.00 g, 8.35 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.01 g, 10.02 mmol, 1.2 equiv; commercially available) in anhydrous DMF (10 mL) was heated by microwave irradiation to 110° C. for 4 h. A solution of 1 M NaOH (100 mL) was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (5:1→3:1) to yield 1.65 g (49%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.36-1.41 (m, 2H), 1.40 (s, 9H), 1.95-1.97 (m, 2H), 2.85-2.93 (m, 2H), 3.81 (s, 3H), 3.92-3.98 (m, 1H), 3.98-4.05 (m, 2H), 5.12 (d, J=8.1 Hz, 1H), 6.59 (s, 1H), 8.68 (s, 1H). 19F NMR (282 MHz, CDCl3): δ−62.38. MS (ISP): 404.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:22]([NH:32][C:33](=[O:49])[CH2:34][N:35]3[C:39]4[C:40]([F:45])([F:44])[C@@H:41]5[CH2:43][C@@H:42]5[C:38]=4[C:37]([CH:46]([F:48])[F:47])=[N:36]3)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)=[N:13][C:14]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[N:5][N:6]2[CH3:50].[F:56]C1(F)C2N(CC(O)=O)N=C(C(F)(F)F)C=2[C@H]2C[C@@H]12>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:22]([NH:32][C:33](=[O:49])[CH2:34][N:35]3[C:39]4[C:40]([F:44])([F:45])[C@@H:41]5[CH2:43][C@@H:42]5[C:38]=4[C:37]([C:46]([F:56])([F:47])[F:48])=[N:36]3)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)=[N:13][C:14]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])=[N:5][N:6]2[CH3:50]
Reactant: CN(CCO)c1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Product: CN(CCO)c1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1

Procedure:
The title compound (58) was prepared according to the method presented for the synthesis of compound 57G of Example 57 utilizing 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (30J). 1H NMR (400 MHz, Methanol-d4) δ 7.43-6.05 (m, 7H), 5.18-5.09 (m, 1H), 4.85-4.75 (m 2H), 4.04-3.69 (m, 3H), 3.42 (s, 2H), 3.27-3.20 (m, 6H), 3.20-3.11 (m, 2H), 3.05 (s, 1H), 2.95 (s, 1H), 2.61-2.43 (m, 2H), 1.51-1.35 (m, 1H), 1.11 (m, 1H). MS (m/z) 829.20 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=[O:7])=C.[O:12]=[O+][O-].CSC>CO.C(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=[O:7])=[O:12]
Reactant: C=Cc1cc(C(=O)O)ccn1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cc(C(=O)O)ccn1
Temperature: 25 °C

Procedure:
A solution of 2-vinyl-isonicotinic acid in methanol/DCM 1/1 was cooled to −78° C. and ozone bubbled through it until the solution becomes blue. A stream of nitrogen is then passed through to remove the ozone excess and 1.5 equivalent of methyl sulfide added. The solution was allowed to warm up to room temperature and was concentrated. The product (iic) was then purified by silica flash chromatography.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[S:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:19])=[O:18]>>[C:10]1([CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:2]([CH3:1])[S:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CNC(c1ccccc1)c1ccccc1
Product: COC(=O)CS(=O)(=O)N(C)C(c1ccccc1)c1ccccc1
Yield: 37 %

Procedure:
The subtitle compound (3.05 g, 37%) was prepared as a clear brown oil from N-methyl benzhydrylamine (prepared according to the method of Z. Horii, T Sakai and Inoi, Pharm Bull., 1955, 3, 159) (10.7 g, 50.7 mmol) and methyl chlorosulfonylacetate (4.27 g, 24.7 mmol), using the method of Example 1(a).
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([N+]([O-])=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([S:24][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CCCCS
Reactant: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O

Procedure:
25.1 g (100 mmols) of 3,5-dinitrophthalic acid N-methylimide, 19.8 g (220 mmols) of n-butylmercaptan, 41.5 g (300 mmols) of anhydrous potassium carbonate and 250 ml of absolute tetrahydrofuran are kept under reflux overnight. The reaction mixture is filtered, the filtrate is evaporated and the residue is taken up in methylene chloride/2 N HCl. The extracts are washed with saturated NaCl solution, dried over sodium sulfate and evaporated. After recrystallisation from cyclohexane, 11.96 g (41% of theory) of the title imide are obtained; melting point: 106°-108° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH:22]=[CH:21][CH:20]=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([CH2:29][O:30][C:31]2[CH:32]=C(CN)C=[CH:35][CH:36]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[C:14]([O:13][C:11](=[O:12])/[N:10]=[C:9](\[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])/[NH:18][CH2:22][C:21]1[CH:20]=[CH:35][CH:36]=[C:31]([O:30][CH2:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:32]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: NCc1cccc(OCC2CCCCC2)c1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CC#N
Product: CC(C)(C)OC(=O)/N=C(/NCc1cccc(OCC2CCCCC2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (0.71 g, 2.28 mmol) and (3-(cyclohexylmethoxy)phenyl)methanamine (0.50 g, 2.28 mmol) in acetonitrile (15 ml) was stirred at 50° C. for 18 h under argon. After cooling to room temperature, a white solid was formed, collected via filtration, and dried under vacuum to give (Z)-tert-butyl(tert-butoxycarbonylamino)(3-(cyclohexylmethoxy)benzylamino)methylenecarbamate. Yield (400 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.61 (t, J=6.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.77-6.86 (m, 3H), 4.44 (d, J=5.6 Hz, 2H), 3.72 (d, J=6.4 Hz, 2H), 1.60-1.80 (m, 6H), 1.45 (s, 9H), 1.36 (s, 9H), 0.95-1.25 (m, 5H).