Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-])=O.C(OCC)(=O)C>[Pd].C(O)C>[NH2:18][C:3]1[CH:4]=[C:5]([S:8]([NH:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(S(=O)(=O)NOC2CCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NOC2CCCC2)cc1N
Reaction time: 72 h
Yield: 100.7 %

Procedure:
A solution of 4-amino-N-(cyclopentyloxy)-3-nitrobenzenesulfonamide (4.50 g, 14.95 mmol) in 1:1 ethyl acetate:ethanol (150 mL) was combined with 5% Pd on barium sulfate and reduced under a hydrogen atmosphere over 72 hours. The reaction mixture was filtered through a pad of diatomaceous earth and evaporated in vacuo to a residue which crystallized on standing. The solid was slurried in hexane, filtered and dried under high vacuum to provide 3,4-diamino-N-(cyclopentyloxy)benzenesulfonamide (4.086 g, 100%) as a light brown solid H1-NMR (dimethylsulfoxide-D6): 1.61 (m, 8H), 4.37 (m, 1H), 4.90 (b, 2H), 5.38 (b, 2H), 6.57 (d, 1H), 6.88 (m, 1H), 6.96 (d, 1H), 9.64 (s, 1H). MS(ESI): 272(M+H).
Reaction SMILES: II.C([O:5][CH:6](OCC)[CH:7]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[O:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:32])C>CC(C)=O>[OH:5][CH:6]=[C:7]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[O:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:32]
Reactant: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OCc1ccccc1)CC2
Agent: II
Solvent: CC(C)=O
Product: O=C1C(=CO)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Temperature: 35 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Iodine (2.88 g, 11.4 mmol) was slowly added to a solution of benzyl 3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (20.6 g, 45.4 mmol) in acetone (515 mL) and the mixture was stirred at 35° C. overnight. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0-40% ethyl acetate in hexane) to afford benzyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (15.2 g, 88%). ESI-MS m/z calc. 379.1. found 380.3 (M+1)+; Retention time: 2.00 minutes (3 min run).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:60][CH2:61][N:62]([CH3:64])[CH3:63]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCN(C)C)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF was added potassium carbonate (4.4 eq.) and 2-chloro-N,N-dimethylethanamine hydrochloride (2.5 eq.). The reaction was heated to 80° C. and stirred for 4 hr. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with 5% aqueous potassium carbonate solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 2%→5% [2 M NH3 in MeOH] in DCM) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=O)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Product: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Temperature: 110 °C
Yield: 96 %

Procedure:
3-(4-Methoxyphenyl)isoquinolin-1-one (1.70 g) was added to phosphorus oxychloride (10 ml), and the resulting mixture was heated at 110° C. for 3 hr. The reaction mixture was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a white powder (1.76 g, yield; 96%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([O:20]CC)=[O:19])=[CH:6]2)[CH3:2].C(O)C.O.[OH-].[Li+].Cl>O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)c(O)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Yield: 94 %

Procedure:
To the product of step 2 was added 80 mL of ethanol, followed by addition of a solution of 3.5 g (83 mmol) of lithium hydroxide hydrate in 80 mL of water. The resulting solution was heated to reflux for three h. The mixture was concd, the residue treated with 50 mL of water and the resulting solution acidified to pH=1.0 with dilute hydrochloric acid. The product was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was further purified by silica chromatography with 1% HOAc in EtOAc/hexane (2:8) to afford 5.6 g (94%) of a green-yellow solid: 1H NMR (CDCl3/400 MHz) 7.80(s, 1H), 7.01(s, 1H), 6.43(s, 1H), 5.62(q, J=6.8Hz, 1H), 2.56(q, J=7.6 Hz, 2H), 1.26(t, J=7.6 Hz, 3H). MS (ESI+) 289.1(M+1, 100). MS(ES−) 287.1(M−H, 100). HRMS (ES−) m/z calcd for (M−H; C13H10F3O4): 287.0526, found 287.0504.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[NH2:12]
Reactant: Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(F)(F)F)cc1N
Yield: 79.9 %

Procedure:
2-Methyl-5-trifluoromethylnitrobenzene (14.8 g) was dissolved in ethanol (100 ml) and hydrogenated at ambient temperature and pressure in the presence of palladium on charcoal (10%; 0.5 g). The solution was filtered and evaporated to dryness to give 2-methyl-5-trifluoromethylaniline (10.1 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:17]1([NH:23][C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:30]([C:29]5[CH:32]=[CH:33][C:26]([C:24]([NH:23][C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[O:25])=[CH:27][CH:28]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:30]1[C:29]1[CH:28]=[CH:27][C:26]([C:24]([NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(-c4ccc5nc(-c6ccc(C(=O)Nc7ccccc7)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 261 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C40H28N6O2: 625.23; found: 625.53.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]4[C:8]=3[C:9]3[N:10]([C:28]5[C:33]([C:34]=3[C:5]=2[C:4](=[O:35])[N:3]1[Si](C(C)C)(C(C)C)C(C)C)=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:12](=[O:22])(=[O:21])[CH2:13]4.CS(C)=O.C([O-])(=O)C.[Na+]>O>[O:1]=[C:2]1[C:6]2[C:7]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]4[C:8]=3[C:9]3[N:10]([C:28]5[C:33]([C:34]=3[C:5]=2[C:4](=[O:35])[NH:3]1)=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:12](=[O:22])(=[O:21])[CH2:13]4
Reactant: CCOC(=O)C1n2c3ccccc3c3c4c(c5c6ccccc6n(c5c32)CS1(=O)=O)C(=O)N([Si](C(C)C)(C(C)C)C(C)C)C4=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1n2c3ccccc3c3c4c(c5c6ccccc6n(c5c32)CS1(=O)=O)C(=O)NC4=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
In a 10 mL flask were placed 0.07 g of the compound from Example 44, 4.0 mL of dimethyl sulfoxide, 1.0 mL of water and 0.05 g of sodium acetate. The resulting mixture was stirred at room temperature for 16 hours, cooled and poured in to ice and water. The resulting yellow precipitate was collected, washed with water and dried in vacuo (2.0 mm Hg) for 2 days to give 0.04 g of the title compound. mp: 298°-300° C.; HRMS: calc'd: 487.0838; measured: 487.0831 ##STR69##
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30])#[N:2]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccccc1Cn1c2cccc(OCC(=O)O)c2c2c(C(N)=O)cccc21
Yield: 100.7 %

Procedure:
A suspension of the {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (110 mg, 0.266 mM) and 0.29 mL (0.29 mM) of 1 N NaOH in 5 mL of ethanol was sonicated for 2 hours at 25° C. The resultant white precipitate was collected by filtration, washed with small amounts of EtOH, diethyl ether, and hexanes, then dried in vacuo to afford 107 mg (95%) of the {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.9 (d, 1H, J=8 Hz), 7.6 (br s, 1H), 7.5 (d, 1H, J=8 Hz), 7.45-7.4 (m, 3H), 7.35 (t, 1H, J=8 Hz), 7.25 (t, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 7.05 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.4 (d, 1H, J=8 Hz), 5.8 (s, 2H), and 4.3 (s, 2H). IR (KBr, cm−1) 2220, 1652, and 1613. MS (ES) m/e 398, 400.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.C([O:14][C:15](=O)[CH2:16][N:17]1[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:19]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[N:18]1)C>C(Cl)Cl>[C:2]1([NH:1][C:15](=[O:14])[CH2:16][N:17]2[C:21]([C:22]([F:25])([F:23])[F:24])=[C:20]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:19]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[N:18]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Agent: C[Al](C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nn(CC(=O)Nc3ccccc3)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
Aniline (0.07 g, 0.75 mmol) was added to a methylene chloride solution of trimethyl aluminum (0.38 mL, 0.75 mmol, 2.0M in hexanes) at 25° C. under nitrogen. After gas evolution had ceased (approx. 30 minutes), ethyl[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (Example 8) (0.25 g, 0.5 mmol) was added and the mixture stirred for 24 hours at 25° C. The reaction was quenched with dilute aqueous HCl and extracted with two portions ethyl acetate and the extracts washed with brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave N-phenyl-[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide as a white crystalline solid (0.18 g, 68% yield). Elemental analysis for C25H19N3F4SO3Calc'd: C, 58.02, H, 3.70, N, 8.12, S, 6.20. Found: C, 57.48, H, 3.78, N, 8.03, S, 6.46.
Reaction SMILES: [P:1]([O-:5])([O-:4])([OH:3])=[O:2].[Na+].[Na+].P([O-])([O-])([O-])=O.O.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17]>O>[C:14]([O-:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([O-:24])=[O:23])([C:18]([O-:20])=[O:19])[OH:17].[P:1]([O-:5])([O-:4])([O-:3])=[O:2]
Reactant: O=P([O-])([O-])O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Reagent(ii) is a buffer prepared by first dissolving 144.8 grams (1.020 mol) of disodium hydrogen phosphate in 1.00 liter hot deionized water. The phosphate dissolved in the hot deionized water upon stirring. To this solution 102.95 grams (0.4902 mol) of citric acid monohydrate were added. The resulting solution was then diluted to 10.0 liters with additional deionized water, thus forming a citrate-phosphate solution, with a pH of 5.0.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][CH:27]([CH2:31][CH3:32])[C:28](O)=[O:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:28](=[O:29])[CH:27]([CH3:26])[CH2:31][CH3:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CCC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (17.7 mg, 62.7%), MS (ISP) m/z=415.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and 2-methylbutanoic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Yield: 97.5 %

Procedure:
A solution of N-(1,3-benzoxazol-2-yl)-N′-(3-nitropyridin-2-yl)benzene-1,4-diamine (0.330 g) in methanol (20 mL) was treated with palladium on carbon (0.060 g, 10% wt on activated carbon) and the mixture was hydrogenated (1 atm H2) for 1 h. After this time, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to afford N2-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine (0.294 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[F:32]C1C=CC(CCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:7]1[CH:6]=[CH:5][C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2ccc(F)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(4-fluoro-phenyl)-propanoic-acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][NH:20][O:21][CH3:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:20]([O:21][CH3:22])[CH2:19][C:18]2[CH:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(OC)cc1
Product: COc1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-methoxybenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (97% yield): mp 113-114° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.66 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.38 (1H, s, CH), 6.85 (2H, m, aromatics), 7.29 (2H, m, aromatics). Anal. calcd. for C16H19NO6: C, 59.80; H, 5.96; N, 4.35. Found: C, 59.87; H, 5.76; N, 4.17.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22]2[S:30][C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][C:33]=3[F:41])[CH:23]=2)=[CH:20][CH:21]=1)[CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.O.[Fe]>[C:1]([O:5][C:6](=[O:42])[N:7]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22]2[S:30][C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][C:33]=3[F:41])[CH:23]=2)=[CH:20][CH:21]=1)[CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C

Procedure:
To nitro compound 328 (0.20 g, 0.33 mmol) in MeOH (75 mL) was added iron dust (0.37 g, 6.7 mmol) and ammonium chloride (0.089 g, 1.7 mmol) in water (5 mL). The resulting mixture was heated to reflux for 4 h, then cooled, filtered through celite and concentrated. The residue was partitioned between ethyl acetate and water, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The product 329 (0.18 g, 95%) was used crude in the next step. LRMS (M+H): 569.5
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[S:27](Cl)(=[O:29])=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:28])=[O:29]
Reactant: O=S(=O)(Cl)c1c(Cc2ccccc2)sc2ccccc12
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccccc3)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-benzylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.39 g) and THF (7 ml). Flash chromatography (5% methanol/chloroform) followed by recrystallization from chloroform and hexanes provided 0.11 g (24%) of a tan crystalline solid, m.p. 120°-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[C:5]([C:16]([OH:18])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:11]([C:12]([F:13])([F:14])[F:15])=[CH:10][C:9]2[C:4](=[C:5]([C:16]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:18])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cccc2cc(C(F)(F)F)c(Cl)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cccc2cc(C(F)(F)F)c(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 2-chloro-3-(trifluoromethyl)quinoline-8-carboxylic acid (165 mg, 0.60 mmol), 3-aminopyridine (73 mg, 0.78 mmol), HATU (365 mg, 0.96 mmol), DIPEA (312 mg, 2.4 mmol) in CH2Cl2 (4 ml) was stirred at room temperature under N2 overnight. The reaction mixture was washed with water (5 mL) and brine (3×5 mL). The organic solution was dried, concentrated, and purified by silica gel column chromatography (25% ethyl acetate in pentane to give 2-chloro-N-(pyridin-3-yl)-3-(trifluoromethyl)quinoline-8-carboxamide as a white solid. (36 mg 65% yield.)
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])C.CO.[OH-].[Na+]>O1CCCC1>[C:28]([CH2:27][CH2:26][CH2:25][N:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:16][C:17]3[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:23])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3])#[N:29]
Reactant: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#CCCCn1c(C(=O)O)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(3-Cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid ethyl ester (1.89 g, 4.38 mmol), from Example 1(c), was dissolved in tetrahydrofuran (5 mL). Methanol (5 mL) and 1.0 N NaOH (5 mL) were added and the reaction mixture was stirred at ambient temperature for 12 h. The tetrahydrofuran and methanol were removed under reduced pressure and water (10 mL) was added. The solution was acidified to pH 2 with 10% aqueous HCl solution. The product precipitated as a white solid (1.52 g, 86%) and was collected through vaccuum filtration. (MS(ES) m/e 403.0 [M +H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1>CN(C)C=O>[Cl:16][C:17]1[N:18]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:20]([C:24]([F:27])([F:25])[F:26])=[CH:21][N:22]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 1.6 %

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, was added Sodium hydride (100 mg) and the reaction mixture was allowed to stirred at 0 degree for 20 minutes. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (350 mg, 1.6 mmol) was added in one portion and the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with Ethyl acetate. The combined Ethyl acetate layers were dried over Sodium Sulfate and solvent was removed under reduced pressure. The residue was purified by Prep-HPLC to yield the desired product as a white solid (10 mg, 2% yield).