Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:14]([Zn]CC)[CH3:15]>O1CCOCC1>[CH2:14]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:15]
Reactant: CCOC(=O)c1c(F)cncc1Br
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Product: CCOC(=O)c1c(F)cncc1CC
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 50.7 %

Procedure:
To a solution of ethyl 3-bromo-5-fluoropyridine-4-carboxylate (4.8 g, 20 mmol) in anhydrous 1,4-dioxane (30 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (325 mg, 0.43 mmol), followed by a diethylzinc solution (22 mL, 20 mmol, 1.1 M solution in toluene). The mixture was stirred at 70° C. for 45 minutes. After cooling to room temperature, the reaction was quenched with MeOH. Ethyl acetate (100 mL) was added. The mixture was extracted with 0.1 N HCl (200 mL). The organic layer was recovered. The pH of the aqueous phase was brought to 6 with 2 N NaOH. The mixture was extracted with EtOAc (1×100 mL). The combined organic extracts were dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% ethyl acetate/hexane), affording ethyl 3-ethyl-5-fluoropyridine-4-carboxylate (2.0 g, 51% yield)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:32][Si](C)(C)C.CO>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8]([NH2:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
A solution of 3-cylopentyl-2-(4-phenoxy-phenyl)-propionic acid (200 mg, 0.64 mmol) in methylene chloride (10 mL) with one drop of N,N-dimethylformamide was cooled to 0° C. under a nitrogen atmosphere. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.48 mL, 0.97 mmol), and the resulting reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was then treated with 1,1,1,3,3,3-hexamethyldisilazane (0.47 mL, 2.24 mmol) and then allowed to warm to 25° C. where it was stirred for 16 h. After such time, the reaction mixture was treated with methanol (10 mL) and then allowed to stir at 25° C. for 10 min. The resulting reaction mixture was washed with a 5% aqueous sulfuric acid solution (2×10 mL). The combined aqueous extracts were further extracted with methylene chloride (2×10 mL). The combined organic extracts were then washed with a saturated aqueous sodium chloride solution (1×10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionamide (120 mg, 61%,) as a white solid: mp 91.6-94.4° C.; EI-HRMS m/e calcd for C20H23NO2 (M+) 309.1729, found 309.1733.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:17])[N:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[C:9]1[C:32]([OH:34])=[O:33])=O)(C)(C)C.O.CSC.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[Cl:17][C:13]1[N:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=3)=[C:9]([C:32]([OH:34])=[O:33])[NH:8][C:12]=12.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c21
Solvent: CSC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1[nH]c2c(Cl)nccc2c1CCOc1ccc(OC(F)(F)F)cc1

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-7-chloro-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (9.4 mg, 0.019 mmol) in DCM (0.5 mL) was added water (0.01 mL), dimethylsulfide (0.01 mL), and then TFA (0.5 mL, 6.5 mmol). Upon complete consumption of starting material, the mixture was concentrated in vacuo to yield the title compound as a TFA salt (7.8 mg). HRMS (ESI) calc (M+H)+=401.0510. found 401.0509.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)[N:10]=1)(=O)=O.[NH3:19]>>[Cl:18][C:13]1[CH:12]=[C:11]([C:9]2[N:10]=[C:5]([NH2:19])[N:6]=[N:7][CH:8]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: N
Reactant: CS(=O)(=O)c1nncc(-c2cc(F)cc(Cl)c2)n1
Product: Nc1nncc(-c2cc(F)cc(Cl)c2)n1
Yield: 73 %

Procedure:
5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-3-amine (1.70 g, 73%) was prepared from 3-(methylsulfonyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16.0 g, 55.5 mmol) and ammonia gas according to the general procedure of Preparation 2.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[S:20][C:19]([CH2:21][CH2:22][OH:23])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:15][C:16]1[S:20][C:19]([CH2:21][CH2:22][O:23][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:18][CH:17]=1
Reactant: OCCc1ccc(Cl)s1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1c2cc(OCCc3ccc(Cl)s3)nc(=O)n2CC1(C)C
Temperature: 130 °C
Reaction time: 5 h

Procedure:
To a solution of 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (90.0 mg, 0.421 mmol) and 2-(5-chlorothiophen-2-yl)ethanol (68.5 mg, 0.421 mmol) in N,N-dimethylformamide (DMF) (3 mL) was added Cs2CO3 (274 mg, 0.842 mmol). The reaction mixture was stirred at 130° C. for 5 h, quenched with water. Purification via MDAP afforded the title product as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]3[C:13]4[CH2:18][CH2:17][NH:16][CH2:15][C:14]=4[C:19](=[O:21])[O:20][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:22].[Cl:23][CH2:24][CH2:25][N:26]1[CH2:32][CH:31]2[CH2:33][CH2:34][CH:28]([CH2:29][CH2:30]2)[CH2:27]1>>[ClH:23].[ClH:22].[CH:31]12[CH2:33][CH2:34][CH:28]([CH2:29][CH2:30]1)[CH2:27][N:26]([CH2:25][CH2:24][N:16]1[CH2:17][CH2:18][C:13]3[C:10]4[CH:11]=[CH:12][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][C:9]=4[O:20][C:19](=[O:21])[C:14]=3[CH2:15]1)[CH2:32]2
Reactant: O=c1oc2cc(-c3ccccc3)ccc2c2c1CNCC2
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Product: O=c1oc2cc(-c3ccccc3)ccc2c2c1CN(CCN1CC3CCC(CC3)C1)CC2
Yield: 9.2 %

Procedure:
Prepared by the method described for Example 1 from 8-phenyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.54 g, 0.02 moles) and 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (4.48 g, 0.02 moles). Recrystallization from methanol gave the product (920 mg), mp 260°-265° C. (dec).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:32][NH:33][CH3:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:33]([CH3:34])[CH3:32])=[O:26])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: CNC
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](C(=O)O)C3)n3nccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 66.8 %

Procedure:
A solution of (R)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 84, 100 mg, 0.236 mmol), dimethylamine (236 μL, 0.472 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 20-40% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (71 mg, 69%). 1H NMR (DMSO-d6) δ: 10.91 (s, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.95-8.03 (m, J=8.6 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.37 (s, 1H), 6.36 (d, J=2.0 Hz, 1H), 4.55 (br. s., 1H), 4.35 (br. s., 1H), 2.97-3.18 (m, 6H), 2.83 (s, 3H), 1.57-2.01 (m, 4H), 1.45 (s, 6H). ESI-MS: m/z 451.0 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]2[CH2:11][CH2:10]2)=[C:5]2[C:12]([O:18][CH3:19])=[C:13](Cl)[C:14]([F:16])=[CH:15][N:4]2[C:3]1=[O:20].[CH3:21][NH:22][C@H:23]([C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:24]>>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]2[CH2:11][CH2:10]2)=[C:5]2[C:12]([O:18][CH3:19])=[C:13]([N:27]3[CH2:28][CH2:29][C@@H:25]([C@@H:23]([NH:22][CH3:21])[CH3:24])[CH2:26]3)[C:14]([F:16])=[CH:15][N:4]2[C:3]1=[O:20]
Reactant: COc1c(Cl)c(F)cn2c(=O)n(N)c(=O)c(C3CC3)c12
Reactant: CN[C@@H](C)[C@@H]1CCNC1
Product: CN[C@@H](C)[C@@H]1CCN(c2c(F)cn3c(=O)n(N)c(=O)c(C4CC4)c3c2OC)C1
Yield: 34.1 %

Procedure:
The title compound (0.04 g) was prepared from 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxypyrido[1,2-c]pyrimidine-1,3-dione (0.09 g, 0.30 mmol [Example 12]), and methyl-((S)—(R)-1-pyrrolidin-3-ylethyl)amine (0.11 g, 0.90 mmol) using the general procedure of Example 4. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H), 5.42 (s, 2H), 3.89-3.58 (m, 5H), 3.22 (s, 3H), 2.67-2.58 (m, 1H), 2.46 (s, 3H), 2.22-2.02 (m, 2H), 1.80-1.61 (m, 2H), 1.21 (d, 3H), 1.10-1.00 (m, 1H), 0.84-0.76 (m, 1H), 0.52-0.44 (m, 1H), 0.40-0.32 (m, 1H). MSCI: m/z=392 (MH+).
Reaction SMILES: O[CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].C(OCC)C.P(Br)(Br)[Br:17]>N1C=CC=CC=1>[Br:17][CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: BrP(Br)Br
Reactant: COC(=O)CCSCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)CCSCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.2 g. of this ester are dissolved in 27 ml. anhydrous diethyl ether, 0.8 ml. pyridine is added thereto and then 1.9 ml. phosphorus tribromide is added dropwise, while cooling with ice. The reaction mixture is subsequently stirred for 5 hours at ambient temperature. Ice water is then added thereto, followed by extraction with diethyl ether. The extract is washed with water, dried and evaporated to give 10.1 g. of an oil which is chromatographed with 480 g. of silica gel, using ligroin-diethyl ether (2:1 v/v) as elution agent, 7.1 g. methyl 3-(2-bromoethylthio)-propionate being obtained in the form of an oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:22]([CH3:21])(=[O:24])=[O:23])=[C:7]([CH3:12])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(NS(C)(=O)=O)c(C)c1

Procedure:
A flask was charged with 3-methyl-4-aminophenyl N-methylcarbamate (3.0g., 0.0166 mole), triethylamine (1.83g., 0.018 mole, 2.53 ml.) and about 100 ml. of benzene. To this slurry was added methanesulfonyl chloride and after one hour at reflux the mixture was cooled and filtered. The solids were stirred vigorously with water to dissolve any residual by-product triethylamine hydrochloride. Refiltration and drying gave 2.3g. of the desired product (m.p. 167°-69° C.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11]S(C(C)(C)C)=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[ClH:18].O1CCOCC1>CO.CCOCC>[ClH:18].[ClH:18].[Br:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH2:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccc(Br)nc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1ccc(Br)nc1
Reaction time: 2 h

Procedure:
To a mixture of 2-methyl-propane-2-sulfinic acid [(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide (5.35 g, 16.76 mmol) in methanol (25 mL) was added a solution of 4 N HCl in dioxane (10 mL, 40.0 mmol). The mixture was monitored by TLC (ethyl acetate-hexanes 3:7). After 2 hour, the mixture was concentrated to near dryness to afford a white solid. The solid was diluted with ether and collected by filtration to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[CH2:8][CH:9]3[CH2:14][N:13]([C:6]=2[CH:5]=1)[CH2:12][CH2:11][NH:10]3)([O-:3])=[O:2].[CH2:17](Br)[CH:18]=[CH2:19].C(=O)(O)[O-].[Na+].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:19]([N:10]1[CH:9]2[CH2:14][N:13]([C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:7]=3[CH2:8]2)[CH2:12][CH2:11]1)[CH:18]=[CH2:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCNC(C2)C1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1CCN2CC1Cc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (17.5 g.), allyl bromide (7.6 ml.), sodium bicarbonate (1 teaspoon) and N,N-dimethylformamide (200 ml.) was stirred overnight at room temperature, then concentrated to dryness. The residue was partitioned between dilute aqueous sodium hydroxide and isopropyl acetate. The isopropyl acetate layer was washed with dilute aqueous sodium hydroxide and brine, filtered and concentrated to dryness. The residue was recrystallized from isopropyl alcohol, and the product was combined with corresponding product (2.3 g.) from a previous a preparation. Ethereal hydrogen chloride was added to a solution of the combined products in ethyl acetate affording 4-allyl-9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (10 g.), the compound of Formula IV wherein Q is allyl.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)([CH3:7])[CH3:6]>C(O)(=O)C.C(OC(=O)C)(=O)C.O.CCCCCC>[CH:5]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:12][C:13]=1[N+:1]([O-:4])=[O:2])([CH3:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1cccc(C(C)C)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: CC(C)c1ccc([N+](=O)[O-])c(C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Nitric acid (70%) (15.6 g, 185 mmol) was added slowly to a solution of 1,3-di-iso-propyl-benzene (available from Aldrich) (20 g, 123 mmol) in acetic acid (50 mL) and acetic anhydride (50 mL) at 0° C. over 20 min. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (250 mL) and hexane (500 mL). The organic layer was then washed with with water (50 mL), saturated Na2CO3 (50 mL), dried (Na2SO4) and concentrated to give the title compound in a crude form (25 g, 98% yield) as a colorless oil:
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=O)(C)(C)C.[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:36]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([S:39]([NH:8][C@H:9]3[CH2:13][CH2:12][N:11]([NH:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]5[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=5)[CH2:19][CH2:20]4)[C:10]3=[O:27])(=[O:41])=[O:40])=[CH:36]2)=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc2ccc(Cl)cc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Product: O=C1[C@@H](NS(=O)(=O)c2ccc3ccc(Cl)cc3c2)CCN1NC1CCN(c2ccncc2)CC1
Yield: 30 %

Procedure:
Similarly to Example 86 and using (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-pyrrolidone (220 mg) and 7-chlornaphthalene-2-sulfonyl chloride (170 mg), the title compound (88 mg) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1F)[C:25]([OH:27])=[O:26])#[N:21]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[C:20]#[N:21])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)COc1ncc(O)cc1Cl
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)COc1ncc(Oc2ccc(C(=O)O)cc2C#N)cc1Cl
Temperature: 90 °C
Reaction time: 16 h
Yield: 118.7 %

Procedure:
5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 0.124 g, 0.62 mmol) and potassium carbonate (0.28 g, 2.03 mmol) were suspended in DMSO (3.0 mL). Then 3-cyano-4-fluorobenzoic acid (0.0835 g, 0.51 mmol) was added portionwise. The reaction was then stirred at 90° C. under nitrogen for 16 hours, diluted in EtOAc (15 mL) and washed twice with an aqueous solution of HCl (2.0 M, 10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase column chromatography (ISCO®, gradient of 5-95% acetonitrile in water, 13 g C18 column) to afford the title compound as an orange oil (0.21 g, 120%):
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:3]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:41]1[CH2:45]OC[CH2:42]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=2)[C:3]=1[CH:26]([CH2:42][CH2:41][CH3:45])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Yield: 72.8 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.340 g; 0.78 mmol), LHMDS 1N in THF (1.17 mL; 1.17 mmol), 1-iodopropane (0.152 mL; 1.56 mmol) in DMF (3.9 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.271 g (73%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].N1C=CC=CC=1>C(OCC)C>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])=[O:18]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1c(NC(=O)c2ccco2)cccc1[N+](=O)[O-]

Procedure:
A solution of 2-methyl-3-nitroaniline (1 mmol) in anhydrous diethyl ether was treated with 2-furoyl chloride (1.1 mmol) and pyridine (3.0 mmol) at 25° C. for 12 h. Extraction and chromatography afforded N-(2-furoyl)-2-methyl-3-nitroaniline as a white solid. TLC: Rf=0.41, 50% EtOAc-hexane.
Reaction SMILES: [CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[C:4]([C:12]([OH:14])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=[N:21]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:6]2[S:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[C:4]([C:12]([NH2:21])=[O:14])=[CH:3][CH:2]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cccc2c1OCCCS2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2c1OCCCS2
Reaction time: 48 h
Yield: 64 %

Procedure:
To 7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene-4-carboxylic acid (16.5g, 78.4 mmol) in 100 mL DMF was added in succession solid HOBT (21.3g, 157.3 mmol), solid EDC hydrochloride (30.1 g, 157.0 mmol), and 25% aqueous ammonia (18 mL, 128.4 mmol). After stirring for 48 h, the reaction mixture was diluted with 200 mL ethyl acetate and washed with water, 1N HCl, saturated NaHCO3, saturated NH4Cl, and brine. Drying over Na2SO4 and concentration yielded the amide as a tan solid (10.5 g, 64%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.C(Cl)(Cl)Cl.[Pd]>[C:26]1([CH2:25][NH:32][C:33]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)NCc1ccccc1)C(C)C
Reaction time: 1 h
Yield: 59 %

Procedure:
CBZValAlaOCH3 (1.35 g, 4.00 mmole) was hydrogenated at 3 atm. over 10% Pd on carbon (150 mg) in CH3OH (40 mL) at room temperature. After 1 hour, the catalyst was removed by filtration through a nylon filter. The filtrate was evaporated in vacuo giving a white solid which was slurried in CHCl3 (40 mL) and treated with benzyl isocyanate (586 mg, 4.4 mmole). After 1 hour at room temperature, the reaction mixture was washed three times with 1N HCl, dried over MgSO4, filtered and concentrated in vacuo giving 791 mg (61%) of the desired product as a white powder. Recrystallization of a portion from ethyl acetate/CH3OH gave an analytical sample: mp 227°-228° C.; 1H NMR (DMSO-d6) δ 0.80 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 1.26 (d, J=7.3 Hz, 3H), 1.85-1.95 (m, 1H), 3.59 (s, 3H), 4.10 (dd, J=5.9, 9.2 Hz, 1H), 4.15-4.3 (m, 3H), 6.08 (d, J=9.3 Hz, 1H), 6.53 (t, J=6.0 Hz, 1H), 7.15-7.35 (m, 5H), 8.39 (d, J=6.7 Hz, 1H); MS (LSIMS) m/e 336 (100, M+ +1), 233 (62), 203 (76); [α]D20 +6.1° (c=1.0, DMF); Analysis calculated for C17H25N3O4 ; C, 60.88; H, 7.51; N, 12.53; found: C, 60.98; H, 7.30; N, 12.34.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:35]([NH:37][C:38]([NH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:39])[CH3:36]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:44]4[CH2:45][CH2:46][CH:41]([NH:40][C:38]([NH:37][CH2:35][CH3:36])=[O:39])[CH2:42][CH2:43]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCNC(=O)NC1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CCNC(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-3-ethyl-urea was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-Ethyl-3-piperidin-4-yl-urea following General Procedure B.