Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>O1CCCC1>[CH3:32][S:33]([N:3]1[CH:4]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[C:5]2[C:20](=[O:21])[CH2:19][CH2:18][C:6]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:2]1=[O:1])(=[O:35])=[O:34]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2,5-Dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 1, 255 mg, 0.64 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 72 mg, 1.8 mmol) in dry tetrahydrofuran (15 mL) and the mixture is stirred at room temperature for 10 min. Methanesulfonyl chloride (104 μL, 1.35 mmol) is added and the mixture is stirred at 50° C. for 2 h. Water (1 mL) is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 230 mg; ESI mass spectrum [M+H]+=476; Retention time HPLC: 0.91 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C>[C:57]([O:56][C:55]([NH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[NH:47][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:61])([CH3:60])([CH3:58])[CH3:59]
Reactant: CCOC(=O)CCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
To a solution of 7-ethoxy-7-oxoheptanoic acid (2.0 g, 10.6 mmol) in DMF (50 mL) were added HBTU (4.4 g, 11.6 mmol), DIEA (4.1 g, 31.8 mmol) at room temperature. The resulting mixture was stirred for 10 min, then tert-butyl (2-aminophenyl)carbamate (2.43 g, 11.7 mmol) was added to the reaction solution. The reaction mixture was stirred for 12 h at room temperature. The reaction was quenched with water (200 mL). The resulting mixture was extracted by EtOAc (200 mL×2). The organic layers were combined, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The resulting solid was purified by column chromatography (elute: EtOAc:PE (petroleum ether)=1:4) to afford the desired compound (3.7 g, yield 92.1%) as a light yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[S:21]([O:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)([CH3:24])(=[O:23])=[O:22]
Reactant: OCCC1COc2ccccc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound 2-hydroxyethyl-1,4-benzodioxan (11.96 g) in dichloromethane (450 ml) was added triethylamine (0.12 mol, 10 ml). Mesylchloride (9.2 g) was then added dropwise and the reaction mixture was stirred for one hour at room temperature. After completion of the reaction, the solution was washed with water, brine, and concentrated to an oil, which was purified by chromatography on silica gel to yield 2-mesyloxyethyl-1,4-benzodioxan, 17.08 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)[CH2:21][CH2:20][N:19]([C:12](=[O:14])[CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH2:18][CH2:17]1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc2ncccc2c1)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h
Yield: 949.1 %

Procedure:
A mixture of 2.8 g (0.015 mol) of 6-quinolylacetic acid, 4.2 g (0.0015 mol) of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 6.63 g (0.015 mol) of BOP and 5.3 ml of triethylamine in 60 ml of methylene chloride is stirred overnight. 100 ml of ethyl acetate are added and the mixture is washed with water and with 1N sodium hydroxide solution and dried over sodium sulphate, and the solvent is evaporated off. 5.9 g of the title compound are obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)=[O:24])=[CH:20][CH:21]=2)[CH:12]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.1 %

Procedure:
To Methyl 3-methyl-2-(3-(4-(3-(4-(trifluoromethyl)phenyl)ureido)phenyl)isoxazole-5-carboxamido)butanoate (250 mg) dissolved in THF (5 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (1 ml) and stirred at RT for 14 h. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was separated, dried over. Na2SO4 and concentrated under reduced pressure to get off white solid which was crystallized from EtOAc to yield 185 mg (76%) white solid. MS (ES+): m/z 491 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ 12.82 (bs, 1H), 9.22 (s, 1H), 9.12 (s, 1H), 8.93 (d, 1H), 7.85 (d, 2H), 7.68 (s, 1H), 7.65 (d, 2H), 7.61 (d, 2H), 7.56 (d, 2H), 4.26 (m, 1H), 2.21 (m, 1H), 0.95 (d, 6H).
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:10][C:9](=[O:16])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>O>[C:1]([O:6][C@@H:7]1[C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:10][C:9](=[O:16])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OC1CC(=O)NC1CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(=O)O[C@H]1CC(=O)N[C@H]1CC(C)C
Reaction time: 70 h

Procedure:
20 g of (4RS,5RS)-4-butyryloxy-5-isobutylpyrrolidin-2-one (produced according to Example 4) and 2 g of Candida cylindracea lipase (Biocatalysts) were stirred in 100 ml of water at room temperature. The pH of the suspension was held constant at 7 by the addition of 1M sodium hydroxide solution. After 70 hours and a consumption of 47.36 ml of 1M sodium hydroxide solution (corresponding to 53.8 percent conversion), the reaction was terminated. The reaction mixture was diluted with 200 ml of water and extracted once with 400 ml and another two times with 200 ml of toluene each. The combined toluene phases were concentrated by evaporation in a vacuum and the residue was dried in a high vacuum. The yield of the title compound was 8.55 g (85.5 percent, relative to one enantiomer). The title compound had a melting point of 94.9° to 95.3° C. Other data concerning the title compound was:
Reaction SMILES: [Fe:1].[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:17]1[C:18]2[C:13](=[CH:19][CH:3]=[CH:2][CH:6]=2)[CH2:14][CH2:15][CH2:16]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Fe+2:1]
Reactant: [Fe]
Reactant: Cc1ccccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: c1ccc2c(c1)CCCC2
Temperature: 375 °C

Procedure:
An iron containing ZSM-5 catalyst was prepared by the following method: about 10 g of the same HZSM-5 as that of Example 1 was heated in a stream of dry air to 375° C. for 4 hours and then was cooled to room temperature. A solution of 0.3331 g of ferrocene (dicyclopentadienyliron) in 30 g dry toluene was then added to the dried zeolite and the slurry was mixed at room temperature overnight. The slurry was filtered and washed once with 100 ml of Tetralin® to remove excess ferrocene from the external surface of the zeolite. Excess Tetralin® was allowed to evaporate at room temperature to give a Tetralin®/ferrocene wetted zeolite. The recovered solid was then calcined in a stream of dry air at about 538° C. for about 6 hours to produce the desired iron containing catalyst, Catalyst C. The iron loading of this catalyst is about 0.66 wt. %.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]=[C:14]=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[NH2:18][C:19]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:21]([O-])=[O:22]>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:21](=[O:22])[CH:20]=[C:19]([C:24]([F:27])([F:26])[F:25])[NH:18][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: NC(=CC(=O)[O-])C(F)(F)F
Reactant: COC(=O)c1c(Cl)ccc(N=C=O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1C
Yield: 58.9 %

Procedure:
This compound was prepared in a manner analogous to the second part of Step D, Example 1. Here, 16.7 grams (0.074 mole) of methyl 6-chloro-3-isocyanato-2-methylbenzoate was combined with 4.4 grams (0.110 mole) of 60% sodium hydride and 14.2 grams (0.076 mole) of 3-amino-4,4,4-trifluoro-2-butenoate in 600 mL of THF. The reaction product was purified by column chromatography on silica using a 1:1 mixture of EtOAc and hexane as eluant. The fractions containing product were combined and concentrated under reduced pressure, yielding 15.8 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:6]2[N:5]=[C:4]3[N:3]=[CH:2][NH:1][C:9]3=[CH:8][CH:7]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]cnc2n1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 74 %

Procedure:
The title compound is prepared from 1H-imidazo[4,5-b]pyridine-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 74% of theory; LC (method 3): tR=2.10 min; Mass spectrum (ESI+): m/z=319 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([NH2:23])=[O:22])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]([NH2:23])=[O:22])[CH2:18][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: NC(=O)c1ccccc1N1CCNCC1
Product: NC(=O)c1ccccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 41.9 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.306 g) and 2-(piperazin-1-yl)benzamide (0.336 g) are converted to 0.236 g of the title compound after chromatography on silica gel using methanol/dichloromethane (8/92) and crystallization from ethyl acetate/dichloromethane. A portion of this material was recrystallized from ethyl acetate/methanol/hexane; mp 178-179° C.; ms m/z 369; IR (mineral oil) 1663, 3289, 1325, 1448, 796 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.08, 3.78, 5.76, 7.13, 7.23, 7.46, 7.52, 7.53, 8.14, 8.17, 9.57.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>>[C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1

Procedure:
Similarly, equimolar amounts of p-carboxy aniline and maleic anhydride reacted to produce N-(p-carboxyphenyl)maleamic acid.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8].Cl>C(O)C>[N+:14]([C:11]1[CH:10]=[C:6]2[C:5](=[CH:13][CH:12]=1)[NH:3][NH:2][C:7]2=[O:8])([O-:16])=[O:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Yield: 45 %

Procedure:
Hydrazine hydrate (4 mL, 124 mmol) was added to a solution of 2-chloro-5-nitro benzoic acid (5 g, 24.8 mmol) in absolute ethanol (30 mL), and the resulting mixture was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure. Residue was trituated with methanol to give 6.5 g of crude intermediate. 2N aq. HCl (40 mL) was added to the crude product, and the mixture was refluxed for 8 h. Reaction mixture was cooled to 0° C., solids were collected via filtration, washed with cold water and dried under vacuum. Residue was purified by flash chromatography using 1% methanol in chloroform as eluent to afford title compound (2 g, 27%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 12.4 (bs, 1H), 11.3 (bs, 1H), 8.67 (s, 1H), 8.12 (dd, J1=2.1 Hz, J2=9.0 Hz, 1H), 7.5 (d, J=9.0 Hz, 1H); ESI-MS m/z: 179 (M+H)+.
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][CH:12]1[C:20](=O)[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH:20]([NH2:10])[C:16]2[CH:17]=[CH:18][S:19][C:15]=2[CH2:14][CH2:13]1
Reactant: CC1CCc2sccc2C1=O
Reactant: NC1CCCc2occc21
Product: CC1CCc2sccc2C1N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.12–6.99, 4.13, 3.89, 3.51, 2.86–2.74, 2.13–1.98, 1.75, 1.65, 1.15, 1.07.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([F:34])([F:33])[F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:43]#[N:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([F:33])([F:32])[F:34])=[N:25][C:21]=3[CH:20]=[C:19]([C:43](=[N:2][OH:3])[NH2:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (44.5 mg, 0.64 mmol), sodium bicarbonate (81 mg, 0.96 mmol), and water (0.64 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (161 mg, 0.32 mmol) dissolved in ethanol (1.5 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C25H29ClF3N7O [M+H]+ 536. found 536.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][O:32][C:33]1[N:38]=[C:37]([C:39]([NH:41][NH2:42])=O)[CH:36]=[CH:35][CH:34]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:39]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([O:32][CH3:31])[N:38]=3)=[N:41][N:42]=[C:14]2[CH2:13]1)=[O:11]
Reactant: COc1cccc(C(=O)NN)n1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)n1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(0.25 g, 0.859 mmol) was dissolved in Dichloromethane (DCM) (2.147 ml) and triethyloxonium tetrafluoroborate (0.196 g, 1.031 mmol) was added. The solution was left to stir under an argon atmosphere for 18 hours. 6-(Methyloxy)-2-pyridinecarbohydrazide (I95) (0.172 g, 1.031 mmol) was added and the solution was left to stir under argon for a further 60 minutes. The Dichloromethane was removed under reduced pressure and 1-butanol (2.147 ml) was added and the reaction mixture was left at reflux for 3 hours. LCMS showed the product had formed so the solvent was removed under reduced pressure and the crude material was purified by flash chromatography (Biotage Isolera 4, 25 g cartridge) with a gradient of methanol 0-10% in Dichloromethane. The solvent was removed under reduced pressure to afford 0.285 g of material that was further purified using MDAP. The solvent was removed to afford the purified desired product in 0.108 g.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:7]([CH3:15])=[N:8][N:9]([CH2:12][CH:13]=[CH2:14])[C:10]=1[CH3:11])C.CO.[OH-].[Na+]>O>[CH3:15][C:7]1[C:6]([CH2:5][C:4]([OH:16])=[O:3])=[C:10]([CH3:11])[N:9]([CH2:12][CH:13]=[CH2:14])[N:8]=1
Reactant: C=CCn1nc(C)c(CC(=O)OCC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCn1nc(C)c(CC(=O)O)c1C
Yield: 48.1 %

Procedure:
5 grams of 3,5-dimethyl-1-allyl-pyrazol-4-acetic acid-ethyl ester were mixed with 25 milliliters methanol and 10 milliliters water. The mixture was heated to the boiling temperature and held there while 11.3 milliliters 2N aqueous sodium hydroxide were added dropwise at such rate, that the pH of 10 was maintained. The reaction mixture thus obtained was worked up by the procedure described in Example (1b). 2.1 grams 3,5-dimethyl-1-allyl-pyrazol-4-acetic acid melting at 139°-140° C. were obtained representing a yield of 48%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:20]([CH3:22])([CH3:21])[S:19](=[O:24])(=[O:23])[C@@H:18]2[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=3[C@@:17]2([CH3:37])[N:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:20]([CH3:22])([CH3:21])[S:19](=[O:24])(=[O:23])[C@@H:18]2[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=3[C@@:17]2([CH3:37])[N:16]=1)[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3CCC[C@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3CCC[C@H]2S(=O)(=O)C1(C)C
Yield: 92.2 %

Procedure:
A solution of tert-butyl-N-((4aR,11bR)-10-nitro-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tert-butoxycarbonyl-carbamate (390 mg, 0.707 mmol) in THF (5 ml) was hydrogenated using a balloon in the presence of palladium (10% wt.) on activated carbon (150 mg, 0.141 mmol) for 1.5 h. The mixture was filtered through pad of celite, filter cake was washed with THF, filtrate was concentrated to afford tert-butyl-N-((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tert-butoxycarbonyl-carbamate (340 mg, 0.652 mmol, 92% yield) which was used in the next step without purification. LC/MS (ESI+) m/z=522 (M+H).
Reaction SMILES: [C:1]([CH2:4][N:5]([CH:22]([CH3:24])[CH3:23])[C:6]([C:8]1[N:9]=[C:10]([N:13]2[CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]2)[S:11][CH:12]=1)=[O:7])(=[O:3])[NH2:2].[C:25]([O-:28])(=[S:27])[CH3:26].[K+]>CN(C)C=O>[C:25]([S:27][CH:15]1[CH2:14][N:13]([C:10]2[S:11][CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:4][C:1](=[O:3])[NH2:2])[CH:22]([CH3:23])[CH3:24])[N:9]=2)[CH2:16]1)(=[O:28])[CH3:26]
Reactant: CC(C)N(CC(N)=O)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(CC(N)=O)C(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
To a solution of 1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (516 mg, 1.37 mmol) (obtained as described in Reference Example 49(5)) in dimethylformamide (15 ml) was added potassium thioacetate (939 mg, 8.22 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (20:1) as the eluant to afford 3-acetylthio-1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidine (347 mg, yield 71%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6]2>C(O)(=O)C.Cl(O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6]2
Reactant: COC(=O)C1Cc2cc(OC)ccc2C1=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COC(=O)C1Cc2ccc(OC)cc2C1
Reaction time: 4 h
Yield: 46 %

Procedure:
A mixture of methyl 5-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (5.5 g, 25 mmol) in acetic acid (0.64 M) and perchloric acid (14.9 M) was suspended in a pressure vessel and was shook under a hydrogen atmosphere (30 psi) for 4 hours. The mixture was filtered through a pad of celite and washed with chloroform. The organic phase was washed with water (5×) until the pH was neutral, followed with a wash with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to provide methyl 5-methoxy-2,3-dihydro-1h-indene-2-carboxylate (696) (46%).