Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[O:11][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1)=O.[NH2:21][C:22]([CH:26]([F:28])[F:27])=[CH:23][C:24]#[N:25]>C(O)(=O)C.C(O)CCC>[C:24]([C:23]1[CH:1]([C:3]2[O:11][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:5]=3[CH:4]=2)[C:23]([C:24]#[N:25])=[C:22]([CH:26]([F:28])[F:27])[NH:21][C:22]=1[CH:26]([F:28])[F:27])#[N:25]
Reactant: N#CC=C(N)C(F)F
Reactant: O=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Solvent: CC(=O)O
Solvent: CCCCO
Product: N#CC1=C(C(F)F)NC(C(F)F)=C(C#N)C1c1cc2c(NC(=O)c3ccccc3)nccc2o1

Procedure:
A solution of 200 mg (0.75 mmol) N-(2-formylfuro[3,2-c]pyridin-4-yl)benzamide (Example 3A) in acetic acid (1.3 ml) was treated with a solution of 200 mg (1.69 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 1-butanol (1.0 ml). The mixture was heated to reflux temperature for 2 h. Upon cooling, the reaction mixture was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aq. sodium bicarbonate solution. The organic layer was separated, washed with brine and with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 100% methanol) yielding 28 mg (8% of th.) of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([OH:20])=[O:19])[NH:15]2)=[CH:11][CH:10]=1)([O-:8])=[O:7].[C:21](=O)(O)[O-].[Na+]>CO>[N+:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[NH:15]2)=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Yield: 81 %

Procedure:
Sulfuric acid (1 mL, 18.76 mmol) was added to a suspension of 6-nitro-1H-indole-2-carboxylic acid (0.5 g, 2.425 mmol) in methanol (5 mL). The mixture was heated to reflux for 2 h. The reaction mixture was cooled to RT, poured into ice/water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate, and concentrated to give the title compound (0.433 g, 81%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 9.31 (s, 1H), 8.41 (s, 1H), 8.05 (dd, 1H), 7.79 (d, 1H), 7.29 (s, 1H), 3.70-4.24 (m, 3H). MS: m/z 221 (M+1).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:30][C:31]([OH:33])=O)[C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:14]=1.[C:34]([O:38][C:39]([NH:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30][C:31]([N:44]2[CH2:45][CH2:46][C@H:42]([NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:43]2)=[O:33])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (9.39 g, 0.049 mol) was added to a solution of {(4-Bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid 2 (13.82 g, 0.038 mol), (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (9.13 g, 0.049 mol), 1-hydroxy-7-azabenzotriazole (6.67 g, 0.049 mol) and N-methylmorpholine (8.4 mL, 0.08 mol) in DMF (150 mL). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid (×3), brine, saturated aqueous sodium bicarbonate (×2) and brine. The title compound began to crystallize during work-up and was collected by filtration. The mother liquor was concentrated to provide a further quantity of product. Total yield of title compound: 17.43 g, 86%. 1HNMR (300 MHz) (CDCl3) δ 1.45 (6H, s), 1.60 (3H, s), 1.7-2.3 (2H, m), 3.4-3.8 (4H, m), 4.1-4.9 (3H, m), 6.36 (1H, d, J=16 Hz), 7.36 (2H, d), 7.2-7.4 (5H, m), 7.55 (2H, d) and 7.70 (1H, d, J=16 Hz).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (80 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (83.0 mg), tetrakis(triphenylphosphine)palladium(0) (22.6 mg) and potassium carbonate (54.0 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (46.2 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:7][Br:20])[CH3:2]
Reactant: CCOC(=O)C=C(C)Oc1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1cccc2ccccc12
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.15 g, 4.48 mmol) in carbon tetrachloride (24.9 mL) was treated with N-bromosuccinimide (0.87 g, 4.93 mmol) and benzoyl peroxide (87 mg, 0.35 mmol). The reaction was then heated to reflux for 5 h. At this time, the reaction was cooled to 25° C. and then was placed in the freezer over the weekend. At this time, the reaction was removed from the freezer and allowed to thaw. The resulting precipitate was removed by filtration and was rinsed with carbon tetrachloride (5 mL). The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded impure 4-bromo-3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.28 g, 85%) as a light purple oil. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[CH:31][C:32]=1F>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:32]2[CH:31]=[CH:30][C:29]([N+:34]([O-:36])=[O:35])=[CH:28][C:27]=2[Cl:26])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
A mixture of 10.0 g (0.032 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro -3-methyl-1,2,4-triazol-5(1H)-one, 5.52 g (0.040 mole) of potassium carbonate, and 7.02 g (0.040 mole) of 3-chloro-4-fluoronitrobenzene in 60 ml of N,N-dimethylformamide was stirred at room temperature for approximately 18 hours. The reaction mixture was poured into ice-water. This aqueous mixture was extracted with diethyl ether. The extract :;as dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel to yield 10.4 g of 1-[2,4-dichloro-5-(2-chloro-4-nitrophenoxy)phenyl]-4-difluoromethyl -4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid, m.p. 135°-135.5° C., compound 179 of Table 1.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(OCC)=O)C.CC(C)([O-])C.[K+].[Cl:18][C:19]1[N:20]=[C:21]([CH2:46][CH3:47])[NH:22][C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40]([CH:42]=O)[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]>C1COCC1>[Cl:18][C:19]1[N:20]=[C:21]([CH2:46][CH3:47])[NH:22][C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40](/[CH:42]=[CH:9]/[C:10]#[N:11])[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C=O)c3)c2F)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(/C=C/C#N)c3)c2F)[nH]1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
A solution of diethylphosphonoacetonitrile (15 μL, 0.094 mmol) in THF (1 mL) was cooled to 5° C. in an ice bath and potassium t-butoxide (1 M in THF, 94 μL, 0.094 mmol) was added dropwise. The reaction was stirred at 5° C. for 30 min and a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-2-ethyl-1H-imidazole-5-carboxamide (40 mg, 0.085 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at 5° C. for 30 min, warmed to room temperature and stirred for an additional 60 min. The reaction was quenched with water (1 mL) and concentrated to a yellow oil. The crude material was purified by column chromatography (10% to 100% EtOAc/hexanes gradient) to afford the title compound (32 mg, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.69 (s, 1H), 8.05 (t, 1H), 7.58 (d, 1H), 7.53 (s, 1H), 7.47-7.44 (m, 1H), 7.31 (t, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 6.58 (d, 1H), 4.49 (d, 2H), 2.55 (q, 2H), 1.13 (t, 3H). MS: m/z 493, 495 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH2:8]([N:12]=[C:13]=[S:14])[CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:12]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:13]1=[S:14])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: CC(C)CN=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(CC(C)C)C1=S
Yield: 23.2 %

Procedure:
The title compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 5.7 g of isobutyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Title compound (2.3 g) was obtained as an oil. Anal. Calcd. for. C9 H16N2O S: C, 53.97; H, 8.05; N, 13.99. Found: C, 54.01; H, 8.21; N, 14.00. Mass spectrum (EI, M.+) m/z 200.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.O.NN>[Ni].CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1cc([N+](=O)[O-])c2ncccc2c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc(N)c2ncccc2c1
Yield: 62.8 %

Procedure:
In a similar fashion using route 6 general procedure 14, 6-methyl-8-nitroquinoline (Intermediate 42) (300 mg, 1.6 mmol), Raney nickel (60 mg, 20% wt) hydrazine hydrate (0.32 ml, 6.30 mmol) and MeOH (8 ml) gave the title compound (159 mg) which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[N:30]=2)=[C:25]([CH:28]=1)[CH:26]=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:26]1[C:25]1[CH:28]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: Cc1noc(-c2ccc(Cl)cc2C=O)n1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccc(Cl)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (25 mg, 0.10 mmol) and 5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (27 mg, 0.12 mmol) in DMF (5.0 mL) is added oxone (60 mg, 0.10 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2) and dried with Na2SO4. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 5% MeOH in CH2Cl2 as the eluent to afford the title compound (30 mg, 45%) as a white solid. LCMS (ESMS): m/z 460.20 (M++1)
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C:11](=[O:29])[CH2:10]1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:11](=[O:29])[CH2:10]1
Reactant: CN1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CC2CCNCC2)C(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred solution of tert-butyl 4-[(4-methyl-2-oxo-piperazin-1-yl)methyl]piperidine-1-carboxylate (98 mg, 0.3147 mmol) in DCM (2 mL) and the reaction stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 5 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo to give 4-methyl-1-(piperidin-4-ylmethyl)piperazin-2-one as a colourless oil (65 mg, 98% Yield). MS (ES+) 212.0.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>C(#N)C>[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:22]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: NCC1CCCNC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC(CN)C3)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.9 %

Procedure:
A mixture of 1.04 g (3.84 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 100 ml of acetonitrile and 1.32 g (11.5 mmole) of 3-aminomethylpiperidine [J. Org. Chem., 44, 4536 (1979)] were stirred at room temperature for four days. The reaction was filtered and the precipitate dissolved in aqueous ammonia, pH 10.5. The solution was filtered and the solvent removed at reduced pressure. The product was washed with water, then ether until dry to give 1.23 g of 7-[3-(aminomethyl)-1-piperidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 120°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: Nc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc(NCc2ccc(Br)cn2)cc1

Procedure:
To 5-Bromo-pyridine-2-carbaldehyde (52, 1.00 g, 5.38 mmol) in acetonitrile (50.0 mL) were added p-chloroaniline (53, 0.686 g, 5.38 mmol), triethylsilane (6.00 mL, 0.0376 mol) and trifluoroacetic acid (3.00 mL, 0.0389 mol). The reaction was heated to reflux for 3 hours. The reaction was concentrated, poured into water and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (54, 0.75 g, 47.0%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([N:19]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[N:10]([CH3:39])[N:9]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([S:26]([N:19]([C:11]2[N:10]([CH3:39])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COCCOCN(c1c(-c2ccccc2)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCCOCN(c1c(-c2ccccc2)c(OCCO)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-[(5-{{[4-(tert-butyl)phenyl]sulfonyl}[(2-methoxyethoxy)methyl]amino}-1-methyl-4-phenyl-1H-pyrazol-3-yl)oxy]ethyl acetate (Preparation 16) (1.112 g) in solution in methanol (100 ml) was added a solution of potassium carbonate (890 mg) in water (25 ml), at room temperature. The reaction was stirred at room temperature for 1.5 hours, and then overnight. The reaction was stripped down and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The aqueous layer was extracted with dichloromethane (10 ml). The organics were combined and back-washed with brine (10 ml). The solution was dried on magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product as an off white solid (528 mg)
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]([O:29]CC)=[O:28])[CH:21]=3)[NH:16]2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]([OH:29])=[O:28])[CH:21]=3)[NH:16]2)=[O:7])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NC(=O)c1ccc(F)cc1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2NC(=O)c2ccc(F)cc2)Nc2ccc(C(=O)O)cc21

Procedure:
To a stirred solution of ethyl 2-(2-(4-fluorobenzamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (about 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water at room temperature. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(4-fluoro-benzoylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid LC/MS m/e obsd. (ESI+) [(M+H)+] 419.10.
Reaction SMILES: COC1[C@@H](C(C)C)N=[C:6]([O:17][CH3:18])[C@H:7]([CH2:9][C:10]2[C:11]([CH3:16])=[N:12][O:13][C:14]=2[CH3:15])[N:8]=1.Cl.[O:23]1CCOCC1>>[NH2:8][C@@H:7]([CH2:9][C:10]1[C:11]([CH3:16])=[N:12][O:13][C:14]=1[CH3:15])[C:6]([O:17][CH3:18])=[O:23]
Reactant: C1COCCO1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1c(C)noc1C
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1c(C)noc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2R,5S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(3,5-dimethyl-4-isoxazolylmethyl)pyrazine (2 g, 6.8 mmol), 1.0M HCl (13.6 ml, 13.6 mmol) and dioxane (13.6 ml) was stirred at ambient temperature overnight under N2. Dioxane was removed under reduced pressure and the water phase extracted with diethyl ether (20 ml). Aqueous ammonia was added to the water phase until pH 9, extracted with CHCl3 (3×30 ml), dried (MgSO4) and the solvent removed under reduced pressure. The valine methyl ester was removed by bulb-to-bulb distillation at 40°-50° C. (0.05 mbar). The undistilled title compound was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:11]([OH:42])[C:12]2[N:13]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[C:6]([F:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:50][CH3:51]>CN(C=O)C.CCOC(C)=O>[CH2:50]([O:9][C:7]1[C:6]([F:10])=[C:5]([CH:11]([C:12]2[N:13]([C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[OH:42])[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=1)[CH3:51]
Reactant: CCI
Reactant: CCc1cc(O)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CC)cc(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
To a solution of Intermediate 448.2 (1.00 g, 1.80 mmol) in 10 mL DMF at rt, were added K2CO3 (229 mg, 2.16 mmol) and iodoethane (432 μL, 5.4 mmol). The mixture was stirred at rt for 19 h, then diluted with EtOAc. The organic phase was washed with H2O (2×), sat. Na2SO3 and brine, dried (Na2SO4), filtered through 1″ SiO2 and concentrated to afford 1.05 g of Intermediate 448.3 as a colorless solid. LCMS (2 min gradient) RT=1.92 min, 583.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](=[S:13])[N:12]=2)=[CH:4][CH:3]=1.[Na].Br[C:16]1[S:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([S:13][C:16]3[S:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: S=C1N=NC(c2ccc(Cl)cc2)=N1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: [Na]
Product: O=[N+]([O-])c1cnc(Sc2nc(-c3ccc(Cl)cc3)n[nH]2)s1

Procedure:
The title compound was prepared in the manner described in Example 1. Substituting 4-chlorobenzoyl chloride for the benzoyl chloride in Example 1 gave 4-chlorobenzoyl thiosemicarbazide and then 3-(4-chlorophenyl)-1,2,4-triazole-5-thione. Reaction of 2.34 g of the sodium salt of 3-(4-chlorophenyl)1,2,4-triazole-5-thione with 2.09 g of 2-bromo-5-nitrothiazole as in Example 1 yielded 1.5 g of 3-(4-chlorophenyl)-5-[(5-nitrothiazol-2-yl)mercapto]-1,2,4-triazole, a light brown solid, MP 181-184° C.