Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[N:20]=1.C1C(=O)N([Cl:29])C(=O)C1>CC#N>[Cl:29][C:5]1[C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:9][CH2:8][C:7]=2[N:20]=[C:3]([O:2][CH3:1])[C:4]=1[NH2:21]
Reactant: COc1nc2c(cc1N)C(C)CN(C(=O)C(F)(F)F)CC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1nc2c(c(Cl)c1N)C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (303 mg, 1.00 mmol) in MeCN (6 ml) was added a solution of NCS (134 mg, 1.00 mmol) in MeCN (6 ml). The resulting mixture was stirred for 2 h at 50° C. and then quenched with excess of sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 165 mg (49%) of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.28 (0.5H), 3.95 (2.5H), 3.88 (3H), 3.71 (2H), 3.61 (1H), 3.34 (1H), 3.16 (1H), 2.99 (1H), 1.13 (3H) ppm. To a solution of CuBr2 (43.0 mg, 0.19 mmol) and nBuNO2 (28.0 μl, 0.24 mmol) in MeCN (2.7 ml) was added a solution of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (54.0 mg, 0.16 mmol) in MeCN (2 ml) at room temperature. After leaving the mixture for 16 h at room temperature, it was heated at 50° C. for 4 h. After removal of MeCN under reduced pressure, the reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 45 mg (70%) of 3-bromo-4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H NMR (CDCl3) δ 4.29 (0.5H), 4.00 (0.5H), 3.90 (3H), 3.85 (1H), 3.75 (1H), 3.40 (1H), 3.30 (1H), 3.20 (1H), 3.10 (1H), 1.16 (3H) ppm. A mixture of 3-bromo-4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (60 mg, 0.15 mmol), K2CO3 (62 mg, 0.45 mmol), MeOH (2.4 ml) and H2O (0.5 ml) was heated at 55-60° C. for 1 h. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to give 45 mg (98%) of 3-bromo-4-chloro-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 3.89 (s, 3H), 3.58 (m, 1H), 3.22 (m, 2H), 3.09 (dd, 1H), 2.93 (m, 2H), 2.71 (dd, 1H), 1.24 (d, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:9]2)[O:7][NH:32]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (14.9 g, 35.87 mmol) was dissolved in MeOH (120 mL) and cooled to −40° C. Sodium hydroxide (1.495 g, 37.38 mmol) dissolved in water (14.4 mL) was added over 2 min and the resulting solution stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 2.2 mL, 35.90 mmol) was added over 1 min and stirring continued between −40° C. and −45° C. for 80 min. The reaction mixture was then poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (400 mL, 2400.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over Na2SO4 and evaporated. Crude cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (12.88 g, 94%) was isolated. MS m/z 385 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[N:23]=[CH:22][C:21]3[C:16](=[N:17][C:18](Br)=[CH:19][N:20]=3)[C:15]2=[O:25])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:30]1C=[CH:33][N:32]=[CH:31]1)[C:28]#[CH:29].C([N:37](CC)CC)C>CN(C)C=O.[Cu]I.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>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[N:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([C:29]#[C:28][CH2:27][N:30]4[CH:31]=[N:32][CH:33]=[N:37]4)=[CH:19][N:20]=3)[C:15]2=[O:25])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2ncc3ncc(Br)nc3c2=O)cc1
Reactant: CCN(CC)CC
Reactant: C#CCn1ccnc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2ncc3ncc(C#CCn4cncn4)nc3c2=O)cc1

Procedure:
The coupling of 4-(7-bromo-1-oxo-1H-3,5,8-triazaisoquinolin-2-ylmethyl)benzoic acid tert-butyl ester (0.70 g, 1.69 mmol) with 1-prop-2-ynyl-1H-imidazole (0.45 g, 4.22 mmol) using triethylamine (0.94 mL, 6.76 mmol), CuI (0.023 g, 0.12 mmol), and Pd(Ph3P)4 (0.08 g, 0.07 mmol) in dimethyl-formamide is carried out as described in Example 1, Step (2). The silica gel mesh is purified on a 3.5×18 cm silica gel column eluted with hexanes/ethyl acetate 1:1, methylene chloride/THF 7:1, then methylene chloride/THF 4:1. Evaporation and drying will afford the desired product.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:29][CH2:30]2)[CH:24]=1
Reactant: CC(C)Oc1ccc(Cl)cc1N1CCNCC1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Cl)cc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
To a suspension of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.241 g, 1.02 mmol, 1 eq) and 1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.382 g, 1.13 mmol, 1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.583 g, 2.75 mmol, 2.67 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (100% EtOAc) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.219 g, 25%). MS: APCI: M+1: 473.2 (Exact Mass: 472.22).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:12][CH:13]([CH3:24])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])=O)=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(O)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[N:9][N:8]2[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])=[C:13]([CH3:24])[O:12][C:7]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OC(C)C(=O)c2ccc(C)cc2C)n[nH]c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C)nn2c(-c3ccc(C)cc3C)c(C)oc12
Yield: 88 %

Procedure:
A mixture of 3-[2-(2,4-dimethyl-phenyl)-1-methyl-2-oxo-ethoxy]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (273 mg, 0.83 mmol), para-toluenesulfonic acid mono-hydrate (160 mg, 0.83 mmol) in toluene (15 ml) and AcOH (5 ml) is refluxed for 3 days. The reaction mixture is concentrated in vacuo and the residue is dissolved in EtOAc (40 ml). The organic solution is washed successively with Na2CO3 2M in water (2×20 ml) and brine (20 ml), dried over Na2SO4, filtered and concentrated to dryness. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, iso-hexane/TBME 98:2→7:3) to yield the title compound (227 mg, 0.73 mmol, 88%) as a colorless oil. TLC: RF=0.81 (iso-hexane/TBME 1:1); HPLC: AtRet=2.85; MS: m/z 313.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J 7.1, 3H), 2.20 (s, 3H), 2.34 (s, 3H), 2.36 (s, 3H), 2.41 (s, 3H), 4.26 (q, J 7.1, 2H), 7.17 (m, 1H), 7.24 (br. s., 1H), 7.31 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[OH-].[Na+].O.NC(C)(CC1C=CC=CC=1OC)C(O)=[O:24]>C(#N)C>[C:13]([NH:14][C:10]([CH3:17])([CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:11]([OH:24])=[O:16])(=[O:15])[NH2:12]
Reactant: COc1ccccc1CC1(C)NC(=O)NC1=O
Reactant: COc1ccccc1CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1CC(C)(NC(N)=O)C(=O)O

Procedure:
First, 4.40 g of 5-(2-methoxyphenylmethyl)-5-methyl-hydantoin was mixed with 2.64 g of sodium hydroxide and 3.5 g of water, and the mixture was subjected to reaction at 94° C. to 96° C. for 30 hours. The HPLC analysis (column: COSMOSIL 5C18-ARII (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=20/80, flow rate: 1.0 ml/min, detection wavelength: 210 nm, column temperature: 40° C.) of the reaction mixture showed the production of the title compound, 2-amino-3-(2-methoxyphenyl)-2-methyl propionic acid, and the raw material at an area ratio of 78.8:5.5:15.5.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[F:22].C(OCC)(=O)C>CN(C=O)C>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: N#Cc1ccc(CBr)c(F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cl
Product: N#Cc1ccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c(F)c1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
A solution of 2-amino-5-chloronicotinamide (150 mg) and 4-(bromomethyl)-3-fluorobenzonitrile (282 mg) in DMF (3 ml) was stirred at 100° C. for 24 hr. After cooling to room temperature, ethyl acetate was added, and the precipitated crystals were filtered. The obtained crystals were dissolved in methanol (3 ml) and partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0-9/1). 4N Hydrochloric acid-ethyl acetate solution was added to the obtained yellow oil, and the precipitated crystals were filtered and recrystallized to give the title compound (47 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].N[C:11]1N=C(O)C=CC=1.BrBr>C(O)(=O)C.O>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:11])=[CH:5][CH:4]=1
Reactant: Nc1cccc(O)n1
Reactant: Nc1nc(O)ccc1Br
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(N)n1
Reaction time: 0.25 h

Procedure:
In accordance with scheme 1, the compound of formula V (6-amino-5-bromo-pyridin-2-ol) may be prepared as described in Kelly, T. R.; Jagoe, C. T.; Gu, Z. Tetrahedron Letters 1991, 32, 4263-4266) as follows: To a solution of 6-amino-pyridin-2-ol in acetic acid at room temperature is added bromine and stirred for 15 min. The mixture is diluted with water and the precipitate is filtered off. The filtrate is extracted and the combined organic layers are dried and evaporated to dryness. Then a suspension of 6-amino-5-bromo-pyridin-2-ol is treated with KOH pellets and dimethylsulfate. The mixture is stirred for 4 h at room temperature and evaporated to dryness. The residue is purified and 3-bromo-6-methoxy-pyridin-2-yl-amine (IV) is obtained. Furthermore, a mixture of 3-bromo-6-methoxy-pyridin-2-yl-amine, phenylboronic acid (wherein the phenyl ring may be substituted by R1), Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium II) dichloromethane adduct in dioxane is heated to 110° C. for 2 h. The mixture is concentrated, diluted Na2CO3 aq. is added and extracted. The combined organic phases are dried and evaporated. The residue is purified to yield the corresponding compound of formula II, for example 6-methoxy-3-phenyl-pyridin-2-yl-amine. A mixture 6-methoxy-3-phenyl-pyridin-2-yl-amine (II) and ethoxycarbonyl isothiocyanate is stirred at room temperature for 2 h and afterwards evaporated to dryness. The obtained compound of formula III is then treated with a mixture of hydroxylamine hydrochloride and N-ethyldiisopropylamine (DIPEA). The mixture is heated to 80° C. for 16 h, evaporate to dryness, taken up in water and extracted with diethyl ether. The combined organic phases are dried and evaporated to yield, for example, 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine (Ia). A mixture of 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and a compound of formula R2Cl, for example 3-fluorophenyl carboxylic acid chloride, and NEt3 in dioxane is heated to 90° C. for 16 h. The mixture is purified to give a compound of formula I, for example 3-fluoro-N-(5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.OC1C2C(=NC(C)=CC=2)N=CC=1C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCCN)CC2)C=CC=CC=1>>[C:34]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:13]([C:3]3[CH:4]=[N:5][C:6]4[C:11]([C:2]=3[SH:1])=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=4)=[O:15])[CH2:27][CH2:28]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1ccc2c(S)c(C(=O)O)cnc2n1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Agent: NCCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Product: Cc1ccc2c(S)c(C(=O)NCCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)cnc2n1

Procedure:
The procedures of Example 1 are repeated except that 4-mercapto-7-methyl-1,8-naphthyridine-3-carboxylic acid, prepared according to the method described in Farmaco. Ed. Sci., 28, 722 (1973), and 4-(4-diphenylmethyl-1-piperazinyl)butylamine are employed in place of 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid and 4-(4-diphenylmethylene-1-piperidyl)butylamine to give N-[4-(4-diphenylmethyl-1-piperazinyl)butyl ]-4-mercapto-7-methyl-1,8-naphthyridine-3-carboxamide as oils, which is converted into fumarate in a conventional manner. The fumarate is recrystallized from ethanol - water to give the desired compound. m.p. 209° to 212° C.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:32])[NH2:14])=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (11.47 g), Lawesson's reagent (15.2 g) and tetrahydrofuran (150 ml) was stirred at 50° C. for 4 hr. The reaction mixture was concentrated, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (11.16 g, yield 93%) as yellow crystals. melting point 239-240° C.
Reaction SMILES: Cl.Cl.N1CCOC([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])C1.N1C=CC=CC=1.[CH2:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@@H:45]1NC)[CH3:43]>C1COCC1>[CH2:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@@H:45]1[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH:18]=1)=[O:12])[CH3:43]
Reactant: CCCCc1nnc(C(=O)NCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CCN1CCC[C@@H]1NC
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCc1nnc(C(=O)NC[C@H]2CCCN2CC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (Example 90, 0.18 mmol, 0.1 g) and 0.1 mL of pyridine in 2 mL of THF was added ((R)-1-ethyl-pyrrolidin-2-yl)-methylamine (0.4 mmol, 0.05 g). The mixture was shaken at room temperature, upon completion, the solvent was removed and the residue was chromatographed with 4% methanolic solution of ammonia (2.0 M ammonia in methanol) in EtOAc afforded 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid ((R)-1-ethyl-pyrrolidin-2-ylmethyl)-amide. LCMS: m/z 464.9. 1H NMR (400 MHz, CD3OD) δ 8.27 (1H, s), 7.42 (2H, d), 7.09 (2H, d), 4.44-4.40 (1H, m), 4.00-3.96 (1H, m), 3.80-3.68 (4H, m), 3.20-3.10 (4H, m), 2.34-2.28 (1H, m), 2.16-2.02 (5H, m), 1.84-1.80 (2H, m), 1.64-1.27 (13H. m), 0.83 (3H, t).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([NH:15][C:16]2[C:17](=[O:33])[N:18]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:25](OC)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13]1.C([Mg]Cl)(C)C.Cl>C1COCC1.O>[CH:1]1([NH:4][C:25](=[O:26])[C:24]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]4([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[OH:5])[CH2:14][CH2:13]4)[C:17]3=[O:33])[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To cyclopropylamine (0.60 mL, 8.46 mmol) and Methyl 3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 167c, 0.331 g) in THF (5 mL) at rt was added isopropylmagnesium chloride (0.85 mL of a 2M solution in THF) dropwise. The reaction was stirred for 1 h and then further isopropylmagnesium chloride (0.85 mL of 2M solution in THF) was added and the reaction stirred for 16 h. Water and 2M aqueous HCl were cautiously added and the aqueous layer extracted with dichloromethane (2×). The combined organics were dried (Na2SO4) and the solvent removed in vacuo to give the subtitle product as a yellow solid (0.342 g).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[Ni:5](Cl)Cl>>[N+:1]([O-:4])([O-:3])=[O:2].[Ni+2:5].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cl[Ni]Cl
Product: O=[N+]([O-])[O-]
Product: [Ni+2]

Procedure:
Where hydrochloric or nitric acid is used as the leachant, nickel chloride or nickel nitrate is formed and concentrated following ion exchange. The nickel chloride or nickel nitrate solution is subjected to pyro-hydrolysis to form nickel oxide and recycle acid, e.g. HCl or HNO3.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[CH2:15][C@@H:16]([C:22]1[CH:43]=[CH:42][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34]C(=O)OC(C)(C)C)[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:42]=[CH:43][C:22]([C@@H:16]([C:17]2[CH:21]=[CH:20][O:19][N:18]=2)[CH2:15][C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:44])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a cooled solution (0° C.) of carbamate 27.2 (430 mg, 0.719 mmol) in DCM (4 mL), was slowly added TFA (4 mL). The reaction mixture was allowed to slowly warm to room temperature over three hours. The mixture was then concentrated to dryness under reduced pressure and dissolved in DCM (100 mL). The resulting mixture was extracted with saturated sodium bicarbonate solution (1×30 mL). The aqueous layer was then extracted with DCM (1×50 mL). The organic layers were then combined and washed with brine (1×50 mL) and dried over magnesium sulfate. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 20 to 60% EtOAc:DCM) to give 27.3 (204 mg). MS ESI (pos.) m/e 498.1 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (1H, d, J=1.6 Hz), 7.09-7.29 (8H, m), 6.75-6.88 (4H, m), 6.68 (1H, dd, J=7.6, 2.2 Hz), 6.06 (1H, d, J=1.6 Hz), 4.89 (2H, s), 4.67 (1H, dd, J=8.2, 6.7 Hz), 4.50-4.58 (1H, m), 4.01-4.06 (2H, m), 3.94 (1H, dd, J=17.6, 8.6 Hz), 3.42-3.49 (1H, m), 3.13 (1H, dd, J=13.5, 3.3 Hz), 2.68 (1H, dd, J=13.5, 9.6 Hz).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=2.S(OC)(O[CH3:23])(=O)=O>[OH-].[Na+].CO>[CH3:23][N:6]1[C:7]2[C:12](=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=2)[C:13](=[O:15])[CH:14]=[C:5]1[CH2:4][C:3]([OH:2])=[O:18]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)Cc1cc(=O)c2c(OC)cccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc2c1c(=O)cc(CC(=O)O)n2C

Procedure:
The starting material can be obtained by condensation of 3-amino-4-chloroanisole with acetonedicarboxylic acid dimethyl ester to give 4-oxo-5-methoxy-8-chloro-1,4-dihydro-quinoline-2-acetic acid methyl ester, hydrogenation on 5% Pd-on-charcoal in dioxan at 6 atmospheres and 60° to give 4-oxo-5-methoxy-1,4-dihydroquinoline-2-acetic acid methyl ester, reaction with dimethyl sulphate in sodium hydroxide solution to give 1-methyl-4-oxo-5-methoxy-1,4-dihydroquinoline-2-acetic acid, hydrogenation on PtO2 in methanol at 20° and normal pressure to give 1-methyl-4-oxo-5-methoxy-1,2,3,4-tetrahydroquinoline-2-acetic acid, reaction, via the chloride and the amide, to give the nitrile, ether splitting by means of BBr3 to give 1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydroquinoline-2-acetonitrile, reaction with Raney nickel to give 1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydroquinoline-2-acetaldehyde, condensation with 2-phenyl-2-thiazolin-5-one to give 2-phenyl-4-[2-(1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydro-2-quinolyl)-ethylidene]-2-thiazolin-5-one, condensation with acetone dicarboxylic acid monomethyl ester-monoamide to give 4-thiobenzamido-1,4,4a,5,5a,6,11,12-octahydro-3,10,12-trihydroxy-6-methyl-1,11-dioxo-6-aza-naphthacene-2-carboxamide (mixture of stereoisomers), epimerization with pyridine to give 4-de-dimethylamino-4-thiobenzamido-6-methyl-12a-dehydroxy-6-aza-tetracycline and hydroxylation.