Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:23]=[CH:24][C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][CH:4]=3)=[C:10]([N+:25]([O-:27])=[O:26])[CH:11]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.1 %

Procedure:
The product of Example 13A (200 mg, 0.4501 mmol) was dissolved in anhydrous pyridine (4 mL) under a nitrogen atmosphere, treated with methanesulfonyl chloride (0.084 mL, 1.080 mmol), and stirred at room temperature for 19 hours. The solvent was removed by rotary evaporation under vacuum, and the residue dissolved in methylene chloride (100 mL) and washed with 1N aqueous hydrochloric acid (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the title compound as a yellow solid (233 mg, 99%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][O:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)=[O:10]>>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C:9]([O:8][CH3:7])=[O:10])=[CH:12][CH:13]=1)=[O:16]
Reactant: NCCCCO
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(C(=O)NCCCCO)cc1

Procedure:
The same procedure as a series of reactions of Example 17 was carried out, except that 4-amino-1-butanol was used in place of the compound 16 and 4-(methoxycarbonyl)benzoic acid was used in place of 1H-imidazole-2-carboxylic acid, to obtain the title compound having the following physical properties.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[O:13][CH3:14].CO>CCOCC>[CH3:14][O:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: COC(=O)c1cccc(C)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: COc1c(C)cccc1CO
Reaction time: 0.08 h

Procedure:
LiBH4 (5.10 g, 0.23 mmol) was added to a solution of 2-methoxy-3-methyl-benzoic acid methyl ester (8.46 g, 47.00 mmol) in Et2O at 0° C. The reaction mixture was stirred for 5 minutes, MeOH (9.50 mL, 0.23 mmol) was added in a dropwise fashion. The reaction mixture was then stirred for 30 minutes, and was quenched into 1N NaOH. The resulting solution was extracted with Et2O (3×200 mL) and the combined organic phases were washed with brine (1×150 mL), dried over MgSO4 and concentrated to afford the title compound.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f17) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=O.[O:12]=[S:13]([Cl:15])[Cl:14].[NH3:16]>>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7]#[N:16])=[CH:5][N:4]=1.[O:12]=[S:13]([Cl:15])[Cl:14]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: N
Solvent: O=S(Cl)Cl
Product: N#Cc1cnc(Cl)c(Cl)c1

Procedure:
2,3-Dichloro 5-cyano pyridine 4 was prepared from 5,6-Dichloronicotinic acid (ALDRICH). The acid was converted to the acid chloride by treatment with excess SOCl2 and refluxed for 1.5 hours. The intermediate acid chloride was reacted with ammonia (aqueous) to get the primary amide which on dehydration with excess SOCl2 at reflux condition afforded 2, 3-Dichloro 5-cyano pyridine 4. [Ref. George et al J. Org. Chem, 1979, 44, 2697.]
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([C:12]1([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OCC3C=CC=CC=3)[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[H][H].[ClH:38]>C(O)C.[Pd]>[ClH:38].[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([C:12]1([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCCCC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of 6 (0.111 g, 0.232 mmol) in 2% HCl in ethanol (60 mL) was added palladium on activated charcoal (0.025 g) under an atmosphere of argon. The mixture was subsequently saturated with hydrogen using a hydrogen balloon. After 4 h, the mixture was flushed with argon, filtered using ethanol and methanol. Preparative HPLC afforded 7 (0.055 g, 69%) as a bright yellow solid. 1H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.52-7.34 (m, 1H), 6.94 (m, 2H), 6.53 (br s, 2H), 2.74 (t, J=7.4 Hz, 2H), 2.65 (m, 1H), 2.63-2.56 (m, 1H), 2.54 (m, 1H), 2.44 (m, 1H), 2.31 (m, 1H), 2.21 (m, 1H), 2.02 (m, 1H), 1.52 (m, 1H), 1.48-1.38 (m, 1H), 1.26 (m, 2H). MS (ESI) m/z calcd for C17H21N4O4 [M+H]+ 345.4, found 345.7.
Reaction SMILES: [C:1]1([C:7]([N:20]=[N+:21]=[N-:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([OH:27])[CH2:24][C:25]#[CH:26]>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:20]2[CH:26]=[C:25]([CH2:24][CH2:23][OH:27])[N:22]=[N:21]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCCO
Reactant: [N-]=[N+]=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1

Procedure:
In toluene (90 ml) were dissolved triphenylmethyl azide (8.23 g) and 3-butyn-1-ol (2.2 ml). The solution was heated for 60 hours under reflux. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 150 g, developing solvent: ethyl acetate). The resulting crystalline product was washed with isopropyl ether to give the title compound (3.06 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][O:9][C:10]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([S:21]([O-:24])(=[O:23])=[O:22])=[C:14]([N+:25]([O-:27])=[O:26])[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+]>O.CO>[S:21]([C:15]1[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]([C:10]([O:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:11])=[CH:13][C:14]=1[N+:25]([O-:27])=[O:26])([OH:24])(=[O:23])=[O:22]
Reactant: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(S(=O)(=O)[O-])c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(S(=O)(=O)O)c([N+](=O)[O-])c1

Procedure:
11.20 parts of sodium 4-(2-cyclohexylethoxycarbonyl)-2,6-dinitrobenzenesulfonate was dissolved in 60.0 parts of ion-exchanged water and 60 parts of methanol. The solution was passed thrice through a column filled with 32.07 parts of ion-exchange resin (Duolite C20 H type, manufactured by Sumitomo Chemical Co., Ltd.). After concentrating to eliminate methanol, the concentrate was freeze-dried to obtain 9.87 parts of 2-cyclohexylethyl 4-sulfo-3,5-dinitrobenzoate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.CCN(C(C)C)C(C)C.[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH:24]1[N:33]=[C:34]=[O:35])[CH2:30]2.Cl>C(Cl)Cl>[CH:25]12[CH2:31][CH:29]3[CH2:28][CH:27]([CH2:32][CH:23]([CH2:30]3)[CH:24]1[NH:33][C:34]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)=[O:35])[CH2:26]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 19.8 %

Procedure:
A vial was charged with (R)-tert-butyl pyrrolidin-3-ylcarbamate (21 mg, 0.11 mmol) and i-Pr2NEt (0.025 mL, 0.14 mmol). A solution of 2-adamantyl isocyanate (25 mg, 0.14 mmol) in CH2Cl2 (2 mL) was added with stirring. After stirring overnight the mixture was applied to a 10-mL ChemElut cartridge that had been prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was applied to a 2-g silica SPE cartridge. The cartridge was eluted sequentially with 0, 10, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford six fractions. Fractions 4 and 5 were pooled and concentrated to afford (R)-tert-butyl 1-(2-adamantylcarbamoyl)pyrrolidin-3-ylcarbamate (7.9 mg, 15%). LC-MS Method 1, tR=1.83 min, m/z=364; 1H NMR (CDCl3) 1.42 (s, 9H), 1.60-1.95 (15H), 2.17 (m, 1H), 3.21 (m, 1H), 3.46 (m, 2H), 3.61 (m, 1H), 3.96 (m, 1H), 4.22 (1H), 4.53 (d, 1H), 4.72 (1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])[NH:11]1.II.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C-:13]([N+:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1
Agent: II
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2nn(-c3c(Cl)cc(Cl)cc3Cl)c(=O)[c-]2-[n+]2ccccc2)c1
Temperature: 0 °C

Procedure:
A mixture of 7.1 g of 1-(2,4,6-trichlorophenyl)-3-[2-chloro-5-(n-tetradecanamido)anilino]-5-pyrazolone, 2.5 g of iodine and 100 ml of pyridine was heated on a steam bath for 5 hours. After cooling, the reaction mixture was poured into a large volume of ice water. The precipitate was collected by filtration and dried. The powder was recrystallized from a solvent mixture of hexane and ethyl acetate to give 4.8 g of Compound 18 as yellow crystals having a melting point of 124° to 128°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)=[CH:30][CH:29]=1)[C:22](N(OC)C)=[O:23])[CH3:19]>>[CH2:18]([O:20][CH:21]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)=[CH:32][CH:33]=1)[C:22]([C:15]1[O:14][C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1)=[O:23])[CH3:19]
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC
Reactant: CCOC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: CCOC(C(=O)c1ccc(-c2cc(OC)c(OC)c(OC)c2)o1)c1ccc(-c2nnc(C)o2)cc1

Procedure:
2-Ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanone was prepared from 2-(3,4,5-trimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.060 g, 15% yield). MS: m/z 479.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:16]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:22]=[CH:21][C:20]=2[F:32])=[C:15]([F:33])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][C:7]([O:9]C(C)C)=[O:8])#[N:2].[Li+].[OH-]>C1COCC1.O>[C:1]([C:3]1[C:16]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:22]=[CH:21][C:20]=2[F:32])=[C:15]([F:33])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(OCC(=O)O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of isopropyl 2-[2-cyano-4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (220 mg, 0.48 mmol, 1 eq) in a mixture of THF (10 mL) and water (10 mL) was added LiOH (20 mg, 0.96 mmol, 2 eq). The reaction was stirred for 3 h then the THF removed in vacuo. The aqueous solution that remained was acidified to pH 4 with 3M HCl and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was triturated with a mixture of 2-methoxy-2-methylpropane (5 mL) and petroleum ether (20 mL) to give the desired product as an off-white solid (110 mg, 56%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]=[C:7]([NH:10]C(=O)C)[S:8][CH:9]=1)[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)[CH3:2]
Reactant: CCOCc1csc(NC(C)=O)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCOCc1csc(N)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To N-(4-ethoxymethyl-thiazol-2-yl)-acetamide (35 mg, 0.175 mmol) in THF (2 ml) was added 6N HCl (2 ml). The reaction was heated at 60° C. for 4 hours, stirred at room temperature overnight and then heated at 60° C. for additional 3 hours. The solution was concentrated to afford 4-ethoxymethyl-thiazol-2-ylamine as a viscous yellow oil (22 mg, 65% ). LC/MS m/z 159.05 (M+1)+; HPLC Rt: 0.34 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[N:13]1([CH2:18][CH2:19]O)[CH:17]=[CH:16][N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[N:13]1([CH2:18][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]3)=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: OCCn1ccnc1
Reactant: O=C1CCNc2cc(O)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCNc2cc(OCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 11.7 %

Procedure:
Under N2, a solution of 0.8 g (5.0 mmol) of 7-hydroxy-1,2,3,4-tetrahydro-4-quinolinone in 20 mL of THF was treated with 0.62 g (5.5 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and 1.13 (5.0 mmol) of tripenylphosphine. The mixture was warmed to effect solution, then allowed to cool to room temperature. This was then treated over 10 minutes with 0.8 mL (5.0 mmol) of diethyl azodicarboxylate. Some solid formed and the mixture was allowed to stir at room temperature for 3 days. The mixture was diluted with EtOAc and filtered. The filtrate was washed twice with H2O, saturated NaHCO3, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (90/10), gave 150 mg (11.8% yield) of the product as a golden oil. The structure was confirmed by mass spectroscopy. MS m/z 258 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7](Cl)[N:6]=2)[CH2:3][CH2:2]1.[NH3:14].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH:11][CH3:12])[N:8]=[C:7]([NH2:14])[N:6]=2)[CH2:3][CH2:2]1
Reactant: N
Reactant: CNc1nc(Cl)nc(NC2CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(N)nc(NC2CC2)n1
Temperature: 140 °C

Procedure:
A mixture of 12.7 g of 2-cyclopropylamino-4-methylamino-6-chloro-s-triazine, 17.4 g of 28% aqueous ammonia solution and 30 ml of dioxan is heated at 140° C. in an autoclave for 4 hours. After cooling, the reaction mixture is poured into 350 ml of a solution, which has been cooled to 0° C., of potassium carbonate in water and extracted with 1:1 benzene/ether. After drying over sodium sulfate, the solvents are removed in vacuo and the residue is recrystallised from isopropanol/hexane; melting point 159°-162° C.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]([CH3:30])[C:27](=[O:29])[CH:28]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]([CH3:30])[C:27](=[O:29])[CH:28]=2)=[C:16]([F:21])[CH:15]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of i-Pr2NH (0.39 mL, 2.80 mmol) in THF (4 mL) at 0° C. was added n-BuLi (1.1 mL, 2.80 mmol, 2.5 M solution in hexanes). After stirring 15 minutes, the mixture was cooled to −78° C. 4-Bromo-2-fluorophenylamine (0.38 g, 2.0 mmol) was added. After vigorous stirring for 10 minutes, a mixture of the 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g, 0.80 mmol) in THF (5 mL) was added. The dry-ice bath was removed after 30 minutes, and the reaction mixture was stirred for 17 hours at room temperature. The reaction mixture was treated with a 10% aqueous HCl solution (15 mL), extracted with EtOAc, dried (MgSO4), and concentrated. Trituration with methylene chloride gave 0.21 g (77%) desired product. MS APCI (−) m/z 339, 341 (M−, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 9.61 (s, 1H), 8.53 (s, 1H), 7.69 (dd, 1H), 7.46 (m, 2H), 3.41 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[F:22])=[CH:11][C:10]([C:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=1)=[C:9]([O:36][CH3:37])[CH:8]=2)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:36][CH3:37])=[C:10]([C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=3)[CH:11]=2)[N:6]=[N:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1=CCNCC1
Yield: 79.6 %

Procedure:
A solution of tert-butyl 4-(3-carbamoyl-4-(2-fluoro-4-methylphenylamino)-7-methoxycinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 53, 1.5 g, 2.96 mmol) in CH2Cl2 (11.84 mL) and trifluoroacetic acid (11.84 mL, 153.68 mmol) was stirred for 16 hours, concentrated under reduced pressure, and the residue purified with silica chromatography CH2Cl2/5% MeOH (1% NH4OH) to give 960 mg (80%) product. m/z 408.
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:30])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH2:1]([N:8]([C@H:16]([C@@H:24]([OH:30])[CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -20 °C
Yield: 56.5 %

Procedure:
2(S)-(N,N-Dibenzylamino)-1-phenyl-3-oxo-6-methylheptane (100 g) was dissolved in a mixture of methanol (500 ml) and tetrahydrofuran (500 ml), and the solution was cooled to -20° C. To the solution was portionwise added sodium borohydride (63 g) at said temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (500 ml) and water (500 ml) were added to the residue for extraction. The water layer was re-extracted with ethyl acetate (250 ml ). The combined organic layer was washed with saturated brine (500 ml), and the organic layer was concentrated. Water (100 ml) was added to the residual oily substance, and azeotropic distillation was performed. After 8 times of azeotropic distillation, toluene (100 ml) was added. Additional azeotropic distillation gave 2(S)-(N,N-dibenzylamino)-1-phenyl-3(S)-hydroxy-6-methylheptane (56.8 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH3:24]>>[NH2:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1Cl
Reactant: N
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-6-phenoxyquinoline-3-carboxylate (Example 8b) and ammonia as a off-white solid (82%). 1H NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=8.0 Hz, 3H), 4.35 (q, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 7.40 (m, d, 2H), 7.46 (dd, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 8.13 (d, J=4.0 Hz, 1H), 8.27 (bs, 2H), 8.87 (s, 1H). MS 309 (MH+).
Reaction SMILES: [C:1]([C:5]([CH2:7][CH3:8])=O)([CH3:4])([CH3:3])[CH3:2].[C:9]([O:13][C:14](=[O:17])[NH:15][NH2:16])([CH3:12])([CH3:11])[CH3:10]>CO.C(O)(=O)C>[C:9]([O:13][C:14]([NH:15][N:16]=[C:5]([CH2:7][CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCC(=O)C(C)(C)C
Solvent: CC(=O)O
Solvent: CO
Product: CCC(=NNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tert-butylethylketone (5 g) was mixed with tert-butylcarbazate (6.4 g, 1.1 eq.) in 30 mL of methanol with 3 drops of acetic acid at room temperature. A solid formed within one hour; more methanol was added, and the mixture was stirred at room temperature for three days to produce N′-(1-ethyl-2,2-dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3, 500 MHz) δ (ppm): 7.5 (br, 1H), 2.23 (q, 2H)), 1.51 (s, 9H), 1.15 (s, 9H), 1.1 (t, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([S:18][CH2:19][CH3:20])=[C:12]([F:17])[CH:13]=2)[N:8]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[N:10][C:11]=1[S:18][CH2:19][CH3:20])[N:8]([C:21]([CH3:23])([CH3:24])[CH3:22])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(SCC)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCSc1nc2c(cc1F)c(=O)c(C(=O)O)cn2C(C)(C)C
Yield: 93 %

Procedure:
A suspension of 0.23 g (0.65 mmoles) of 6-fluoro-7-ethylthio-(1,1-dimethylethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 1 mL of water was treated with 1.3 mL of 1N aqueous sodium hydroxide and the mixture was heated under reflux for 45 minutes. The resulting precipitate was acidified with 1 mL of 2N hydrochloric acid, filtered, washed with water and dried in vacuo at 50° C. to give 0.196 g of titled compound. MP 215° C.