Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH3:14])=[O:12].[BH4-].[Na+]>CO.O1CCCC1>[OH:8][CH2:7][C:6]1[N:1]=[C:2]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=[CH:4][CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A suspension of dimethyl 2,6-pyridine-dicarboxylate (50 g, 0.25 mol) in methanol (400 mL) and tetrahydrofuran (150 mL) was heated to dissolve and while the solution was still hot, it was treated in portions with sodium borohydride (9.1 g, 0.24 mol). The mixture was stirred for 1 hour after the addition, cooled to 25° C., quenched with 10% citric acid (80 mL), stirred for 15 minutes, filtered, and concentrated. A solution of the concentrate in dichloromethane was dried over sodium sulfate, filtered, and concentrated. A solution of the residue in hot ethyl acetate was allowed to stand for 16 hours at 25° C. The resulting precipitate (23 g) was collected by filtration. The mother liquor was concentrated and the resulting solid was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane to give the crude white solid (24 g). The solid was crystallized in ethyl acetate to give a total yield of the title compound (36 g, 84% yield).
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:13])=[CH:3][C:2]2=1.[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([N:12]1[CH:9]2[CH2:10][CH2:11][CH:1]1[C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[CH2:8]2)[CH3:15]
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1C2CCC1c1cc(N)ccc1C2
Reaction time: 1 h

Procedure:
A solution of (+/−)-12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (150 mg, 0.86 mmol) in acetone (4 mL) was treated with ethyl iodide (0.07 mL, 0.86 mmol), potassium carbonate (237 mg, 1.72 mmol) and stirred for 1 h. The mixture was partitioned between dichloromethane and brine and the organic layer dried (MgSO4), filtered and concentrated to give (+/−)-12-Ethyl-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>CO>[F:28][C:23]1[CH:22]=[C:21]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:6][CH:7]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: CN
Reactant: CCC(=C(c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1)c1ccccc1
Solvent: CO
Product: CCC(=C(c1ccc(OCCNC)cc1)c1ccc(O)c(F)c1)c1ccccc1
Temperature: 85 °C
Yield: 59 %

Procedure:
To a stirred solution of 4-(1-(4-(2-chloroethoxy)phenyl)-2-phenylbut-1-enyl)-2-fluorophenol in 5 mL MeOH was added 2 mL CH3NH2 (30% aq) and heated at 85° C. overnight. The mixture was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (CH2Cl2/MeOH(NH3 gas)=10/1) to give the desired product (59% yield, Z/E=1/1 as a white solid. m/z=392[M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[C:5]2=[CH:4][N:3]=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=3)=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: Fc1cccc(F)c1-c1n[nH]c2nc(Cl)ncc12
Reactant: Nc1ccc(F)cc1
Product: Fc1ccc(Nc2ncc3c(-c4c(F)cccc4F)n[nH]c3n2)cc1
Yield: 59 %

Procedure:
The compound was prepared from 6-chloro-3-(2,6-difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 12) and 4-fluoroaniline (Aldrich) in an analogous manner as described in Example 32 (160° C.). Filtration and washing with 2-propanol after the reaction gave the title product (59%). MS (M+H)+, 342.1
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH3:14])[C:10]#[N:11].[Cl:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH3:14])[C:10]#[N:11]
Reactant: Oc1cccc(Cl)c1
Reactant: CON=C(C#N)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(C#N)c1ccccc1COc1cccc(Cl)c1
Yield: 61.5 %

Procedure:
2-Bromomethyl-α-methoxyiminophenylacetonitrile (5.0 g, 20 mmol) and 3-chlorophenol (3.0 g, 23 mmol) were dissolved in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 2 hours in the presence of potassium carbonate (3.3 g, 24 mmol). After completion of the reaction, diethyl ether (ca. 100 ml) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and crystallized from diethyl ether/n-hexane to give 2-(3-chlorophenoxymethyl)-α-methoxyiminophenylacetonitrile (3.7 g, 62%) as colorless crystals.
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2>[Cl-].[Zn+2].[Cl-]>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[CH2:4][CH2:3][CH2:2][C:1]2=[O:6])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C1CCCN1c1cccc2cccnc12

Procedure:
A mixture of γ-butyrolactone (4.3 g), 8-aminoquinoline (7.2 g) and zinc chloride (0.7 g) was heated at 225° for 20 hours in an autoclave. The cooled reaction mixture was partitioned between chloroform and 0.2 N hydrochloric acid. The aqueous layer was basified with sodium hydroxide then extracted with methylene chloride. Following treatment of the methylene chloride extract with FILTROL No. 1 (Trade Name) the solvent was vacuum-stripped to give 1-(8-quinolyl)-2-pyrrolidinone, identical by tlc with the product of Example 1.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:2]1([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:31])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCCCCCN
Product: NCCCCCCCCCCCCCCCCCCC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 11 g of galactose and 20 g of octadecylamine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(C)n1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(=O)n(CCOc2ccc(C=O)cc2)c(C)n1
Yield: 28 %

Procedure:
The title compound (0.8 g, 30%) was prepared from 2,4-dimethyl-1,6-dihydro-6-pyrimidone (1.3 g. 10.48 mmol) and 4-[2-bromoethoxy]benzaldehyde (2.4 g, 10.48 mmol) in the presence of a base K2CO3 (2.89 g, 20.96 mmol) by a similar procedure as described in preparation 1.
Reaction SMILES: [CH2:1]([C:8]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:15]=2)[NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:15]=2)[NH:10][C:9]1=[S:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(Cc2ccccc2)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Solvent: Cc1ccccc1
Product: CC1(Cc2ccccc2)C(=S)Nc2ccc(-c3cccc(Cl)c3)cc21
Yield: 21 %

Procedure:
The title compound was prepared from 3-benzyl-5-(3-chloro-phenyl)-3-methyl-1,3-dihydro-indol-2-one (100 mg) and Lawesson's reagent (120 mg) in toluene (10 ml) at reflux, according to General Procedure A, to afford the title compound (0.022 g) as an off white solid: mp. 168-170° C.; 1H NMR (CDCl3) δ 9.23 (br s, 1H), 7.49 (s, 1H), 7.49-7.30 (m, 4H), 7.21 (s, 1H), 7.15-7.09 (m, 3H), 6.96-6.94 (m, 2H), 6.89 (d, 1H, J=8.0 Hz), 3.19 (dd, 2H, J=40.5 and 13 Hz) and 1.57 (s, 3H); MS (EI) m/z 363/365 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:17])[CH3:15])[C:5]([C:6]([NH:19][NH2:20])=[O:7])=[CH:4][N:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Solvent: O
Solvent: CCO
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (3 g, 12.39 mmol) in ethanol (10 mL), hydrazine hydrate (3 mL) was added and refluxed at 80° C. for 3 h. The reaction mixture was cooled and concentrated to obtain crude compound. The residue obtained was triturated with diethyl ether and hexane and filtered to get solid, 6-chloro-4-(isopropylamino)nicotinohydrazide (10). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.58 min; LCMS (ES-API), m/z 229.6 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.C1COCC1.[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][C:43]=1[NH2:48].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:48][C:43]4[N:44]=[CH:45][CH:46]=[CH:47][N:42]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ncccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ncccn3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.00 g, 8.47 mmol), and THF (85 ml). To this, was added pyrimidin-2-amine (1.208 g, 12.71 mmol) and the reaction was cooled to 0° C. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (18.63 ml, 18.63 mmol) was added dropwise and allowed to stir at 0° C. After 1 hour, the mixture was diluted with 1N aq. HCl (10 mL) and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40 g Redi-Sep Gold column, 10-50% of a 3:1 EtOAc/EtOH solution in heptane) to give 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (3.54 g, 7.06 mmol, 83% yield) as an off white solid. m/z (ESI) 502.8 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:8]=[C:7]2[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:11][C:6]2=[CH:5][CH:4]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:11]2[C:6]3[C:7](=[N:8][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=3)[CH:9]=[C:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2nc(C(F)(F)F)ccc2[nH]1
Reactant: OCc1ccncc1
Product: CCOC(=O)c1cc2nc(C(F)(F)F)ccc2n1Cc1ccncc1
Yield: 65.3 %

Procedure:
According to a process similar to that described in Example 24.1, using 5 g (18.4 mmol) of ethyl 5-tri-fluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (Example 23.3) and 3.04 g (27.6 mmol) of (pyridin-4-yl)methanol, 4.2 g of the expected compound are isolated.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][S:5]([CH3:8])(=[O:7])=[O:6].[CH3:11][NH2:12].C1COCC1>CO>[CH3:8][S:5]([NH:4][C:3]([S:2][CH3:1])=[N:12][CH3:11])(=[O:7])=[O:6]
Reactant: CN
Reactant: CSC(=NS(C)(=O)=O)SC
Solvent: CO
Solvent: C1CCOC1
Product: CN=C(NS(C)(=O)=O)SC
Temperature: 50 °C
Yield: 70 %

Procedure:
To a solution of N-methanesulfonylcarbonimidodithioic acid dimethyl ester (1.5 g, 8.02 mmol) in MeOH (15 ml) was added a solution of methylamine in THF (2.0 M, 4.8 ml, 9.6 mmol) and the reaction heated to 50° C. for 2.5 h before another portion of methylamine was added (4.8 ml, 9.6 mmol) and the reaction heated to 50° C. for an additional 1 h. The mixture was concentrated and purified by column chromatography on silica gel (EtOAc/Hexanes, 1:1) to afford S-methyl N-methanesulfonyl-N′-methylcarbamimidothioate (0.95 g, 70%) as a clear oil. 1H NMR (CDCl3) δ 2.40 (s, 3H), 2.96 (d, 3H, J=6 Hz), 3.01 (s, 3H), 7.95 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:14][C:13](=[O:15])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([C:10]([O:12][CH2:13][C:6]2[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=2)=[O:11])[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
In DMF (60 mL) was stirred 5-nitro-1,3-benzenedicarboxylic acid (2.1 g, 10 mmol) and potassium carbonate (8.3 g, 60 mmol). To this was added benzyl bromide (3.60 g, 21 mmol) and the mixture stirred at room temperature for 18 hours. The mixture was then filtered free of solids and the DMF solution evaporated at reduced pressure to give an oil. The oil was partitioned between methylene chloride (100 mL) and 10% citric acid solution (100 mL). The organic phase was separated, washed successively with saturated sodium bicarbonate solution (100 mL) and then brine (100 mL). The organic phase was dried over magnesium sulfate and evaporated at reduced pressure to give 1.5 g (39%) of the solid diester. MS: M-benzyl=300.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2F)[C:6]=1[CH:7]1[CH2:9][CH2:8]1.C([O:26][C:27](=O)[CH2:28][C:29]([CH3:31])=[O:30])(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:27](=[O:26])[CH2:28][C:29](=[O:30])[CH3:31])=[CH:12][CH:11]=2)[C:6]=1[CH:7]1[CH2:9][CH2:8]1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)c(F)c1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Temperature: 145 °C
Yield: 72.5 %

Procedure:
Intermediate 34 (1.83 g, 5.72 mmol) and t-Butylacetoacetate (1.9 ml, 11.4 mmol) were dissolved in xylene (5 ml) and heated to 145° C. f°r 90 mins. Reaction mixture was cooled to rt to obtain a solid. Solid that formed was filtered, washed with petether and dried to obtain N-{4-[4-chloro-5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-oxobutanamide (1.6 g).
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]#[N:12]>O1CCCC1.CCOCC>[NH2:12][C:11]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)=[CH:4][C:3]#[N:5]
Reactant: N#Cc1cccs1
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC=C(N)c1cccs1
Reaction time: 0.5 h

Procedure:
About 100 ml. of ammonia is condensed in the reaction flask and a small piece of sodium is added, giving a blue color. The color is discharged with ferric chloride and 2.7 g. of sodium is added. When the blue color disappears, 4.91 ml. of acetonitrile in 10 ml. of ether is added. The reaction is cooled in a dry ice-acetone bath and 9.28 g. of 2-thiophenecarbonitrile in 25 ml. of tetrahydrofuran is added dropwise. Cooling is continued for 30 minutes, then the ammonia and solvent are allowed to evaporate. A 50 ml. portion of water is added and the mixture is extracted with methylene chloride. The methylene chloride extracts are dried over sodium sulfate and then passed through Magnesol. Hexanes are added and the filtrate is evaporated on a steam bath to an oil. The oil is dry column chromatographed on silica gel, eluting with methylene chloride. The fraction containing the desired product is taken up in methylene chloride, passed through Magnesol and the filtrate is evaporated on a steam bath with the addition of hexanes until an oil comes out. Cooling and seeding gives the desired product as crystals, mp. 50°-45° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])[C:10](=[O:21])[CH2:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.OS([O-])(=O)=O.[Na+]>CCO>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])[CH:10]([OH:21])[CH2:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(=O)Cc1ncccc1C(=O)O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(O)Cc1ncccc1C(=O)O
Reaction time: 0.33 h

Procedure:
To a solution of 2-[3-tert-butoxycarbonylamino-4-(2-fluoro-phenyl)-2-oxo-butyl]-nicotinic acid (14 g, 35 mmol) in 100 mL of EtOH at 0° C. is added NaBH4 (5.3 g, 140 mmol). After 20 min, 30 mL of water is added to the reaction and the reaction poured into 300 ml of water. The pH is adjusted to ˜pH3 with 2M NaHSO4 at which point a white solid precipitates and isolation by filtration gives the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:13][CH2:12][CH2:11][C:9]3[O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2cccs2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)N2CCN(CCCc3cc(-c4cccs4)no3)CC2)cc1
Yield: 71.2 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-(diphenylmethyl)piperazine (12 mg, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.2 hr and followed the same processes as in Example 1 to obtain 15.8 mg (74.2%) of the target compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17](F)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:27])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]2[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH:32]1[CH3:37])(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([C:17]2[CH:16]=[C:15]3[C:10]([C:11](=[O:27])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]3[CH:21]3[CH2:23][CH2:22]3)=[C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:18]=2[F:19])[CH2:33][CH:32]1[CH3:37])(=[O:30])[CH3:29]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Reactant: CC(=O)N1CCNCC1C
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2cc3c(c(NCc4ccccc4)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C

Procedure:
A mixture of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-acetyl-2-methylpiperazine and pyridine was heated under reflux. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The extract was dried and chloroform was evaporated. Ethanol was added to the residue, and the crystals were collected by filtration to give 7-(4-acetyl-3-methyl-1-piperazinyl)-5-benzylamino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. It was recrystallized from ethanol/diisopropyl ether. m.p. 235°-236° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([Cl:20])[CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([Cl:20])[CH:3]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Yield: 65.9 %

Procedure:
To a suspension of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid (4.3975 g, 11.2 mmol) in a mixture 70 ml MeOH and 70 ml toluene was added TMS-diazomethane (10 ml, 20 mmol, 2M/hexanes) in small portions at room temperature. At the end of the addition the suspension turned into a solution, and then a precipitate was formed again. The suspension was diluted with hexanes and filtered. And the precipitate was washed with hexanes and dried in vacuo to obtain the title compound 3.03 g (66%).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH3:35])[CH2:30][C:29]2=[O:36])[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH2:34]([N:31]1[CH2:32][CH2:33][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([NH:21][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:23]=2)[C:29](=[O:36])[CH2:30]1)[CH3:35]
Reactant: CCN1CCN(c2cccc(N)c2)C(=O)C1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CCN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)C(=O)C1

Procedure:
205 d) 4-Ethyl-1-{3-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-2-one was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-(3-amino-phenyl)-4-ethyl-piperazin-2-one (79.0 mg, 0.360 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (27.0 mg, 0.0494 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.059 g, 37%). MP=210-212° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 8.24 (d, J=8.0 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H), 7.76 (s, 1H), 7.65 (d, J=6.9 Hz, 1H), 7.42-7.34 (m, 2H), 7.04 (t, J=6.5 Hz. 1H), 6.96-6.92 (m, 2H), 3.80-3.75 (m, 2H), 3.36 (s, 2H), 3.10 (s, 3H), 2.88-2.83 (m, 2H), 2.58 (q, J=7.0 Hz, 2H), 1.18 (t, J=6.4 Hz, 3H). MS=491 (MH)+.