Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=1.[NH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1.C(O)(=O)/C=C/C(O)=O>C(O)CCC.C(O)(C)C.O>[CH2:7]([N:6]1[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=[C:2]1[NH:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[CH3:8]
Reactant: CN1CCC(N)C1
Reactant: CCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: O
Solvent: CCCCO
Product: CCn1c(NC2CCN(C)C2)nc2ccccc21
Yield: 63 %

Procedure:
A solution of 38.6 g (0.21 mol) of 2-chloro-1-ethylbenzimidazole and 24 g (0.24 mol) of 3-amino-1-methylpyrrolidine in 150 mL of n-butanol was heated to reflux for 72 h and concentrated on the rotary evaporator (70° C./30 mm). The residue was partitioned between CHCl3 and dilute NaOH. The CHCl3 solution was dried (Na2SO4) and concentrated. For purification the material obtained was converted to the difumarate salt. The residue (68 g) was treated with a boiling solution of 64 g of fumaric acid in 600 mL of isopropyl alcohol and 100 mL of H2O. The resulting salt weighted 48 g (63% yield). A sample was recrystallized from ethanol-H2O, mp 204°-212° C. (dec).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCCCCCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 46.2 %

Procedure:
8-Aminooctanoic acid (1.0 g, 0.006 mol) was treated with 4-fluorobenzenesulphonyl chloride (1.22 g, 0.006 mol) in the presence of sodium hydroxide (0.8 g, 0.019 mol) in 15 ml water, tetrabutylammonium hydroxide (4 drops, 40% solution) and dichloromethane and the resulting mixture was subjected to vigorous stirring for 3 hours. The organic layer was then separated and evaporated to dryness and the residue was recrystallised from 2-propanol-water to give the title compound (0.88 g, m.p. 97°-8° C.).
Reaction SMILES: [C:1](O)(=O)C.FC(F)(F)C(O)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][NH2:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C1N2CN3CN(C2)CN1C3>O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:1]=[N:24][CH2:23][CH2:22]2
Reactant: CC(=O)O
Reactant: COc1ccc(CCN)cc1OC
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)CCN=C2
Yield: 95 %

Procedure:
Acetic acid/trifluoroacetic acid (100 mL) was added to a solution of 2-(3,4-dimethoxyphenyl)ethanamine (20 g, 110.38 mmol, 1.00 equiv) and hexamethylenetetramine (31 g, 221.11 mmol, 2.00 equiv). The resulting solution was heated at reflux for about 5 hours in an oil bath. After adding water (100 mL), the solution was extracted with dichloromethane (3×200 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Solids were removed by filtration, and the resulting filtrate was concentrated in vacuo to give the title product as a yellow oil (20 g, yield=95%). LC-MS: m/z=192 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: C1COCCN1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCOCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3.1 g), morpholine (2 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 4-[(2-phenylquinazolin-4-yl)-carbonyl]-morpholine (3 g), melting at 148° C., is obtained.
Reaction SMILES: C[O-].[Na+].[BH4-].[Na+].[SH:6][CH2:7][CH2:8][CH2:9][OH:10].CS(O[CH2:16][CH:17]([O:40][CH3:41])[CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:39])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])(=O)=O>O1CCCC1.CO>[OH:10][CH2:9][CH2:8][CH2:7][S:6][CH2:16][CH:17]([O:40][CH3:41])[CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:39])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36]
Reactant: OCCCS
Reactant: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)COS(C)(=O)=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)CSCCCO
Yield: 96.5 %

Procedure:
To 30 ml of teterahydrofuran are added 11.8 ml of a methanol solution of sodium methoxide (28% solution), 0.57 g of sodium borohydride and 4.14 g of 3-mercaptopropanol, to which is added dropwise a solution of 6.97 g of 2-methoxy-3(3,7,11,15-tetramethylhexadecyloxy)propyl methanesulfonate in 50 ml of tetrahydrofuran at room temperature with stirring under nitrogen streams. Thereafter, the reaction mixture is stirred at room temperature for 16 hours. The solvent is distilled off under reduced pressure and the residue is extracted with hexane. The extract layer is washed successively with water, dilute hydrochloric acid, water, an aqueous sodium bicarbonate solution and then with water. After drying, the solvent is distilled off under reduced pressure to leave 6.67 g of the captioned compound as an oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=[O:19].[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][CH:23]=[C:22]([N:4]2[C:5]3[C:6](=[N:7][C:8]([C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]#[N:14])=[CH:9][CH:10]=3)[N:2]([CH3:1])[C:3]2=[O:19])[CH:21]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(-c2cccc(-c3ccccc3)c2)c2ccc(-c3ccccc3C#N)nc21
Reaction time: 96 h

Procedure:
To a solution of 4-1 (13 mg, 0.052 mmol) in DCM (0.25 mL) was added copper (II) acetate, biphenyl-3-ylboronic acid (30 mg, 0.16 mmol) and triethylamine (0.022 mL, 16 mg, 0.16 mmol) at room temperature. After 4 days, the crude mixture was diluted in DCM (4 mL), filtered, concentrated and purified via reverse phase chromatography (1-100% Acetonitrile, 0.1% TFA in H2O) and the desired fractions were concentrated to give 76-1. MS (M+H)+: observed=403.0, calculated=403.2.
Reaction SMILES: [C:1]1([S:7]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[S:34][C:33]([CH3:35])=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12>>[C:1]1([S:7]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([NH:20][CH:21]2[C:39](=[O:40])[N:23]3[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]4[S:34][C:33]([CH3:35])=[N:32][N:31]=4)[CH2:26][S:27][C@H:22]23)=[O:12])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: CCCCCCCC(C(=O)O)S(=O)c1ccccc1
Product: CCCCCCCC(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)S(=O)c1ccccc1

Procedure:
564 mg. of 2-(phenylsulfinyl)nonanoic acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 341 mg. of 7-[2-(phenylsulfinyl)nonanamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]Br.[Na+].[I-].[C:13]([S-:15])#[N:14].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][N:14]=[C:13]=[S:15]
Reactant: N#C[S-]
Reactant: Fc1ccc(Br)c(CBr)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(CN=C=S)c1
Temperature: 80 °C

Procedure:
To a solution of 1-bromo-2-(bromomethyl)-4-fluorobenzene (12, 5.36 g, 20.0 mmol) in dry DMF (20 mL) was added NaI (1.20 g, 8.00 mmol) and KSCN (3.88 g, 40.0 mmol). The mixture was heated under N2 at 80° C. for 12 h. After cooling to RT, the mixture was diluted with water (100 mL), and extracted with EtOAc (50 mL×2). The combined extracts were washed with brine, dried over MgSO4 and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with petroleum ether to provide 1-bromo-4-fluoro-2-(isothiocyanatomethyl)benzene (13).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[NH:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CC(C)C
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CC(C)C)NCCC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.5 g) in trifluoroacetic acid (15 mL). The reaction mixture was reduced on a Parr apparatus under 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with aqueous sodium bicarbonate then a small amount of 10% sodium hydroxide was added. The resulting precipitate was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 1-5% methanol in dichloromethane containing 0.5% ammonium hydroxide). The eluant was concentrated under vacuum. The residue was recrystallized from hexane/ethyl acetate to provide 6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a solid, m.p. 143-147° C. Analysis: Calculated for C17H27N5: % C, 67.74; % H, 9.03; % N, 23.23; Found: % C, 61.90; % H, 7.51; % N, 19.91.
Reaction SMILES: [H-].[Na+].[CH:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([OH:19])[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[O:4].Cl.[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1>CS(C)=O.O>[Cl:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][O:19][C:8]1[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=[C:12]2[C:7]=1[CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[N:5]([CH:3]=[O:4])[CH2:14][CH2:13]2
Reactant: COc1cccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C=O)c1
Reactant: ClCc1cccc(CCl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(CC2c3c(cc(OC)c(OC)c3OCc3cccc(CCl)c3)CCN2C=O)c1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (80 mg, 1.96 mmole, 60%) in dimethyl sulfoxide (1 ml) was added a solution of intermediate 2 obtained in Referential Example 2 (350 mg, 0.98 mmole) at room temperature under nitrogen, and the reaction mixture was stirred for 10 minutes. The resulting mixture was added dropwise to a solution of α,α'-dichloro-m-xylene (172 mg, 0.98 mmole) in dimethyl sulfoxide (1 ml) at room temperature, and stirred for 2 hours. The reaction mixture was chilled in ice, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel/ethyl acetate) to give the desired compound (387 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH:10]([CH3:23])[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:23])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:8]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: Cc1ccc(C(=O)C(C)Br)cc1[N+](=O)[O-]
Solvent: CC#N
Product: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1[N+](=O)[O-]
Yield: 57.8 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (2.38 g, 18.3 mmol) and 2-bromo-1-(4-methyl-3-nitrophenyl)propan-1-one (5.0 g, 18.3 mmol) in acetonitrile (100 mL) is heated at 80° C. for 16 hours. The mixture is concentrated to dryness and then purified via silica chromatography (hexanes to EtOAc) to afford the title compound (3.2 g, 57%) as a light yellow solid: Rf 0.30 (CH2Cl2); LCMS (m/z)=303.3, 305.2 [M+H]+, tR=2.84 min.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][C:9]([N:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:24]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][N:11]2[CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(CC(c1ccccc1)(c1ccccc1)c1cccs1)N1CC2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2cccs2)cc1

Procedure:
1 Part of 3,3-(diphenyl)-3-(2-thienyl)propionyl chloride (Martenson and Nilson Acta Chem. Scand. 19 711, (1965) is reacted with 20 parts of 2-azabicyclo[2. 2. 2]octane in 50 parts of benzene. The precipitated amide is filtered and the benzene solution washed with water, dried with magnesium sulfate, and the benzene evaporated. The remaining oil is crystallized to provide 2-[3,3-diphenyl-3-(2-thienyl)propionyl]2-azabicyclo[2. 2. 2]octane. This amide is reduced with lithium aluminum hydride as described in Example 1 to provide 2-[3,3-diphenyl-3-(2-thienyl)propyl]2-azabicyclo[2. 2. 2]octane. This compound has the following structural formula ##STR33##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][NH2:9].[C:17](#[N:20])[CH:18]=[CH2:19]>C(O)(=O)C>[C:17]([CH2:18][CH2:19][N:9]([CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:3][CH2:2][N:1]([CH2:4][CH2:3][C:2]#[N:1])[CH2:12][CH2:11][C:10]#[N:5])[CH2:6][CH2:7][C:8]#[N:9])#[N:20]
Reactant: NCCCN(CCCN)Cc1ccccc1
Reactant: C=CC#N
Solvent: CC(=O)O
Product: N#CCCN(CCC#N)CCCN(CCCN(CCC#N)CCC#N)Cc1ccccc1

Procedure:
4.43 g of acetic acid was added to 4.00 g of N,N-bis(3-aminopropyl)benzylamine and 100 mL of acrylonitrile and the mixture was heated under reflux for 14 hours. After the reaction mixture was concentrated, 150 mL of water was added thereto and the mixture was neutralized by 4.60 g of 28% ammonia water, followed by extraction of the mixture with ethyl acetate (150 mL). After the organic layer was washed with water, it was dried with anhydrous magnesium sulfate. The solvent was distilled off to give 6.59 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[N:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH:24]([F:27])[CH2:23][CH2:22]2)[CH2:5][CH2:4]1>[Pd].C1COCC1>[F:30][C:2]([F:1])([F:29])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[N:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH:24]([F:27])[CH2:23][CH2:22]2)[CH2:7][CH2:8]1
Reactant: Nc1nc(N2CCC(F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CCC(F)CC2)nc1N

Procedure:
The subtitle compound is prepared in analogy to 2c from N-(trans-4-trifluoromethyl-cyclohexyl)-6-amino-5-nitro-2-(4-fluoro-piperidinyl)-nicotinic acid amide, Pd/C (50 mg) and THF (15 mL) under 50 psi H2-atmosphere.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[F:23][C:24]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:28]([F:40])=[CH:27][C:25]=1[NH2:26].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:26][C:25]1[C:24]([F:23])=[CH:30][C:29]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[C:28]([F:40])[CH:27]=1
Reactant: CC1(C)OB(c2cc(F)c(N)cc2F)OC1(C)C
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(F)c(N)cc3F)c(F)cn2c1=O
Temperature: 85 °C
Yield: 75 %

Procedure:
Ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.32 mmol), 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (667 mg, 2.06 mmol), tricyclohexylphosphine (105 mg, 0.41 mmol) and cesium fluoride (482 mg, 3.2 mmol) were added to ACN (5 mL). The reaction mixture was degassed with argon. Palladium(II) acetate (24 mg, 0.11 mmol) was added. The reaction mixture was heated at 85° C. for 2 h. The reaction mixture was cooled and evaporated in vacuum. Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (100 mg, 35%).
Reaction SMILES: NC1S[C:4]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[O:8])=[CH:5]N=1.[CH2:18]([O:20]C=CC(Cl)=O)[CH3:19].ClC1C=CC=C(C)C=1N.Cl>O1CCCC1.O.N1C=CC=CC=1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[NH:9][C:7](=[O:8])/[CH:4]=[CH:5]/[O:20][CH2:18][CH3:19]
Reactant: CCOC=CC(=O)Cl
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Agent: Cc1cccc(Cl)c1N
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
PCT Publication No. WO 2005/077945 provides a process for the preparation of 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c) which involves adding 3-ethoxyacryloyl chloride to a cold stirring solution of 2-chloro-6-methylaniline and pyridine in tetrahydrofuran at a temperature of 0° C. to 5° C. The mixture thus obtained was then warmed, stirred for 2 hours at 20° C., and hydrochloric acid was added at 0° C. to 10° C. The mixture was diluted with water and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene and stirred for 15 minutes at 20° C. to 22° C. then for 1 hour at 0° C. to obtain (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: COc1ccc(O)c(Br)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(COc1ccc(OC)cc1Br)OCC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step A (1.01 g, 5 mmol), 2-bromo-1,1-diethoxyethane (1.05 g, 5.25 mmol) and Cs2CO3 (2.04 g, 6 mmol) in DMF (10 mL) was stirred at 120° C. for 2 hrs. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (eluted with PE:EtOAc=6:1) to the title compound (2.7 g, 85%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.12 (d, J=3.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.81 (dd, J=9.0, 3.0 Hz, 1H), 4.87 (t, J=5.2 Hz, 1H), 4.02 (d, J=5.2 Hz, 2H), 3.84-3.78 (m, 2H), 3.77 (s, 3H), 3.73-3.67 (m, 2H), 1.27 (t, J=7.1 Hz, 6H) ppm.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC#N.CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH2:10][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CCOCC
Solvent: CC#N
Product: Nc1ncc(Br)cc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
An ice-cold suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (10.0 g, 28.8 mmol) in MeCN (100 mL) was treated with piperidine (6.4 mL, 64.8 mmol). After stirring at room temperature for 3.5 h, the mixture was diluted with Et2O (500 mL). The solution was filtered and then concentrated to give the title compound (4.16 g, 53%) as a pale, yellow solid: MS (ESI) m/e 270 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([N:34]4[C:46](=[O:47])[C:45]5[S:44][C:43]6[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=6[C:37]=5[CH:36]=[N:35]4)[C:29]=3[CH:48]=[O:49])[CH:21]=2)=[N:17][CH:18]=1.[BH4-].[Na+]>CO>[CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:9][O:10][CH2:11]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([N:34]4[C:46](=[O:47])[C:45]5[S:44][C:43]6[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=6[C:37]=5[CH:36]=[N:35]4)[C:29]=3[CH2:48][OH:49])[CH:21]=2)=[N:17][CH:18]=1
Reactant: CC1CN(C2COC2)C(C)CN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
A mixture of 159a (130 mg, 0.19 mmol), NaBH4 (22 mg, 0.60), and methanol (10 mL) was stirred at 25° C. for 1 h. The mixture was then quenched with water (8 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 159 (28 mg, 22%). MS-ESI: [M+H]+ 681. 1H NMR (500 MHz, CDCl3) δ 8.71 (d, J=2.5 Hz, 1H), 8.65 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.87 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.55 (d, J=5.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 6.81 (d, J=9.0 Hz, 1H), 4.67-4.61 (m, 2H), 4.71-4.64 (m, 2H), 4.44-4.42 (m, 2H), 4.34-4.33 (m, 1H), 3.83-3.76 (m, 1H), 3.72 (s, 3H), 3.20-3.16 (m, 1H), 2.99-2.84 (m, 6H), 2.79-2.71 (m, 2H), 2.50-2.48 (m, 1H), 2.02-1.98 (m, 4H), 0.91 (d, J=6.0 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH3:10])=[N:6][CH:7]=1.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1>>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:8]([C:5]2[N:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:9][CH3:10])=[CH:18][CH:17]=1
Reactant: CCC(=O)c1ccc(O)cn1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)cn1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(5-hydroxypyridin-2-yl)propan-1-one (0.15 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (0.549 g, 2.0 eq) to give the desired product (Z/E=1/1).