Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccccc2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reaction time: 18 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (42 mg, 0.15 mmol) and benzoic acid (0.40 mmol) were mixed in THF (5 ml). Carbodiimde resin (495 mg, 0.5 mmol) was added and shaking continued for 18 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX) to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)benzamide. NMR; δH [2H6]—DMSO 10.25,(1H, s), 8.62,(1H, t), 7.95-7.92,(4H, m), 7.73,(1H, dd), 7.69,(1H, d), 7.60-7.50,(3H, m), 7.44,(2H, d), 7.28,(1H, d), 3.16,(2H, t), 2.20,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.41 min, MH+385.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])[CH2:2][CH3:3].N1C=CC=CC=1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:1]([O:4][CH2:5][CH3:6])([O:7][CH2:8][CH3:9])[CH:2]([Br:19])[CH3:3])[CH3:12]
Reactant: BrBr
Reactant: CCOC(CC)(OCC)OCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(OCC)(OCC)C(C)Br
Reaction time: 24 h
Yield: 80.7 %

Procedure:
A solution of 176 g (1 mole) of triethyl orthopropionate and 96 g (1.2 moles) of pyridine in 1 l of carbon tetrachloride was placed in a 2 l flask and 160 g (1 mole) of bromine was slowly added over two hours to the solution under ice-cooling. The resultant reaction mixture was allowed to stand at room temperature for one day to form a precipitate, which was then filtered off. The filtrate was concentrated by evaporation of the solvent and the residue was subjected to distillation under reduced pressure to afford 206 g (81%) of 1,1,1-triethoxy-2-bromopropane with a boiling point of 85° C./13 mmHg.
Reaction SMILES: [Al]([NH2:4])(C)C.C1C=CC=CC=1.C([O:13][C:14](=O)[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([S:35][CH3:36])=[C:22]2[CH2:37][C:38]([NH2:40])=[O:39])C.Cl>C1C=CC=CC=1>[NH2:4][C:14](=[O:13])[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]([S:35][CH3:36])=[C:22]2[CH2:37][C:38]([NH2:40])=[O:39]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Reactant: C[Al](C)N
Agent: Cl
Solvent: c1ccccc1
Product: CSc1c(CC(N)=O)c2cc(OCCCC(N)=O)ccc2n1Cc1ccccc1
Temperature: 50 °C
Yield: 84 %

Procedure:
Ten mL of 0.6M (CH3)2AlNH2/benzene was added to 200 mg (0.45 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-methylthio-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester (Example 46) in 25 mL of benzene and the mixture heated at 50° C. for 1.75 hours. After cooling the mixture was decomposed with ice and 1N HCl added, The mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was crystallized from EtOH/CH2Cl2 to give 155 mg (84% yield) of 5-(4-amino-4-oxobutoxy)-2-(methylthio)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 185° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CO>[O:12]1[CH2:13][CH2:14][N:9]([C:6]2[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:8][C:1](=[O:2])[C:3](=[O:4])[CH:5]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: Oc1ccccc1O
Solvent: CO
Product: O=C1C=C(N2CCOCC2)C(N2CCOCC2)=CC1=O

Procedure:
Pyrocatechol (99.0 g; 0.9 mole) was dissolved in methanol (2.5 l), then morpholine (360 ml; 4.1 mole) and cupric acetate (9.0 g) were added. Air was bubbled through the reaction solution for about 9 hours. The mixture was cooled and filtered; the solid was washed with methanol (1.5 l) and air dried. The yield was 150.3 g (60%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:10]=1[CH2:11][N:12]1[C@@H:21]2[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[NH:15][C:14](=O)[CH2:13]1>C1COCC1>[CH3:7][O:8][C:9]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:10]=1[CH2:11][N:12]1[C@@H:21]2[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[NH:15][CH2:14][CH2:13]1
Reactant: COc1ccc(CN2CC(=O)N[C@H]3CCCC[C@@H]32)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCN[C@H]3CCCC[C@@H]32)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
To an ice-cold 1.0M solution of LiAlH4 in THF (4.10 mL, 4.10 mmol) was added a solution of (4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydroquinoxalin-2(1H)-one (500 mg, 1.64 mmol) in THF (10 mL). The mixture was heated at reflux for 8 h. The reaction was cooled to 0° C. and carefully quenched with EtOAc (50 mL) and 1 N NaOH solution (20 mL). The mixture stirred for 30 min and the layers were separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0% to 60% 90:9:1 CH2Cl2/CH3OH/NH4OH in CH2Cl2) afforded (4aS,8aS)-1-(2,4-dimethoxybenzyl)decahydroquinoxaline (120.1 mg, 25.4%). 1H NMR and MS consistent.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.Cl>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(O)cc2)cc1
Yield: 46.3 %

Procedure:
Hydroquinone (18 g, 163.5 mmol), 4-fluorobenzonitrile (10 g, 81.75 mmol) and potassium carbonate (23 g, 163.5 mmol) were heated to 150° C. in dimethylformamide (40 mL) for 6 hours. The cooled mixture was diluted with water and 1 N hydrochloric acid and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed yielding 8 g of the title compound. MS (m/z, APCI): 210 [M−H]−.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](=[O:23])[N:14]([CH3:22])[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)(=O)C.O.[OH-].[K+]>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([N:14]([CH3:22])[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:23])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(/C=C/C(=O)N(C)Cc2cccnc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(Cc1cccnc1)C(=O)/C=C/c1ccc(O)cc1
Yield: 77.1 %

Procedure:
1.50 g of 4-[(E)-2-[N-methyl-N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl acetate was dissolved in 10 ml methanol, and then stirred with 1 ml of water and 0.36 g of potassium hydroxide at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was neutralized with diluted hydrochloric acid, extracted with ethyl acetate, washed with water, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (dichloromethane:methanol=30:1) to provide (E)-3-(4-hydroxyphenyl)-N-methyl-N-(3-pyridylmethyl)-2-propenoic acid amide (1.00 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10](F)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1.C([OH:18])C#CC.CC(C)([O-])C.[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[C:10]([OH:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1
Reactant: CC#CCO
Reactant: COC(=O)c1c(F)cc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1c(O)cc(Br)cc1F
Temperature: 25 °C
Yield: 38.1 %

Procedure:
Methyl 4-bromo-2,6-difluorobenzoate (0.5 g, 2.0 mmol), 2-butyn-1-ol (0.16 ml, 2.1 mmol), potassium tertbutoxide (0.47 g, 4.2 mmol) in dry DMSO (5 ml) was heated in a microwave oven at 125° C. for 2.5 min. The reaction mixture was cooled to ambient temperature and quenched with water. The mixture was acidified with aqueous HCl (1 M) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated to dryness to afford an oil. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (0.19 g, 35%). MS m/z (rel. intensity, 70 eV) 250 (M+, 43), 248 (M+, 44), 218 (96), 216 (bp), 190 (44),188 (45).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][C:21]=1[F:34])=[O:19]>CN(C=O)C>[CH3:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([C:2](=[S:3])[NH:1][C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=2)[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][C:21]=1[F:34])=[O:19]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CCOC(=O)CCNc1ccc(C(=O)NC)c(F)c1
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C(=S)Nc1ccc(C#N)c(C(F)(F)F)c1)c1ccc(C(=O)NC)c(F)c1

Procedure:
A solution of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (320 mg, 1.51 mmol) 3.2 and ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate (404 mg, 1.51 mmol) 5 (R1=CH3) in DMF (8 ml) was heated at 60° C. in microwave stove for 8 h. The reaction mixture was evaporated in vacuo, and by means of colomn chromatography on SiO2 (eluent—n-hexane:AcOEt=1:2) ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alaninate 6(2) (R1=CH3, X═S) was isolated. LCMS (M+H)+ 497. A solution of NaOH (32 mg, 0.8 mmol) in water (0.25 ml) was added to a solution of ester (200 mg, 0.4 mmol) 6(2) in alcohol (1 ml), and the resultant mixture was stirred at 80° C. for 2 h (LCMS control), cooled and neutralized with HCl (69 mkl, 0.8 mmol), evaporated in vacuo, the residue was extracted with hot isopropanol and evaporated in vacuo again. It gave N-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alanine 6(3) (R1=CH3, X═S). LCMS (M+H)+ 469. TBTU (86 mg, 0.36 mmol) and diisopropylethylamine (110 mg, 0.84 mmol) were added to the solution of the prepared acid (114 mg, 0.24 mmol) 6(3) in DMF (1.5 ml). The reaction mixture was stirred at 45° C. for 15 h. When the reaction was completed (LCMS control) the solution was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, evaporated in vacuo and by HPLC method N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-4-oxo-2-thioxo-tetrahydropyrimidin-1(2H)-yl}-2-fluorobenzamide 1.3.2(2) (R1=CH3, X═S) was isolated; Ki1.3.2(2)=95.2 nM. LCMS (M+H)+ 451. 1H NMR (DMSO-d6, 400 MHz): 8.35 (q, J=4.4 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.83 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.71 (t, J=8.2 Hz, 1H), 7.42 (dd, J1=11.0 Hz, J2=1.8 Hz, 1H), 7.33 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H), 4.13 (t, J=6.8 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 2.78 (d, J=4.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11](=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:11]1[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: O=c1nc(-c2ccc(F)c(F)c2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1F

Procedure:
The title compound was prepared from 4-(3,4-difluoro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (14.7 g, 0.053 mol) and phosphoroxychloride (148 mL) according to the general procedure I. Obtained as a light brown solid (15.6 g, 99%). MS (EI) 294.0 [(M)+]; mp 53° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[S:15][C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[CH:13][C:12]=1[CH3:33].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:32][C:27]1[CH:26]=[C:25]([C:19]2([C:21]([F:22])([F:24])[F:23])[O:18][N:17]=[C:16]([C:14]3[S:15][C:11]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:12]([CH3:33])[CH:13]=3)[CH2:20]2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1-c1ccncc1
Reaction time: 22 h
Yield: 40.2 %

Procedure:
Pyridine-4-boronic acid (30 mg) is added to a solution of 3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (100 mg), K2CO3 (90 mg) and Pd(PPh3)4 (20 mg) in a mixture of THF and water (0.4 ml, 9:1). After 22 hours at 70° C., the reaction is quenched with water and extracted three times with ethyl acetate. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 4-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-pyridine (40 mg) as a colorless oil. MS (HPLC/MS): 457 (MH+). Retention time: 5.20 min.
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([O:22]C)=O)[CH:16]=[CH:17][CH:18]=1.[C:26]1([CH2:32][C:33]#[N:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:33]([CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20](=[O:22])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:25])[F:24])[CH:14]=1)#[N:34]
Reactant: N#CCc1ccccc1
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#CC(C(=O)Cc1cccc(C(F)(F)F)c1)c1ccccc1

Procedure:
To a flame-dried flask was added 8.1 g. of sodium methoxide, 125 ml. of toluene and 21 ml. of methanol. The mixture was brought to reflux at 85°-87°, and to it was added dropwise a mixture of 22.8 g. of methyl (3-trifluoromethylphenyl)acetate and 12.9 g. of phenylacetonitrile. The apparatus was then set up for distillation, and the mixture was heated to 110°, removing about 46 ml. of distillate. The mixture was then cooled to about 12°, and to it was added 50 ml. of ice-water. The aqueous layer was removed and washed with 20 ml. of cold toluene. The organics were combined and washed with cold water. The aqueous layers were combined, and the pH was adjusted to 3.5 with cold hydrochloric acid. The oily product was collected by extracting the aqueous portion with three 40 ml. portions of dichloromethane, drying the organic layer over sodium sulfate and evaporating it under vacuum to obtain 30.5 g. of oil, which was 89% pure product by vapor phase chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH:30][C:25]1[C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:32][CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:9])([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)cc1
Yield: 83.3 %

Procedure:
Using the procedure described in Example 102, Part A, 3-nitro-4-methoxybenzoic acid (3.1 mmol) and N1-(4-methoxybenzoyl)-1,2-benzenediamine (2.1 mmol) yielded 737 mg (83%) of the title compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1ccc(-c2ccc(F)nc2)cc1=O
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2ccc(F)nc2)CC1=O
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a steel bomb, a solution of 6-fluoro-1′-methyl-[3,4′-bipyridin]-2′(1′H)-one (340 mg, 1.665 mmol) in MeOH (remaining 60% head space) was added followed by addition of Pd—C (Degussa) (354 mg, 0.333 mmol). After degassing with nitrogen stream, the steel bomb was filled with hydrogen (250 psi). The reaction mixture was stirred overnight. The reaction mixture was filtered off through Celite (washed with EtOAc/MeOH). The volatile materials were concentrated in vacuo to give crude (+/−)-4-(6-fluoropyridin-3-yl)-1-methylpiperidin-2-one (341 mg, 1.638 mmol, 98% yield) which was used for the next step without further purification. LCMS (m/z): 209.1 (MH+), 0.47 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11]C)[NH:7][N:6]=[C:5]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[NH:7][N:6]=[C:5]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1
Reactant: COc1cc2[nH]nc(Cc3cccc(C)c3)c2cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc(Cc2n[nH]c3cc(O)c(Br)cc23)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4.3 1.24 g of “4b” are dissolved in 12 ml of dichloromethane under argon and cooled to 0° C. 3.45 ml of boron tribromide are added dropwise, and the mixture is stirred at room temperature for a further 16 hours. The mixture is subjected to conventional work-up, and the residue is, for further purification, chromatographed over a 120 g RP18 silica-gel column, giving 578 mg of 5-bromo-6-hydroxy-3-(3-methylbenzyl)-1H-indazole (“4c”).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH2:37])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]([C:48](O)=[O:49])[CH:39]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH:37][C:48]([C:40]1[CH:39]=[N:38][C:47]2[C:42]([CH:41]=1)=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@@H](N)CCCC(=O)OCc1ccccc1
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-aminopentanoyl]oxyhexadecanamide hydrochloride (1.79 g), 3-quinolinecarboxylic acid (630 mg) and 1-hydroxybenzotriazole (536 mg) in N,N-dimethylformamide (40 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (616 mg) at 0° C., and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate (200 ml) and washed with 0.5N hydrochloric acid (200 ml), 10% aqueous citric acid (200 ml), saturated aqueous sodium bicarbonate (200 ml) and brine, successively. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give (3S)-3-[(2S)-5-benzyloxycarbonyl-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (2.16 g).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([CH:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:33][CH:34]=4)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(NCc5cccnc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-[3-({2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyridin-2-yl]-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (47.0 mg, 0.247 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.061 g, 57%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (dd, J=4.7, 1.5 Hz, 1H), 7.87-7.80 (m, 2H), 7.50 (d, J=8.5 Hz, 2H), 7.29-7.25 (m, 1H), 7.20 (d, J=8.5 Hz, 2H), 6.69-6.62 (m, 2H), 6.30 (d, J=7.6 Hz, 1H), 5.29 (t, 5.8 Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 3.32 (s, 3H), 3.09 (s, 3H), 3.01-2.94 (m, 2H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 3.10-2.00 (m, 2H), 1.87-1.73 (m, 4H). MS=521 (MH)+.
Reaction SMILES: FC1C=C(C=CC([C:12]2[N:19]3[C:15]([S:16][C:17]4CCCC[CH2:20][C:18]=43)=[N:14][CH:13]=2)=O)C=CC=1.[BH4-].[Na+].C([OH:29])C>>[S:16]1[CH:17]=[C:18]([CH2:20][OH:29])[N:19]2[CH:12]=[CH:13][N:14]=[C:15]12
Reactant: CCO
Reactant: O=C(C=Cc1cccc(F)c1)c1cnc2sc3c(n12)CCCCC3
Agent: [BH4-]
Agent: [Na+]
Product: OCc1csc2nccn12

Procedure:
3-(3-Fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5, X=3-fluoro), 0.34 g, in ethanol (35 mL) was treated with NaBH4 (0.11 g), reacted for 3 hours, and solvent removed in vacuo. The residue was suspended in water, filtered and the filter cake was crystallized from acetonitrile to provide pure α-[2-(3-fluorophenyl) ethenyl]-6,7,8,9-tetrahydro-5H, imidazo[2,1-b]thiazole-3-methanol, 0.30 g, m.p. 175-176° (Formula N-8, X=3-fluoro).