Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:11][C@@H:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:17]1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C[C@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccccc2[N+](=O)[O-])CCN1
Yield: 479.1 %

Procedure:
To a solution of 2-bromonitrobenzene (0.600 g, 3.00 mmol) in 1,4-dioxane (15 mL) was added (S)-(+)-2-methylpiperazine (0.500 g, 0.500 mmol) and powdered K2CO3 (15.0 mmol, 1.50 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was removed in vacuo. The resulting residue was purified by column chromatography (1/1 hexane/EtOAc followed by 4/1 EtOAc/MeOH), giving (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, 80%).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12](OCC)(=[O:16])[CH:13]([CH3:15])[OH:14]>>[C:12]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:16])[CH:13]([CH3:15])[OH:14]
Reactant: CC(C)CCCC(C)CCO
Reactant: CCOC(=O)C(C)O
Product: CC(C)CCCC(C)CCOC(=O)C(C)O
Temperature: 60 °C
Yield: 62.2 %

Procedure:
A mixture of Novozym 435 (2.81 g), molecular sieves (23.17 g), 3,7-dimethyl-1-octanol (4.64 g), and ethyl lactate (14.78 g) in a 250 mL beaker was maintained at 60° C. in a convection oven for 28 hours. Upon work-up, 4.2 g of 3,7-dimethyl-1-octyl lactate (62% yield) was obtained as an amber-colored liquid. The purity of the product was >96% as assessed by HPLC-RI.
Reaction SMILES: O1CC1COC1C=CC=CC=1C#N.N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1.[CH3:28][C:29]([N:41](CC(O)COC1C=CC=CC=1C#N)[CH2:42][CH:43]([OH:54])[CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]#[N:53])([CH3:40])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.[ClH:68]>CC(O)C.CO.CCO>[ClH:68].[OH:54][CH:43]([CH2:42][NH:41][C:29]([CH3:40])([CH3:28])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]#[N:53]
Reactant: CC(C)(Cc1c[nH]c2ccccc12)N(CC(O)COc1ccccc1C#N)CC(O)COc1ccccc1C#N
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: N#Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Solvent: CCO
Solvent: CO
Product: CC(C)(Cc1c[nH]c2ccccc12)NCC(O)COc1ccccc1C#N
Reaction time: 18 h

Procedure:
A solution of 2-[(2,3-epoxy)propoxy]benzonitrile (18.3 g., 0.10 mole) and 2-(3-indolyl)-1,1-dimethylethylamine (15.2 g., 0.08 mole), in 500 ml. of abs. EtOH was stirred at reflux overnight. After concentration of the reaction mixture to approximately 200 ml. and seeding, crude product began to precipitate. The mixture was then cooled and the precipitate separated by filtration to give 24.8 g. of the free base form of the product, white solid, m.p. 120°-123°. The crude solid was dissolved in 400 ml. of boiling MeOH, and the solution was cooled with stirring, as a by-product 1,1'-[[1,1-dimethyl-2-(1H-indol-3yl)ethyl]imino]bis[3-(2-cyanophenoxy)-2-propanol] precipitated. The by-product was collected on a filter and air dried to give 2.2 g., m.p. 180°-187°. The MeOH filtrate was then taken to dryness. The residual solid was dissolved in 200 ml. of i-PrOH and acidified with ethanolic HCl. Seeding followed by 18 hours standing in the cold afforded the product as the crystalline hydrochloride. Filtration of the mixture gave 19.8 g., of solid, m.p. 179°-183°. One recrystallization from abs. EtOH gave 15.5 g. (48%) of white solid, m.p. 185°-187°. TLC on silica gel (9CH2Cl2, 10 MeOH, 1NH4OH) showed a single spot (Rf =0.5, u.v.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:16])[CH:13]=[N+]=[N-])[CH:6]=[CH:5]2.[BrH:17].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:17][CH2:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)=[O:16]
Reactant: Br
Reactant: [N-]=[N+]=CC(=O)c1ccc2cc(Br)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reaction time: 3 h

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-diazoethanone (34.7 g) were dissolved in ethyl acetate (500 mL), and hydrobromic acid solution (21.1 mL, 5.7 M in acetic acid) was added at 0° C. Reaction mixture was stirred 3 hours, NaHCO3 solution (200 mL) was added, and mixture was stirred 10 minutes. Ethyl acetate solution was extracted twice with NaHCO3 solution (50 mL), once with brine (50 mL), and evaporated under vacuum, giving 2-bromo-1-(6-bromonaphthalen-2-yl)-ethanone (33.0 g, crude) as a tan solid.
Reaction SMILES: [NH2:1][CH:2]1[C:7](=[O:8])[N:6]2[CH:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10](=[O:16])[N:11]([CH:13]([CH3:15])[CH3:14])[CH2:12][CH:5]2[N:4]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])(=[O:27])=[O:26])[CH2:3]1>C(#N)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:9]2[N:6]3[C:7](=[O:8])[CH:2]([N:1]4[CH2:19][CH2:18][CH2:17][CH2:9][CH2:10]4)[CH2:3][N:4]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])(=[O:27])=[O:26])[CH:5]3[CH2:12][N:11]([CH:13]([CH3:14])[CH3:15])[C:10]2=[O:16])=[CH:19][CH:20]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Solvent: CC#N
Product: CC(C)N1CC2N(C(=O)C(N3CCCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 175 °C
Reaction time: 0.22 h
Yield: 136 %

Procedure:
A mixture of 50 mg (0.089 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione, 2,0 ml of acetonitrile, 0.2 ml (0.2 mmol) of 1M (H2O)—NaHCO3 and 83 mg (0.361 mmol) of 1,5-dibromopropane was heated with stirring in a microwave oven at 175° C. for 800 seconds. After cooling, the mixture was concentrated. The residue was subjected to a flash chromatography on 2 g of SiO2 (elution with EtOAc/DCM, gradient 0-20%). The purified amine was converted into the hydrochloride salt. 38 mg of the desired compound were obtained. LC/MS: (MW calculated, monoisotopic=626.13; measured value (M+H)=627.15)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: COc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: COc1cccc(Nc2ccc3c(NS(=O)(=O)c4cc(F)cc(F)c4)cccc3n2)c1

Procedure:
The title compound, MS: m/e=442.0 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and m-anisidine.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:40]([CH3:42])[CH3:41])[C:8]2[O:12][C:11]([C:13]3[CH:38]=[CH:37][C:16]([C:17]([NH:19][CH2:20][C:21]4([CH3:36])[O:25][C:24](=[O:26])[N:23](CC5C=CC(OC)=CC=5)[CH2:22]4)=[O:18])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:39]=1)#[N:4].Cl[C:44]1[N:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][N:45]=1>CN(C)C=O>[C:3]([C:5]1[CH:6]=[C:7]([CH:40]([CH3:42])[CH3:41])[C:8]2[O:12][C:11]([C:13]3[CH:38]=[CH:37][C:16]([C:17]([NH:19][CH2:20][C:21]4([CH3:36])[O:25][C:24](=[O:26])[N:23]([C:44]5[N:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][N:45]=5)[CH2:22]4)=[O:18])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH:39]=1)#[N:4]
Reactant: COc1ccc(CN2CC(C)(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)OC2=O)cc1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5nccc(C(F)(F)F)n5)C(=O)O4)cc3)oc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a mixture was sodium hydride (9 mg, 60% dispersion) in 5 ml of dimethylformamide was added 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[(5-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl]benzamide (31 mg, EXAMPLE 65) followed by 2-chloro-4-trifluoromethylpyrimidine (14 mg). The mixture was stirred at 70° C. for 1 h. Excess sodium hydride was quenched by addition of 1 ml of methanol. The sample was then purified via mass-directed HPLC on a Kromasil C18 column eluting with a gradient of 10% acetonitrile in water (0.01% TFA) to 60% acetonitrile in water (0.01% TFA) providing the title compound (25 mg, 59%). Mass spectrum (ESI) 565.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.94 (d, J=3.9 Hz, 1H), 8.33 (d, J=7.8 Hz, 2H), 7.95 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.52 (s, 1H), 7.36 (d, J=4.1 Hz, 1H), 6.69 (bs, 1H), 4.26 (d, J=11.2 Hz, 1H), 4.12 (d, J=10.7 Hz, 1H), 3.99 (dd, J=14.6, 6.2 Hz, 1H), 3.55 (dd, J=14.8, 6.1 Hz, 1H), 3.48 (sept, J=6.5 Hz, 1H), 1.66 (s, 3H), 1.46 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N:21]1[C:30](=[O:31])[C:29]2[C:24](=[N:25][C:26]([S:32][CH3:33])=[N:27][CH:28]=2)[N:23]([CH3:34])[C:22]1=[O:35].CN(C=[O:40])C.ClC1C=C(C=CC=1)C(OO)=O>C(Cl)(Cl)Cl>[CH3:33][S:32]([C:26]1[N:25]=[C:24]2[N:23]([CH3:34])[C:22](=[O:35])[N:21]([C:3]3[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])[C:30](=[O:31])[C:29]2=[CH:28][N:27]=1)=[O:40]
Reactant: CN(C)C=O
Reactant: CSc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-n1c(=O)c2cnc(S(C)=O)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirred solution of N-[4-Methyl-3-(1-methyl-7-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (184 mg, 0.37 mmol) in the mixed solvent of DMF (4 mL) and chloroform (4 mL) is added m-chloroperoxybenzoic acid (77% max., 97 mg, 44 mmol) and the mixture is stirred for 1 h at room temperature. The mixture is diluted with chloroform, and washed with 5% aqueous Na2S2O3 solution and saturated NaHCO3 solution. The organic layer is dried over MgSO4 and concentrated under reduced pressure to give N-[3-(7-Methanesulfinyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (167 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](O)=[O:8].CCN=C=NCCC[N:21]([CH3:23])C.Cl.C(N(CC)CC)C.N[O:33][CH3:34].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([N:21]([O:33][CH3:34])[CH3:23])=[O:8])[CH:10]=[CH:11][CH:12]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C=Cc1cccc(F)c1
Reactant: CON
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
A mixture of 3-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g), DMAP (12.2 g), triethylamine (28 mL), and NH2OMe.HCl (12 g) in CH2Cl2 (300 mL) was stirred at room temperature for 16 h. The reaction was quenched with water, and the organic layer was washed with brine, dried over MgSO4 and filtered. The filtrated was evaporated in vacuo, and the crude product was purified by silica gel flash chromatography eluting with 33% hexanes in ethyl acetate gave the title compound (20.2 g) as a solid.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([C:10]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][C:13]([C:22]#[N:23])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH2:6][C:5]=12.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:25][C:9]1([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22]#[N:23])=[CH:12][CH:11]=2)[N:4]2[CH:3]=[N:2][CH:1]=[C:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(-c2ccccc2)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)biphenyl-3-carbonitrile (53 mg, 0.177 mmol) in THF (2 mL) at −40° C. is added LHMDS (1.0 M in THF, 0.27 mL, 0.27 mmol). The resulting brown solution is stirred at −30° C. for 0.5 h. To the reaction mixture is added methyl iodide (0.017 mL, 0.272 mmol) and the mixture is warmed up to ambient temperature and stirred overnight. The reaction mixture is quenched by saturated aqueous NH4Cl and the reaction is partitioned between CH2Cl2 and brine. The organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude oil, which is subject to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 314 (M+H).
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[Cs+].[Cs+].[F:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([OH:24])=[C:12]([CH2:25][OH:26])[CH:11]=1.O>CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:24][CH3:3])=[C:12]([CH2:25][OH:26])[CH:11]=1
Reactant: OCc1cc(F)cc(OCc2ccccc2)c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(CO)cc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Iodomethane (24 mL, 382 mmol) and cesium carbonate (25 g, 76.4 mmol) were added to a solution of 4-fluoro-2-(hydroxymethyl)-6-[(phenylmethyl)oxy]phenol (9.5 g, 38.2 mmol) in DMF (125 mL). The mixture was stirred for 1 h at rt, and then water was added. The resulting aqueous mixture was extracted twice with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}methanol as a yellow solid (7.9 g, 30.2 mmol, 79% yield). 1H NMR (400 MHz, CDCl3): δ 7.44-7.32 (m, 5H), 6.69-6.63 (m, 2H), 5.08 (s, 2H), 4.67 (d, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][C@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH3:3].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].O>C(O)C>[CH2:25]([O:24][C:20](=[O:23])[CH2:21][CH2:22][N:4]([CH2:1][CH2:2][CH3:3])[C@@H:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][C@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:26]
Reactant: CCCN[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Reactant: C=CC(=O)OCC
Solvent: O
Solvent: CCO
Product: CCCN(CCC(=O)OCC)[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 57.3 %

Procedure:
Ethyl 8-(propylamino)-trans-1,4-dioxaspiro[4.5]-decane-7-carboxylate (129.6 g, 0.48 mole) was dissolved in ethanol (1500 ml), then ethyl acrylate (479 g, 4.8 mole) was added. The mixture was refluxed overnight, then additional ethyl acrylate (479 g, 4.8 mole) was added. The mixture was refluxed for 24 hours, at which time a third addition of ethyl acrylate (479 g, 0.48 mole) was made, followed by 60 hours of reflux. The mixture was then cooled to room temperature, poured into water, and the hydrogen ion concentration was adjusted to pH 10. The product was extracted with methylene chloride, dried with sodium sulfate and evaporated to give 177.4 g of crude product. This was purified by HPLC to give 102.1 g of the title product (59.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: CCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 565.7 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1-propylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.055 mL (0.046 mMol) 4-fluorobenzoyl chloride, 0.099 gm (67%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[S:8][C:9]([CH3:16])=[C:10]([C:12](=O)[CH2:13][Br:14])[CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:29][C:30]([NH2:32])=[S:31])[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>>[BrH:14].[CH3:16][C:9]1[S:8][C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:11][C:10]=1[C:12]1[N:32]=[C:30]([NH:29][C:21]2[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=2)[S:31][CH:13]=1
Reactant: COc1cc(NC(N)=S)cc(OC)c1OC
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(=O)CBr
Product: Br
Product: COc1cc(Nc2nc(-c3cc(C(=O)OC(C)C)sc3C)cs2)cc(OC)c1OC
Yield: 47.6 %

Procedure:
Isopropyl-4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (84 mg, 0.27 mmol) was allowed to react with 3,4,5-trimethoxyphenylthiourea (66.5 mg) as described in Example 154, step (a) to give 68 mg (48% yield) of isopropyl 5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. For C21H24N2O5S2, 448.56 (M+H), found 449.0.
Reaction SMILES: C(O)(=O)/C=C/C(O)=[O:5].[CH3:9][C:10]1[CH:41]=[CH:40][CH:39]=[CH:38][C:11]=1[CH2:12][NH:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]([CH3:37])[CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:18]=2[CH:17]=1)=S>C(O)(=O)C>[CH3:9][C:10]1[CH:41]=[CH:40][CH:39]=[CH:38][C:11]=1[CH2:12][NH:13][C:14]([C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]([CH3:37])[CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:18]=2[CH:17]=1)=[O:5]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: Cc1ccccc1CNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: CC(=O)O
Product: Cc1ccccc1CNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 12 h

Procedure:
Fumaric acid (0.7 g) and mercuric acetate (2.5 g) are added in the course of 20 minutes to a solution of N-(2-methylbenzyl)-10[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (3.8 g) in acetic acid (30 cc), and the mixture obtained is stirred for 12 hours at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with Celite and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (100 cc) and the organic phase is washed successively with normal sodium hydroxide (2×20 cc) and distilled water (2×20 cc) and with saturated aqueous sodium chloride solution (20 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and N-(2-methylbenzyl)-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (3.2 g), is thereby obtained in the form of a yellow oil, which is used subsequently without further treatment.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:26])[N:13]([CH:20]2[CH2:25][CH2:24][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:22][CH2:21]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1C(=O)N(C1CCNCC1)C2=O)c1ccc(Cl)s1
Reactant: Brc1ccccn1
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C(=O)N(C1CCN(c3ccccn3)CC1)C2=O)c1ccc(Cl)s1

Procedure:
100 mg (0.257 mmol) of 5-chloro-N-[1,3-dioxo-2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-4-yl]-2-thiophenecarboxamide and 0.05 ml (0.513 mmol) of 2-bromopyridine in 0.5 ml of pyridine are stirred at 110° C. for 48 h. The mixture is concentrated and dried under high vacuum. The product is isolated by preparative RP-HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>CCOCC>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1ccc(Br)cn1
Solvent: CCOCC
Product: Cc1ccc(C2(O)CCC3(CC2)OCCO3)cn1

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-methyl-pyridine (Acros Organics) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:23])[CH2:19][C:20](O)=[O:21]>>[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:16])[N:2]([NH:1][C:20](=[O:21])[CH2:19][C:18]([CH3:17])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[N:11]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1nn(N)c(=O)c2ccccc12
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(C)c1nn(NC(=O)CC(C)(C)c2ccccc2)c(=O)c2ccccc12

Procedure:
The product from Example 62A and 3-methyl-3-phenylbutanoic acid were treated using a method similar to that described in Example 51 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.21 (s, 1H), 8.35-8.39 (m, 2H), 7.93-7.99 (m, 1H), 7.84-7.90 (m, 1H), 7.43-7.47 (m, 2H), 7.24-7.39 (m, 2H), 7.15-7.21 (m, 1H), 2.59 (s, 2H), 1.47 (s, 6H), 1.46 (s, 9H); MS (ESI−) M/Z 376 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][C:28]1[N:33]=[C:32](B(O)O)[CH:31]=[CH:30][CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:27])[N:33]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1cccc(B(O)O)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: Cc1cccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one and 6-methylpyridine-2-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.986 min, m/z=431.1; 1H NMR (CDCl3) 1.33 (m, 2H), 1.52 (d, 3H), 1.69 (m, 1H), 1.97 (m, 2H), 2.12-2.30 (m, 3H), 2.56 (s, 3H), 2.85 (m, 1H), 3.52 (t, 2H), 5.67 (m, 1H), 6.95 (d, 2H), 7.03 (d, 1H), 7.22-7.37 (m, 6H), 7.55 (t, 1H), 7.64 (d, 2H).