Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:26])[CH2:24]Br)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:29])C.[K+].Cl.C(Cl)Cl>C(O)(=O)C>[CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:26])[CH2:24][OH:29])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=C(CBr)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CO)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 112.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A mixture of N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (16 g, 36.3 mmol) and potassium acetate (8.90 g, 91 mmol) in acetic acid (130 ml) was heated to 110-115° C. (slow reflux visible) and stirred for 1 hour (complete by HPLC). Cooled, acetic acid (80 ml) removed under reduced pressure, the residue distributed between DCM (120 ml) and water (120 ml). The organic phase was washed with water, evaporated to half of the volume, diluted with 2-propanol (65.0 ml), the rest of DCM removed. Water (18.20 ml) was added followed by concentrated hydrochloric acid (2.102 ml, 25.4 mmol), residual DCM was distilled off at atmospheric pressure until head temperature reached 77° C., then stirred under reflux for 3 hours. Diluted with water (65 ml), 2-propanol removed at 60° C./180 mbar, to the biphasic residue EA (80 ml) was added followed by sodium bicarbonate with stirring until evolution of gas stopped. The organic phase was dried (MgSO4), evaporated to dryness to give N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide (13.2 g, 34.9 mmol, 96% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:20])[CH3:19])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCC2(CCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (140 mg, 0.58 mmol) in DCM (5.8 mL) was added acetic anhydride (82 μL, 0.87 mmol) and triethylamine (244 μL, 1.75 mmol) and the reaction mixture was stirred (rt, 16 h). The reaction mixture was diluted with DCM (6 mL), washed with water (3×4 mL) and brine (1×4 mL). The organic layer was dried, filtered and concentrated in vacuo to provide 7-acetyl-2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester as a brown oil (164 mg, 100%). This intermediate was dissolved in DCM (0.75 mL), treated with HCl (4M in dioxane, 0.75 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to yield then desired product (128 mg, 100%). MS (ESI): mass calcd. for C10H18N2O, 182.14; m/z found, 183.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]=[C:7]1O[C:9](=[O:10])[CH2:8]1.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[S:17][C:7]([CH2:8][C:9]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:10])([CH3:6])[NH:12][CH:13]1[C:18]([OH:20])=[O:19]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: C=C1CC(=O)O1
Reactant: C1CCNC1
Solvent: c1ccccc1
Product: CC1(CC(=O)N2CCCC2)NC(C(=O)O)C(C)(C)S1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 3.6 g (50 mmoles) of pyrrolidine in 50 mg of anhydrous benzene was added dropwise a solution of 4.2 g (50 mmoles) of diketene in 50 ml of anhydrous benzene at 0°-5° C. over 2 hours. The mixture was allowed to stand at room temperature for 2 hours, and the solvent was distilled off to a half its volume under reduced pressure. To the residue was added 5 g (34 mmoles) of D-penicillamine. The mixture was heated at 80° C. with stirring under a stream of argon for an hour to obtain a pale yellow and clear reaction mixture. The reaction mixture was filtered, the solvent was distilled off and the resulting residue was washed with a mixture of n-hexane and ether. The viscous residue thus obtained was crystallized from hot benzene and further recrystallized from benzene to give 9.5 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-acetopyrrolidide as colorless prisms.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[C:9]([CH3:21])([CH3:20])[C:10](ON1C(=O)CCC1=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C@H:24]([CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)[C:25]([N:27]1[CH2:45][CH2:44][CH2:43][C:29]2([C:33](=[O:34])[N:32]([CH3:35])[CH2:31][CH:30]2[C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:28]1)=[O:26].CCN(C(C)C)C(C)C>C1COCC1.O>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH:30]2[C:29]3([CH2:43][CH2:44][CH2:45][N:27]([C:25](=[O:26])[C@H:24]([NH:23][C:10](=[O:11])[C:9]([N:8]([CH3:22])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:21])[CH3:20])[CH2:46][O:47][CH2:48][C:49]4[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=4)[CH2:28]3)[C:33](=[O:34])[N:32]([CH3:35])[CH2:31]2)=[CH:41][CH:40]=1
Reactant: Cc1ccc(COC[C@@H](N)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccc(F)cc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COC[C@@H](NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,5-dioxopyrrolidin-1-yl 2-(tert-butoxycarbonyl(methyl)amino)-2-methylpropanoate (80 mg, 0.254 mmol) and 7-((R)-2-amino-3-(4-methylbenzyloxy)propanoyl)-4-(4-fluorophenyl)-2-methyl-2,7-diazaspiro[4.5]decan-1-one (115 mg, 0.254 mmol) in THF (3 ml) was added DIPEA (0.044 ml, 0.254 mmol) and the mixture stirred at RT overnight. The mixture was diluted with water (10 ml) and extracted with EtOAc (50 ml). The extracts were dried (MgSO4) and concentrated. The residue was applied to a 12 g silica cartridge which was eluted with ethyl acetate. The appropriate fractions were combined and concentrated to give tert-butyl 1-((2R)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-3-(4-methylbenzyloxy)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-yl(methyl)carbamate as a foam.
Reaction SMILES: [C:1]([C:3]([C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C)#N.[OH-].[K+].C1CCCCC1>C(O)CO.O>[C:5]1([CH:3]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:1])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C#N)(c1ccccc1)c1cccnn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Solvent: OCCO
Product: CC(c1ccccc1)c1cccnn1
Yield: 56.8 %

Procedure:
A solution of 3-(1-cyano-1-phenylethyl)-pyridazine (1 g.) in ethylene glycol (10 ml.) and water (1 ml.) containing potassium hydroxide (0.3 g.) was heated at reflux for 6 hours. The yellow solution was diluted with water (40 ml.) and extracted with chloroform (3 × 25 ml.), dried over magnesium sulphate, filtered and evaporated to give a cream-coloured solid (0.8 g.). 3-(1-Phenylethyl)pyridazine (0.5 g.), m.p. 44°-45° C., was obtained from the cream-coloured solid in the form of colourless crystals by recrystallisation from cyclohexane.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C=O)C.[NH2:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=[CH:17][C:16]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40])=[O:37].O>C(OCC)(=O)C>[NH2:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:18]([Br:1])=[CH:17][C:16]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:40])[CH3:41])=[O:37]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1ccc(C(=O)NC(C)(C)c2ccccc2)c(N)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(N)c(C(=O)NC(C)(C)c2ccccc2)cc1Br
Reaction time: 1 h
Yield: 100.7 %

Procedure:
N-bromosuccinimide (22 mg) was added to a DMF (5 ml) solution containing tert-butyl cis-2-(6-amino-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (60 mg) at 0° C., followed by stirring for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel:silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=4:1 to 3:1), and a white solid of tert-butyl cis-2-(6-amino-3-bromo-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (68 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=O)[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.ClCCl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[S:33])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=S)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
1.0 g (3.0 mmole) of N-({3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-4,5-dihydro-5-isoxazolyl}methyl)acetamide is suspended in 12 ml dioxane in a 50 ml one neck round bottom flask under nitrogen. The suspension is treated with Lawesson's Reagent (1.27 g, 3.15 mmole) and the reaction is stirred at 80° C. for 1 hour. The mixture is cooled to room temperature, brought to homogeneity with dichloromethane and is treated with 10 g silica gel (230-400 mesh) and is concentrated to dryness. The plug is loaded onto a SIM and the material is chromatographed twice over 40 g silica gel (BIOTAGE), eluting with 7% acetone/dichloromethane while collecting 25 ml fractions. Fractions 6-13 are combined and concentrated to afford 902 mg (85%) of the title compound as a solid. mp=219-220° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:30][CH3:31])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1[N:13]([CH2:30][CH3:31])[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[C:2]2[NH2:1]
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCN
Temperature: 25 °C
Yield: 87.2 %

Procedure:
2-[4-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]isoindole-1,3-dione (prepared as described in Example 22, 7.10 g, 17.2 mmol), hydrazine hydrate (4.20 mL, 85.9 mmol), and ethanol (213 mL) were combined and heated at reflux for 30 minutes. The solution was allowed to cool to ambient temperature, then was cooled to 0° C. A white solid precipitated from the solution and was isolated by filtration and washed with ethanol. The crude product was purified by chromatography on a HORIZON HPFC system (silica, gradient elution with 10%-75% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure to afford 4.25 g of 1-(4-aminobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:21][N:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]([CH3:30])=[N:23]1.CN(C)C=O>ClCCl>[CH3:21][N:22]1[C:26]([C:27]2[O:20][C:19]3[C:2]([N:1]=2)=[CH:3][C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[CH:18]=3)=[CH:25][C:24]([CH3:30])=[N:23]1.[CH3:21][N:22]1[C:26]([C:27]([OH:12])=[O:28])=[CH:25][C:24]([CH3:30])=[N:23]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(-c2nc3cc4c(cc3o2)CCNCC4)n(C)n1
Product: Cc1cc(C(=O)O)n(C)n1

Procedure:
The title compound was prepared as described in General Procedure 2 from 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride. The latter reactant had been obtained in dichloromethane solution from the reaction of 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (1.3 eq.) in the presence of a catalytic quantity of dimethylformamide, followed by evaporation of the volatiles after 1.5 h at 25° C.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[C:18]1([C:24]2[O:40][C:27]3[N:28]=[CH:29][N:30]=[C:31]([O:32][C:33]4[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=4)[C:26]=3[CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]3[C:26]4[CH:25]=[C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[O:40][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:38][CH:37]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ncnc3oc(-c4ccccc4)cc23)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3oc(-c4ccccc4)cc23)cc1

Procedure:
After adding toluene (1 ml), acetonitrile (0.5 ml) and 4-fluorophenyl isocyanate (0.03 ml) to 4-(6-phenyl-furo[2.3-d]pyrimidin-4-yloxy)phenylamine (40 mg), the mixture was heated to reflux for 30 minutes. After cooling, the precipitated crystals were filtered out and washed with toluene to obtain the title compound (42 mg) as light yellow crystals.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[N:3]=1.[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.C([O-])(=O)C.[K+]>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>[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[N:3]=1
Reactant: c1ccc2scnc2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Product: COC(=O)c1ccc2nc(-c3nc4ccccc4s3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 170 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a solution of methyl 2-chloro-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (300 mg, 0.98 mmol) in 1,3-benzothiazole (266 mg, 1.97 mmol) was added Pd(PPh3)4 (57 mg, 0.05 mmol,) and potassium acetate (193 mg, 1.97 mmol) under an atmosphere of nitrogen. The resulting solution was stirred for 2 h at 170° C. and then quenched by the addition of NH4Cl solution (150 mL), extracted with dichloromethane (3×20 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1%-5% ethyl acetate in petroleum ether to afford methyl 2-(1,3-benzothiazol-2-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate as a yellow solid (80 mg, 20%).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:25](=[O:28])[CH:26]=[CH2:27])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: C=CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Acryloyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acryloyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>O1CCOCC1.O>[CH3:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2c(C)cc(C)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(-c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 60 °C
Yield: 16 %

Procedure:
Combine 1-iodo-2,4,6-trimethylbenzene (2.966 g, 12.05 mmol), 4-carboxyphenylboronic acid (1.0 g, 6.026 mmol), Pd(OAc)2 (0.0067 g, 0.005 mmol), tetrabutylammonium bromide (0.388 g, 1.2055 mmol), and potassium phosphate (2.557 g, 12.05 mmol). Purge the reaction vessel with argon and add anhydrous dimethylformamide (20 mL) to the reaction mixture. Heat the sealed reaction vessel to 120° C. with stirring until completion as determined by TLC. Cool reaction mixture to room temperature. Add methyl iodide (1.0 mL, 36.63 mmol) to reaction mixture with continued stirring until completion. Dilute the reaction with ethyl acetate and filter though a short plug of celite with additional ethyl acetate. Wash the organics with water, dry over magnesium sulfate, filter and evaporate. Purification by flash column chromatography yields 2′,4′,6′-trimethylbiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in dioxane (45 mL) and water (5 mL) containing 5 eq of LiOH with stirring at 60° C. Upon completion, evaporate the solvent, acidify the reaction mixture with hydrochloric acid, and extract with ethyl acetate. Dry the organics over magnesium sulfate, filter, and evaporate to yield 0.023 g (16%) of the title compound. MS (m/e): 239.1 (M−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([OH:25])=[O:24].[C:26](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc2c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 152.6 %

Procedure:
A solution of 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (50 g, 122 mmol) in dichloromethane (700 mL) was cooled to 0° C., and DMF (1.416 mL, 18.28 mmol) was added. To the cooled solution, oxalyl chloride (16.01 mL, 183 mmol) was added dropwise (slowly) and the mixture was stirred at 0° C. for 1 h. Methanol was added and after 2 h the mixture was warmed to room temperature overnight. The solvent was removed under reduced pressure. The residue was treated with water (200 mL) and saturated aqueous NaHCO3 (300 mL) and extracted with methylene chloride (500 mL). The aqueous phase was extracted with methylene chloride (300 mL). The organic phase was washed with saturated aqueous NaHCO3 and brine, dried, filtered, and concentrated. The resulting solid was combined with material from a separate experiment (51 g) and the material was suspended in 400-500 mL of acetonitrile. The mixture was heated to 75° C. until the solid completely dissolved. The mixture was cooled, and the resulting precipitate was collected by filtration and dried. The filtrate was concentrated and the recrystallization procedure was repeated to give additional product. Both batches were combined to afford methyl 6-bromo-3-(methyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (79 g, 73% overall yield). MS (m/z) 426.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:29][C:28]1[CH:27]=[C:26]([CH3:30])[NH:25][C:24](=[O:31])[C:23]=1[CH2:22][NH:21][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH:11]=1)=[O:15]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccsc3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccsc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.244 mmol), DMSO(2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (68.9 mg, 0.365 mmol) HCl salt, N-methylmorpholine (0.107 mL, 0.974 mmol), 1-hydroxy-7-azabenzotriazole (33.2 mg, 0.244 mmol) and EDC (93 mg, 0.487 mmol). The final product was collected as 75 mg (73%). LCMS E-S (M+H)=422.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.8 Hz, 6 H), 2.13 (s, 3 H), 2.23 (s, 3 H), 4.41 (d, J=4.8 Hz, 2 H), 5.30 (quin, J=6.6 Hz, 1 H), 5.91 (s, 1 H), 7.71 (dd, J=5.0, 3.0 Hz, 1 H), 7.92 (d, J=5.0 Hz, 1 H), 8.09 (s, 1 H), 8.34 (s, 1 H), 8.37 (d, J=1.8 Hz, 1 H), 8.79-8.95 (m, 1 H), 11.58 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]3[S:12][C:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([NH:8][CH2:9]3)[C:6]=2[CH:19]=1.S[CH2:21][CH2:22][OH:23]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([S:12][CH2:21][CH2:22][OH:23])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)C1(c3ccccc3)NCC(N2)S1
Reactant: OCCS
Solvent: C1CCOC1
Product: OCCSC1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
A solution of 7-chloro-2,3,4,5-tetrahydro-5-phenyl-2,5-epithio-1H-1,4-benzodiazepine (1g. ) and 2-mercaptoethanol (1 ml) in THF (15 ml) was heated under reflux overnight. The resulting solution was concentrated under reduced pressure and then diluted with ether to induce crystallization of the product. The product was filtered out and washed with ether to give the above-named compound, m.p. 135°-140° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)C>[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])([O:2][CH3:1])=[O:14]
Reactant: COC(=O)CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CCCCCCCCO
Temperature: 25 °C

Procedure:
To a solution of 165 mL (165 mmol) of a 1.0M solution of boranetetrahydrofuran complex in tetrahydrofuran in 200 mL of dry diethyl ether at 0° C. is added dropwise 25.0 g (123 mmol) of azelaic acid monomethyl ester, added at such a rate as to prevent excessive release of gas and exothermicity. The solution is allowed to warm to room temperature overnight and is worked up by slowly adding water until gas evolution ceases. Then solid potassium carbonate is added and the organic layer is separated. The aqueous layer is extracted three times with diethyl ether. The combined extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 8-carbomethoxyoctan-1-ol as a colorless oil.