Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[N:36]([C:37]4[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=4[Cl:44])[N:35]=[C:34]([CH2:45][OH:46])[CH:33]=3)=[CH:31][C:26]=2[O:25][CH2:24]1>C(Cl)Cl>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[N:36]([C:37]4[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=4[Cl:44])[N:35]=[C:34]([CH:45]=[O:46])[CH:33]=3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: OCc1cc(-c2ccc3c(c2)OCO3)n(-c2cc(Cl)ccc2Cl)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cc(-c2ccc3c(c2)OCO3)n(-c2cc(Cl)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of Dess-Martin periodinane (2.3 g, 5.5 mmol, 2.0 equiv) in CH2Cl2 (10 mL) was added a solution of [5-benzo[1,3]dioxol-5-yl-1-(2,5-dichloro-phenyl)-1H-pyrazol-3-yl]-methanol (prepared by the method of Example 1, Steps A-C; 1.0 g, 2.8 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred overnight at room temperature. Then the reaction was quenched with 1 M NaOH (10 mL), and the resulting mixture was stirred until the layers separated. The aqueous layer was back-extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with 1 M NaOH (20 mL) then H2O (20 mL), dried (MgSO4), and concentrated to provide the pure aldehyde (1.04 g, 2.8 mmol, 99%). HPLC: Rt=5.35 (Method B). MS (ESI): mass calculated for C17H10Cl2N2O3, 360.01; m/z found, 361 [M+H]+. 1H NMR (400 mHz, CDCl3): 10.05 (s, 1H), 7.50-7.43 (m, 1H), 7.25-7.21 (m, 2H), 7.7-7.26 (m, 1H), 6.96 (s, 1H), 6.74-6.72 (m, 1H), 6.68-6.65 (m, 2H), 5.97 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=O)=[C:4]([NH:12][NH2:13])[CH:3]=1>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:10])[NH:7][C:6]3[N:12]([N:13]=[C:4]([CH3:3])[CH:5]=3)[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cnc(Cl)cc1NN
Solvent: CO
Product: Cc1cc2[nH]c(=O)c3cnc(Cl)cc3n2n1

Procedure:
3 g. of 6-chloro-4-hydrazino-3-pyridinecarboxylic acid, methyl ester and 2.4 g. of 3-aminocrotonic acid nitrile are refluxed in 10 ml. of methanol for 72 hours. After this time, 8-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]-pyrimidin-5(4H)-one is filtered off, yield: 2.5 g. (73%); m.p. > 300°.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH2:26][CH3:27])=[C:23]([Cl:25])[N:24]=3)=[O:19])=[C:13]([CH3:28])[CH:12]=2)[O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Li+].CO>O1CCCC1>[Cl:25][C:23]1[N:24]=[C:20]([C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:7]3[O:8][C:9]([CH3:10])=[C:5]([C:3]([OH:4])=[O:2])[N:6]=3)=[CH:12][C:13]=2[CH3:28])=[O:19])[NH:21][C:22]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2C)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(C)o3)cc2C)nc1Cl
Yield: 85.7 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methylphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (108f) (0.12 g, 0.30 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (5 mL) and tetrahydrofuran (5 mL), to obtain 0.10 g of the title compound as a colorless solid (86%).
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22](OCC)=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>CO.CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:30][CH2:29][CH2:27][OH:28])=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3)nc1-2
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NCCO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 65 °C
Yield: 60 %

Procedure:
To a suspension of 0.30 g (0.86 mmol) of ethyl 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in a mixture of 10 mL of methanol and 10 mL of dimethylformamide, 5 mL of ethanolamine were added. The mixture was heated in a close bottle under stirring at 65° C. After 5 hours the solvent was removed, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with diethyl ether and the product collected by filtration (60% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].O=S(Cl)Cl.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:16])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8]
Reactant: CO
Reactant: CCc1sc(C(=O)O)cc1Br
Solvent: O=S(Cl)Cl
Product: CCc1sc(C(=O)OC)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The suspension of 4-bromo-5-ethylthiophene-2-carboxylic acid (800 mg) in MeOH (4 mL) was added dropwise SOCl2 (0.50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, warmed to 60° C., and then stirred for 15 hours. The reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=98:2 to 70:30) to obtain methyl 4-bromo-5-ethylthiophene-2-carboxylate (765.0 mg) as a colorless liquid.
Reaction SMILES: O.C(OC([NH:12][C@@H:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]3[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]3)[CH:19]=2)[CH2:14]1)=O)C1C=CC=CC=1.C(Cl)[Cl:38].Cl>C(O)C.[OH-].[Pd+2].[OH-]>[ClH:38].[NH2:12][C@@H:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][N:23]3[C:27]([C:28]([F:29])([F:30])[F:31])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]3)[CH:19]=2)[CH2:14]1
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)c1C(F)(F)F
Reactant: ClCCl
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](N)C3)c1C(F)(F)F
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Palladium hydroxide (0.092 mmol, 12.96 mg) was wetted with a small volume of water before addition of (S)-ethyl 1-((2-(benzyloxycarbonylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.092 mmol, 45 mg) in Ethanol (5 mL). A small volume DCM was added to aid solubility. Aq. HCl 5N (0.500 ml) was added before the mixture was left to stand at room temp for around 1.5 h before hydrogenating at 2 bar for 45 min. After this time, the mixture was filtered through a filter tip and concentrated to give the desired product as a colourless oil (36 mg, 0.092 mmol, 100%). 1H NMR (400 MHz, CD3OD) δ 1.33 (t, 3H) 2.98 (m, 2H) 3.40 (m, 2H) 4.10 (m, 1H) 4.31 (q, 2H) 5.50 (s, 2H) 7.05 (d, 1H), 7.10 (s, 1H), 7.27 (d, 1H) 8.04 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>C(Cl)Cl>[C:5]([O:17][C:12]1[CH:13]=[CH:14][C:15]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:16][C:11]=1[F:10])(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: Oc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)Oc1ccc(C(=O)CC)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a mixture of aluminum chloride (45.8 g, 0.343 mol) in methylene chloride (140 mL) was added propionyl chloride (10.85 mL, 124.9 mmol) all at once followed by 2-fluorophenol (5.57 mL, 62.44 mmol in 25 mL of methylene chloride with a 10 mL rinse). The mixture was gently refluxed 5 h, cooled to ambient temperature and poured onto ice. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with aqueous bicarbonate and brine. The organic layer was dried over calcium sulfate and concentrated to give 11.43 g (82%) of 4-propionyl-2-fluorophenyl propionate as a clear tan oil which was used without characterization.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:32])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21][C:22]4[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=4)=[C:17]([Cl:28])[CH:16]=3)=[C:12]([C:29]#[N:30])[CH:11]=[N:10][N:9]2[CH:31]=1)=[O:5])C.[OH-].[Na+].CCO.C1COCC1.Cl>CCOC(C)=O>[Cl:28][C:17]1[CH:16]=[C:15]([NH:14][C:13]2[C:8]3[N:9]([CH:31]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH3:32])[N:10]=[CH:11][C:12]=2[C:29]#[N:30])[CH:20]=[CH:19][C:18]=1[S:21][C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
A mixture of 426 (70 mg, 0.15 mmol) and 6N NaOH (2 ml, 1.0 mmol) in a mixed solvents of EtOH/THF (2/1) (3 ml) was stirred at rt for 2 days. Neutralized with concentrated HCl to PH=6, treated with EtOAc (50 ml), the mixture was washed with H2O (2×20 ml) and brine (20 ml), dried with Na2SO4. Removal of the solvent gave 428A (55 mg, 93%) as a yellow solid. The product was used in next step without further purification. It has a retention time of 4.73 min (standard LC1 method, 8 min run). MS Found: (M+H)+=439.1
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C1(C2C(C(=O)NC)=CC(C(O)=O)=C(C)C=2)CCC1.Cl.[F:40][C:41]1([C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[CH2:44][NH:43][CH2:42]1.N1CCC(C2C=C3C(=CC=2)NN=C3)CC1>>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:43]3[CH2:42][C:41]([C:45]4[CH:46]=[CH:47][C:48]([C:49]#[N:50])=[CH:51][CH:52]=4)([F:40])[CH2:44]3)=[O:11])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: Cl
Agent: c1cc2[nH]ncc2cc1C1CCNCC1
Product: Cc1nnc(-c2cc(C(=O)N3CC(F)(c4ccc(C#N)cc4)C3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 62, except 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid (compound 78.4) was used in place of 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 5-(piperidin-4-yl)-1H-indazole (compound 62.5). m/z (ES+) 430 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: CCCc1nc(OC)c(NC(=S)Oc2ccccc2)cc1C
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CCCc1nc(OC)c(NC(=S)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C
Yield: 49 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8]C(=O)C)[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: CC(=O)Nc1cc(F)ccc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(F)cc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
The product from Step (a) (5.00 g, 29.9 mmol, 1 equiv) was dissolved in concentrated H2SO4 (30 mL) and cooled to 0° C. Concentrated HNO3 (2.2 mL) was added slowly via pipet, and the solution gradually became dark brown. After 30 minutes at 0° C., the reaction mixture was poured onto ice (˜200 mL), and the mixture was allowed to stir and warm to room temperature. The solid precipitate was collected by filtration and washed several times with water. The solid was suspended in 6N HCl (30 mL) and the mixture was heated to reflux for 5 hours, then stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O and neutralized with solid K2CO3. The resulting precipitate was collected by filtration and rinsed several times with water, affording 2.82 g (55%) of the title compound as a brown solid. MS (ES+) m/e 171 [M+H].
Reaction SMILES: [C:1]([CH2:4][CH2:5]C(OC1C2C(=CC=CC=2)C=CC=1)C(O)=O)(=[O:3])[NH2:2].N12CCCN=C1CCCCC2.[CH2:32]([O:34][C:35](=[O:53])[CH:36]([O:42][C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][CH:44]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:33].C(N)(=O)C=C.Cl>C(#N)C.O>[CH2:40]([O:39][C:37](=[O:38])[C:36]([CH2:5][CH2:4][C:1](=[O:3])[NH2:2])([O:42][C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][CH:44]=1)[C:35]([O:34][CH2:32][CH3:33])=[O:53])[CH3:41]
Reactant: CCOC(=O)C(Oc1cccc2ccccc12)C(=O)OCC
Reactant: NC(=O)CCC(Oc1cccc2ccccc12)C(=O)O
Agent: C=CC(N)=O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C(CCC(N)=O)(Oc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Carbamoyl-2(R,S)-α-naphthoxybutyric acid: 1.49 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are added to a solution of 3 g of α-naphthoxymalonic acid diethyl ester (Example 36a) and 0.71 g of acrylamide in 5 ml of acetonitrile and the whole is stirred at room temperature for 24 hours. 25 ml of water are added to the reaction mixture, which is adjusted to pH 2 with 2N hydrochloric acid and extracted with ether. The ethereal phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation, leaving (2-carbamoylethyl)-α-naphthoxymalonic acid diethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 1-1 (510 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (506 mg) and n-heptyl bromide (0.235 ml) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (640 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[CH:14]1([CH2:13][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: BrCC1CC1
Product: CC(=O)c1ccc(OCC2CC2)cc1C

Procedure:
Starting from commercially available 1-(4-hydroxy-2-methyl-phenyl)-ethanone and bromomethyl-cyclopropane the title compound is obtained as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:4]=2[S:5][C:6]=1[CH2:7][OH:8]>C1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: OCc1sc2c(F)cccc2c1Cl
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: O=Cc1sc2c(F)cccc2c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.2 %

Procedure:
A suspension of (3-chloro-7-fluoro-benzo[b]thiophen-2-yl)methanol (600 g, 2.78 mmol) and MnO2 (1.69 g, 19.5 mmol) in benzene (25 mL) was stirred at room temperature for 2 d. The solution was filtered through diatomaceous earth and the filtrate concentrated to give the title compound (610 mg, quantitative) as a light, yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.35 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.51 (ddd, J=8.0, 8.0, 4.8 Hz, 1H), 7.32-7.26 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:3]=1[C:4]([O:6]CCOC)=O.[CH3:18][NH2:19]>C[O-].[Na+]>[NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:3]=1[C:4]([NH:19][CH3:18])=[O:6]
Reactant: CN
Reactant: COCCOC(=O)c1cc(C#N)cc(C)c1N
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 97.9 %

Procedure:
The above-described method (Example 3) was repeated to stir 2-methoxyethyl 2-amino-5-cyano-3-methylbenzoate (200 mg, 0.81 mmol) with methylamine (5.40 g, 69.5 mmol, 40% in methanol) and one drop of sodium methoxide (30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and following purification by column chromatography, 2-amino-5-cyano-N,3-dimethylbenzamide (150 mg, 95.0% of theory, 97.8 area % LC) was obtained as a pale brown solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[S:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:2]1[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: Clc1nc2ncccc2s1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro[1,3]thiazolo[4,5-b]pyridine (25 g, 147 mmol) in CH3CN (500 mL) was added 4-hydroxybenzaldehyde (19.8 g, 147 mmol, 1 equiv.) and K2CO3 (22.3 g, 147 mmol, 1 equiv.). The heterogeneous mixture was heated at reflux for 72 h and then cooled to rt. Purification was conducted using one of the following methods.
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH3:14])[C:6]1=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.N1CCCC1>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([C:5]12[CH2:18][CH2:19][C:20](=[O:22])[CH:21]=[C:6]1[C:7]1[C:12](=[C:11]([CH3:14])[C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCC(C)=O)Cc2c(ccc(OC)c2C)C1=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C=C1c1ccc(OC)c(C)c1C2
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A solution of impure 2-butyl-5-methoxy-4-methyl-2-(3-oxo-butyl)-1-indanone (0.96 g, 3.17 mmol), acetic acid (0.182 mL, 3.18 mmol) and pyrrolidine (0.265 mL, 3.18 mmol) in anhydrous toluene (15.9 mL) was stirred and heated in an oil bath at 80° C. for 16 hours. After cooling, the reaction mixture was diluted with Et2O (100 mL), washed with 1N HCl (2×25 mL), 5% NaHCO3 (50 mL), and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to a dark brown oil (0.86 g). The crude product was purified by chromatography on a Biotage FLASH 40S column, eluting with 9:1 hexanes-EtOAc, to afford 9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.50 g) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Br:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1Br
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)ccc2Br)n1
Temperature: 150 °C
Yield: 36 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-bromo-5-chlorobenzoyl chloride (0.134 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.029 g (36% yield) of pure product: MS (ES) m/z 523 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].C(N(CC)CC)C.P(Cl)(Cl)([Cl:19])=O.[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:19])[N:3]=1
Reactant: Cc1ccc[n+]([O-])c1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
2-Chloro-3-methylpyridine 1-oxide (9.00 g, 62.7 mmol) and triethylamine (10.4 ml, 75.2 mmol) were dissolved in dichloromethane (70 ml), and a solution of phosphorus oxychloride (7 ml, 75.3 mmol) in dichloromethane (40 ml) was added dropwise at 0° C. After stirring for 3 hours while elevating reaction temperature to room temperature, the reaction mixture was stirred under reflux for 1 hour. After the reaction was completed, water (30 ml) was added and the reaction mixture was neutralized with a sodium hydroxide solution, and after extracted with dichloromethane (70 ml), dried over magnesium sulfate. The solvent was evaporated and purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=3/100), thereby yielding the title compound (3.47 g) as a white solid 10:3 mixture with 2,4-dichloro-3-methylpyridine.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)([O-:14])=[O:13].CC(C)(C1C=CC=CC=1)CO.[N+](C1C=CC(Cl)=CC=1)([O-])=O>>[CH3:10][C:2]([CH3:1])([O:11][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(O)Cc1ccccc1
Agent: CC(C)(CO)c1ccccc1
Agent: O=[N+]([O-])c1ccc(Cl)cc1
Product: CC(C)(Cc1ccccc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
By a similar manner to reference example 1, 1,1 -dimethyl-2-phenylethylalcohol and 4-nitrofluorobenzene are used in place of 2,2-dimethyl-2-phenylethylalcohol and 4-nitrochlorobenzene respectively to give 4-(1,1-dimethyl-2-phenylethyloxy)-nitrobenzene. Melting point: 78°-79° C.