Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:31])[CH3:32])[C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(N)c1=O)C(=O)C(F)(F)F
Reaction time: 0.25 h

Procedure:
To a solution of 2-[5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide in dichloromethane (35 mL) and anisole (1.2 mL) at 0° C. was added trifluoromethanesulfonic acid, and the resulting suspension was stirred for 15 minutes. The reaction was quenched by addition of sodium bicarbonate and the product extracted into ethyl acetate. The organic layer was washed (brine) and dried. The solvent was removed and the residue was purified by chromatography, with methanol:dichloromethane (gradient, 5:95, 7:93) as the eluent, to provide 2-[5-amino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a yellow solid; 300 MHz NMR (DMSO/D2O): 7.94 (d,1), 7.65 (d,1), 7.30 (s,1), 7.22 (d,1), 7.02 (m,1), 4.84 (d,1), 4.69 (d,1), 4.07 (d,1), 2.24 (m,1), 0.89(d, 3), 0.76 (d,3).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][CH:54]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]3[C:55]2=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:51])[CH2:46][CH2:45]1>CN(C)C=O>[CH:65]1[C:66]2[CH:54]([CH2:53][O:52][C:50]([N:47]3[CH2:48][CH2:49][CH:44]([NH:43][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][C:22]([NH:21][C:19]5[N:18]=[CH:17][C:8]6[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]7[CH2:5][CH2:4][CH2:3][CH2:2]7)[C:7]=6[N:20]=5)=[C:23]([O:31][CH3:32])[CH:24]=4)[CH2:45][CH2:46]3)=[O:51])[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]=2[CH:62]=[CH:63][CH:64]=1
Reactant: NC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a mixture of 0.15 g (0.34 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.24 mL (1.3 mmole) of ethyldiisopropyl amine and 0.13 g (0.37 mmole) of 4-amino-1-Fmoc-piperidine hydrochloride in 5.0 mL of dimethylformamide was added 0.16 g (0.37 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum to give 0.25 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (I-70) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10]>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:10][CH2:9][C:8]([N:7]([CH3:12])[CH3:6])=[O:11])[CH3:2]
Reactant: CCNCC
Reactant: C=CC(=O)N(C)C
Product: CCN(CC)CCC(=O)N(C)C
Yield: 86 %

Procedure:
In accordance with this example, anhydrous diethylamine (44 grams) and N,N-dimethylacrylamide (60 grams) were heated at reflux temperature (about 56°-60°C.) for 48 hours. After this period of time, the reaction mixture was subjected to distillation to separate unreacted amine and amide followed by recovery of product in 86 percent yield at 70°C. and 2 mm. mercury pressure. The liquid product (purity = about 95 percent is designated herein as Amine Catalyst V, and has the formula, (C2H5)2N-CH2CH2C(O)N(CH3)2. The structure of this novel product was confirmed by infrared functional analysis and purity by gas-liquid chromatographic analysis.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:29][OH:30])[N:4]=1.C(N(C(C)C)CC)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[N:4]=1)(=[O:43])=[O:42]
Reactant: COCCOCCOCCN(CCOc1cc(CO)nc(CO)c1)CCC(=O)OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCN(CCOc1cc(COS(C)(=O)=O)nc(COS(C)(=O)=O)c1)CCC(=O)OC
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of 80 mg of methyl 3-([2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate in 8 ml of DCM, precooled to −25° C., was added 183 μl of diisopropylethylamine and 57 μl of methanesulfonyl chloride. The mixture was stirred for 1 hour at −15° C. and then washed with 5 ml of water. The aqueous phase was extracted with 5 ml of DCM. The organic phases were combined, dried over MgSO4 and concentrated under reduced pressure. 110 mg of methyl 3-([2-(2,6-bis-methanesulfonyloxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate were obtained. LC/MS (B): tr=2.67 min; [M+H]+: m/z 587
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.CO.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.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>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][OH:21])[CH:28]=3)[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
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: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CNc1nc(C)c2cc(-c3cccc(CO)c3)c(=O)n(C3CCCC3)c2n1
Yield: 81.2 %

Procedure:
6-Bromo-8-cyclopentyl-4-methyl-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-one (5.00 g, 14.83 mmol), 3-(hydroxymethyl)phenylboronic acid (3.38 g, 22.24 mmol) and Pd(PPh3)4 (0.685 g, 0.593 mmol) were suspended in Toluene (20 mL), MeOH (10 mL) and sat. NaHCO3 (10 mL) and then heated to 100° C. overnight. The reaction was deemed complete by MS and TLC. The organic layer was injected directly onto a column, eluting with CH2Cl2 then 4% MeOH in CH2Cl2. The fractions containing the desired material, as deemed by MS, were combined and evaporated in vacuo to give a greenish beige solid. This was triturated with MeCN and filtered to give crop one, 4.7 g. A second crop was obtained of 0.25 g. A third crop was obtained of 0.10 g. The three crops were deemed to be of sufficient purity based on NMR's and were combined and washed again with MeCN to give a solid (4.39 g, 81.24%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)#[N:2].C([O:15][C@@H:16]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:17]1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1)(=O)C>>[O:18]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:24]=1)[C@@H:17]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:16]1[OH:15]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: N#Cc1ccccc1B(O)O
Product: N#Cc1ccccc1-c1cncc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c1

Procedure:
By following a procedure analogous to Example 122 starting from 2-cyano-phenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 5-(2-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=67%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Yield: 81.3 %

Procedure:
A solution of 6,8 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester in a mixture of 46 ml of glacial acetic acid, 35 ml of water and 4.5 ml of concentrated sulfuric acid was refluxed for 1.5 hours. The resulting suspension was cooled in an ice bath, the solid collected, washed with cold water, dried and recrystallized from hot dimethylformamide, giving 5 g of the desired compound, mp 288°-290° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])=[C:5]([CH3:18])[O:4][N:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Mg]Br)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([OH:17])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(=O)C(=O)N2
Reactant: Br[Mg]c1ccccc1CN1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1CN1CCOCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(3,5-Dimethyl-isoxazol-4-yl)-1H-indole-2,3-dione (100 mg, 0.41 mmol) is dissolved in anhydrous THF (1 mL) and cooled to 0° C. (2-(4-Morpholinylmethyl)phenyl)magnesium bromide (4.0 mL, 1.0 mmol) is added dropwise and then the mixture stirred at room temperature for 2 hours. The mixture is poured onto saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate. The solvent is concentrated to dryness and purified using column chromatography on silica gel using a cyclohexane/ethyl acetate gradient. The product fractions are combined and concentrated to dryness in vacuo.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[Cl:18][C:19]1[CH:35]=[CH:34][C:22](/[CH:23]=[CH:24]/[S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[ClH:18].[Cl:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:23]=[CH:24]/[S:25]([N:28]2[CH2:33][CH2:32][N:31]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)=[CH:16][CH:15]=3)[CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: O=S(=O)(/C=C/c1ccc(Cl)cc1)N1CCNCC1
Agent: Cl
Product: O=C(c1ccc(-c2ccccn2)cc1)N1CCN(S(=O)(=O)/C=C/c2ccc(Cl)cc2)CC1

Procedure:
In the same manner as in Example A-17, a reaction was conducted using 4-(2-pyridyl)benzoic acid hydrochloride and 1-[(E)-4-chlorostyrylsulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:34][CH2:35][CH2:36][OH:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:33]([CH2:34][CH2:35][CH2:36][OH:37])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: OCCCNCc1ccccn1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(CCCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-[(pyridin-2-ylmethyl)-amino]-propan-1-ol
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:49]=[N+:50]=[N-:51].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][N:49]=[N+:50]=[N-:51])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN=[N+]=[N-])C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 98.0 mg of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 18b) in N,N-dimethylformamide are added 94 mg of sodium azide and the resulting mixture is stirred for 24 hours at room temperature. The reaction mixture is diluted with water, extracted with tert-butyl methyl ether, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.47 (EtOAc-heptane 1:1); Rt=5.65.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC1CCCC1
Product: COC(=O)CC(N)c1ccc(OC)c(OC2CCCC2)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-cyclopentyloxy-4-methoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.78-6.88 (m, 3H), 4.76 (s, 1H), 4.34 (t, 1H, J=5 Hz), 3.80 (s, 3H), 3.66 (s, 3H), 2.62 (d, 2H, J=5 Hz), 1.82-1.92 (m, 8H), 1.58 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=O)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:25]3[CH:26]=[N:27][CH:28]=[C:29]([F:30])[C:24]=3[N:23]([CH:31]([CH3:34])[CH2:32][OH:33])[CH:22]=2)=[O:20])[CH:16]=[N:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([C:19]([C:21]3[C:25]4[CH:26]=[N:27][CH:28]=[C:29]([F:30])[C:24]=4[N:23]([CH:31]([CH3:34])[CH2:32][OH:33])[CH:22]=3)=[O:20])[CH:14]=2)=[O:11])=[N:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cn1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using (5-chloropyridin-2-yl)acetic acid (Preparation 80) and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26). The residue was purified using preparative TLC eluting with 5% MeOH in EtOAc.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]-quinazoline (2.0 g, 6.35 mmol) in dry DMF (20 mL) under N2 was added acrylic acid (12.7 mmol, 0.87 mL). The resulting solution was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (7.62 mmol, 1.46 g) was added. The reaction was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stirred for a further 2 hours, after which additional acrylic acid (0.30 mL) and EDCI.HCl (0.30 g) were added. After a further 2 hours, the reaction was complete by tlc, solvent was removed under reduced pressure, and the resulting residue diluted with saturated NaHCO3 and repeatedly extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatography on grade III alumina eluting with EtOAc/MeOH (95:5) followed by recrystallization from EtOAc/hexane gave a spongy white solid, which upon several hours under high vacuum gave N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.06 g, 45%) as a cream powder, mp 258-261° C.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(OCC)C>CN(C)C=O>[CH:29]1([C:27](=[O:28])[CH2:26][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[N:5]2[C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=3)[N:15]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(=O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)C3CCCCC3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
An oily suspension (50% by weight; 3.1 g) of sodium hydride is added at a temperature in the region of -5° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g) in anhydrous dimethylformamide (180 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. A solution of cyclohexyl methyl ketone (8.2 g) in anhydrous dimethylformamide (20 cc) is then added and stirring is continued for 6 hours at a temperature in the region of 0° C. and then for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into distilled water (800 cc). The solid obtained is separated by filtration, washed with water, dried in the air, and then recrystallized in acetonitrile and finally purified by chromatography under pressure (50 kPa) on silica gel (0.04-0.063 mm; 140 g) contained in a column 2.8 cm in diameter. Elution is performed with methylene chloride, collecting 20-cc fractions. Fractions 25 to 62 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is taken up with ethyl ether (100 cc) and separated by filtration. 3-(2-Cyclohexyl-2- oxoethyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (4.8 g), m.p. 140° C., is obtained.
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH2:11])[C:4]([NH2:10])=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:14]=[C:15]([C:20]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([OH:31])[CH:25]=2)=O)=O)[CH:16]=[CH:17][C:18]=1[OH:19].C(OCC)C>CO>[ClH:1].[ClH:1].[OH:12][C:13]1[CH:14]=[C:15]([C:20]2[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([OH:31])[CH:25]=3)=[N:10][C:4]3[C:3](=[CH:8][CH:7]=[C:6]([NH2:9])[CH:5]=3)[N:11]=2)[CH:16]=[CH:17][C:18]=1[OH:19]
Reactant: O=C(C(=O)c1ccc(O)c(O)c1)c1ccc(O)c(O)c1
Reactant: Nc1ccc(N)c(N)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc2nc(-c3ccc(O)c(O)c3)c(-c3ccc(O)c(O)c3)nc2c1
Temperature: 25 °C
Yield: 169.5 %

Procedure:
98.0 mg (0.5 mmol) of 1,2,4-benzenetriamine dihydrochloride and 137.1 mg (0.5 mmol) of 3,3′,4,4′-tetrahydroxybenzil were dissolved in 3 ml of MeOH. The reaction was refluxed for 6 hours. Then the reaction mixture was cooled to r.t. and added dropwise to 40 ml of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacuo to give 184.0 mg (84.7% yield) of the product. 97.7% purity by LC/MS (230 DAD). Mass-spec [ES+]=362.8. 1H NMR (MeOH-d4) 6.73–6.75 (1H, d), 6.78–6.80 (1H, m), 6.88–6.89 (1H, m), 6.94–6.97 (3H, m), 7.03 (1H, d), 7.49–7.51 (1H, dd), 7.97–7.99 (1H, d).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4].[CH3:31][NH:32][CH3:33]>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19]([C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:32]([CH3:33])[CH3:31])=[CH:30][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1)=[O:20]
Reactant: CNC
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CCl)cc1OCC2)c1ccccc1Cl
Product: CN(C)CC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 147 for the synthesis of 237, 8-(2-chloroacetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with dimethylamine to give 210. MS: (ESI+) 470.2
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[C:18]([OH:23])=[N:19][CH:20]=[CH:21][CH:22]=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[C:18]([OH:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1cccnc1O
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O)c2c1C

Procedure:
Prepared analogously to example 1.1 from 0.2 g 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 0.1 g 3-amino-pyridin-2-ol in dioxan.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C1C=CC=CC=1>[CH:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: Oc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(C2CCCCC2)cc1

Procedure:
Referring to FIG. 1, this is a flow diagram of the hydroalkylation and dealkylation stages of an integrated process according to one example of the invention for converting benzene to phenol. In the process shown in FIG. 1, fresh benzene (line 11) and hydrogen (line 12) are introduced to a hydroalkylation reactor 13, where the benzene undergoes hydroalkylation to produce cyclohexylbenzene (CHB) and poly-cyclohexylbenzenes (PCHB). The effluent from the reactor 13, containing unreacted benzene in addition to the CHB and PCHB, is removed via line 14 and fed to a distillation system 15, which divides the effluent into a C6 fraction, a C12 fraction and a C18 fraction.