Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1(C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:48][CH2:47][CH2:46][C@H:2]1[C:3]([N:5]1[CH2:45][CH2:44][CH2:43][C@H:6]1[C:7]([NH:9][C@H:10]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:35])[NH:16][S:17]([C:20]1[C:33]([CH3:34])=[C:31]([CH3:32])[C:30]2[O:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][C:23]=2[C:21]=1[CH3:22])(=[O:19])=[O:18])=[O:8])=[O:4].N1CCCCC1>C(#N)C>[NH:1]1[CH2:48][CH2:47][CH2:46][C@H:2]1[C:3]([N:5]1[CH2:45][CH2:44][CH2:43][C@H:6]1[C:7]([NH:9][C@H:10]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:35])[NH:16][S:17]([C:20]1[C:33]([CH3:34])=[C:31]([CH3:32])[C:30]2[O:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][C:23]=2[C:21]=1[CH3:22])(=[O:19])=[O:18])=[O:8])=[O:4]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)CC2
Solvent: C1CCNCC1
Solvent: CC#N
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2)C(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Fmoc-Pro-Pro-Arg(Pmc)-OtBu 1.7 g (1.86 mmol) was dissolved in acetonitrile (50 mL) and treated with piperidine (2 mL) and the mixture was stirred at RT for 4 h. The solvents were removed and the residue was purified by chromatography using methylene chloride-methanol (8:2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[O:24][NH:23][C:22](=O)[CH:21]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[O:24][N:23]=[C:22]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:21]=1)=[O:19]
Reactant: COC(=O)c1cc(=O)[nH]o1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (1.0 g, 4.8 mmol) in THF (70 mL) was added 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (0.69 g, 4.8 mmol) and triphenylphosphine (1.65 g, 6.3 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (2.7 mL, 6.3 mmol) was added at 4° C. and the reaction mixture was stirred for 3 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 7:3) afforded the title compound (958 mg, 60%) as a white solid. MS: m/e=333.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([S:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[C:11]([S:12][CH3:13])[C:2]=1[CH3:1])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: CSc1cccc(NCC=O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CSc1cccc(N(CC=O)C(=O)CCl)c1C
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-3-methylthioanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-3-methylthioanilino)acetaldehyde.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.BrC[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=O>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[C:6]3=[C:5]([OH:11])[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]3[O:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: Oc1ccc(-c2coc3cc(O)cc(O)c23)cc1
Yield: 38 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(4-methoxyphenyl)ethanone: Yield 38% following procedures B.2, B.3 and B.5; m.p. 220° C. (dec.); IR 3460, 3373, 2914, 1635, 1518, 1229, 1133, 1055 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.75 (s, 1H), 9.36 (s, 1H), 9.33 (s, 1H), 7.62 (s, 1H), 7.46 (d, J=8.5 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 6.37 (d, J=1.7 Hz, 1H), 6.21 (d, J=1.6 Hz, 1H); 13C-NMR (126 MHz, δ ppm, CD3OD) 160.2, 157.7, 157.5, 153.6, 139.7, 131.4, 125.4, 124.1, 115.9, 109.6, 99.0, 90.9.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]2[CH2:9][CH:10]([NH:13]C(=O)C)[CH2:11][CH2:12][C:6]2=[CH:5]1)(=O)C.[OH-].[Na+].C(O)C>O>[CH2:11]1[CH:10]([NH2:13])[CH2:9][C:7]2[C:6](=[CH:5][NH:4][CH:8]=2)[CH2:12]1
Reactant: CC(=O)NC1CCc2cn(C(C)=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1CCc2c[nH]cc2C1

Procedure:
A hydrolysis mixture was prepared from 5.1 g. of dl-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole, 50 g. of sodium hydroxide, 50 ml. of water, and 200 ml. of ethanol. The mixture was heated to refluxing temperature under a nitrogen atmosphere for about 16 hours and was then cooled. The cooled mixture was diluted with water. The alkaline aqueous mixture was extracted several times with methylene dichloride, the methylene dichloride extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and dried. Evaporation of the solvent therefrom yielded a residue comprising dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrol formed in the above reaction. A chloroform solution of the residue was filtered through 105 g. of alumina (grade II). Concentration of the resulting filtrate yielded 2.52 g. of a yellow solid comprising dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole.
Reaction SMILES: [Cl-].[O:2]([CH2:9][C:10]([CH2:12][P+:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>O>[O:2]([CH2:9][C:10]([CH:12]=[P:13]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(COc1ccccc1)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)COc1ccccc1

Procedure:
Phenoxyacetylmethyltriphenylphosphonium chloride (10 g, 22.40 mmol) was suspended in 250 ml water with a few crystals of phenolphthalien added as an indicator. Sodium hydroxide (5%) was added dropwise until the vigorously stirred mixture turned pink. The white solid was collected, washed with water, and dried in a desicator, weight 9 g (98%); mp 127-128.5; ir (KBr, cm-1) 1595, 1580, 1540, 1480, 1435, 1400, 1225, 1105, 1045, 870; nmr (DCCl3, ppm) 7.90-6.90 (m, 21H), 4.53 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)nicotinamide (Stage 13.3) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.82 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=464.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21

Procedure:
In analogy to the procedure described in example 1 c], [6-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid tert-butyl ester was treated with tetrabutylammonium fluoride hydrate to obtain (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester as yellowish oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C)C1C=CC=CC=1.C([O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[C:34]([O:36]CC3C=CC=CC=3)[CH:33]=[C:32]([O:44]CC3C=CC=CC=3)[CH:31]=2)=[CH:24][CH:23]=1)C1C=CC=CC=1>ClCCl>[OH:36][C:34]1[CH:35]=[C:30](/[CH:29]=[CH:28]/[C:25]2[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=2)[CH:31]=[C:32]([OH:44])[CH:33]=1
Reactant: C(=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1)\c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
In a 3 lit. round-bottomed flask equipped with a thermometer are added aluminum chloride (390.35 gm) and N, N-dimethylaniline (413.10 gm) maintaining the temperature at 40-50° C.(exothermic). To this solution, (E)-1-[4-(benzyloxy)phenyl]-2-[3,5-bis(benzyloxy)phenyl]ethene (243 gm) in dichloromethane (800 ml) is added and stirred for further 0.75 hour. After the reaction is over, the reaction mixture is quenched into dil. hydrochloric acid at 0-5° C. and extracted with ethyl acetate. The organic layer is charcoalized and concentrated to get pure (E)-1-(3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)ethene (trans-Resveratrol) in the exclusive trans form. Mp 257-259° C. 1H NMR (DMSO-d6, 400 MHz) δ 6.11 (t, J=1.8 Hz, 1H), 6.38(d, J=1.8 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 6.82(d, J=16.3 Hz, 1H), 6.92(d, J=16.3, 1H), 7.39(d, J=8.4 Hz, 2H); Mass M/e:228.2
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a solution of 4-fluorobenzonitrile (0.500 g, 4.13 mmol) in ethanol (3 mL) was added hydroxylamine HCl (0.427 g, 6.19 mmol) and potassium carbonate (1.14 g, 8.26 mmol). The reaction mass was stirred at RT for 15-17 h. Excess of solvent was removed under vacuum. The obtained residue was diluted with water, acidified with dilute HCl and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.450 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.84 (br s, 2H), 7.17-7.27 (m, 2H), 7.68-7.73 (m, 2H), 9.64 (br s, 1H); MS (m/z): 155.13 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1
Reactant: CC(=O)NC(C)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)c1ccc(CCl)cc1

Procedure:
A solution of N-(1-(4-formylphenyl)ethyl)acetamide (0.32 g) and sodium borohydride (63 mg) in ethanol (10 ml) was stirred at room temperature for 1 hr. Thereto was added 2N hydrochloric acid (1 ml) to stop the reaction, and the reaction mixture was poured into ice water (100 ml) and extracted with ethyl acetate. The extract was washed successively with saturated sodium hydrogencarbonate solution (500 ml) and saturated brine (500 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=2:5, later 1:4) to give N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) as a colorless oil. A solution of the obtained N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) and thionyl chloride (0.050 ml) in chloroform (5 ml) was stirred at 60° C. for 1 hr. This was diluted with ethyl acetate (100 ml) and poured into a saturated sodium hydrogencarbonate solution (100 ml) to separate the organic layer. The aqueous layer was extracted with ethyl acetate (100 ml) and combined with the organic layer obtained earlier. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate alone) to give N-(1-(4-chloromethylphenyl)ethyl)acetamide (92 mg) as yellow crystals.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl.Cl.[CH2:21]([N:23]([CH2:35][CH3:36])[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]1)[CH3:22]>CN(C)C=O>[CH2:35]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:11]2[C:12]3[C:13](=[O:15])[C:14]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:28][CH2:27]1)[CH3:36]
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: CCN(CC)CCN1CCN(CCCl)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN1CCN(CCc2cccc3[nH]c4ccccc4c(=O)c23)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 9.75 g of 9-acridanone, 200 ml of dimethylformamide and 4.8 g sodium hydride is stirred for 0.5 hour, treated portionwise with 17.8 g of 2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]ethyl chloride trihydrochloride, stirred at 70° for 18 hours, then heated to boiling under reflux for 8 hours and evaporated. The residue is treated with 100 ml of water and extracted with dichloromethane. The extract is washed with water, dried and evaporated. The product is crystallized twice from petroleum ether and there is obtained 10-[2-[4-[2-(diethylamino)ethyl]-1-piperazinyl]ethyl-9-acridanone of melting point 106°-108°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=O)[C:6]=2[CH:15]=1.[H][H]>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: [H][H]
Reactant: O=C(O)c1cc(=O)c2cc(F)ccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)C1CCc2cc(F)ccc2O1
Yield: 83 %

Procedure:
A mixture of 63.4 parts of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid and 400 parts of acetic acid was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in petroleumether. The product was filtered off and dried in vacuo at 70° C., yielding 49 parts (83%) of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (int. 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)C(C)C)C>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:6]2[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc(Cl)c2Cl)CC1

Procedure:
A solution of 2,4,5,6-tetrachloro-pyrimidine (1.67 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.85 g (29%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.49-1.60 (m, 2H), 1.73-1.77 (m, 2H), 2.81 (br s, 2H), 3.95-3.98 (m, 2H), 4.09-4.16 (m, 1H), 7.88 (d, J=8.0 Hz, 1H). 13C NMR (100 MHz, DMSO): δ 28.07, 30.45, 43.33, 48.90, 78.65, 109.37, 153.80, 154.62, 155.66, 158.74. MS (ISP): 383.0 [M+H]+.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([Si:18]([CH3:21])([CH3:20])[O:7][C@H:4]1[CH2:5][CH2:6][C@H:1]([OH:8])[CH2:2][CH2:3]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trans-1,4-cyclohexanediol (3 g, 26 mmol) in anhydrous N,N-dimethylformamide (30 mL) at 0° C. was added imidazole (1.7 g, 26 mmol) and tert-butyldimethylchlorosilane (3.87 g, 26 mmol). The reaction mixture was then stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1;2) to give trans-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol as a white solid (3.9 g, 65%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)[CH2:4][OH:5].C(N(CC)CC)C.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C@H:31]1[CH2:33][C@@H:32]1[C:34](Cl)=[O:35]>ClCCl>[OH:5][CH2:4][C@H:3]([NH:2][C:34]([C@H:32]1[CH2:33][C@@H:31]1[C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: CCCC(C)COc1ccc([C@@H](N)CO)cc1
Reactant: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(C)COc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (0.110 g, 0.66 mmol) in dichloromethane (10 ml) in an ice-bath was added oxalyl chloride (0.58 ml, 6.60 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 50 ml round-bottom flask was charged with (R)-2-Amino-2-[4-(2-methyl-pentyloxy)-phenyl]-ethanol HCl (0.47 mmol), dichloromethane (6 ml) and triethylamine (0.31 ml, 2.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×10 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (0.088 g, 48% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (m, 2H), 6.99 (dd, J=5.2, 1.1 Hz, 1H), 6.81 (m, 3 H), 6.72 (d, J=3.3 Hz, 1H), 6.14 (d, J=6.3 Hz, 1H), 4.95 (m, 1H), 3.80 (m, 2H), 3.67 (m, 2H), 2.72 (dd, J=7.1, 4.8 Hz, 1H), 2.62 (m, 1H), 1.85 (m, 1H), 1.60 (m, 2H), 1.27 (m, 5H), 0.92 (d, J=6.8 Hz, 3H), 0.83 (m, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C22H30NO3S 374.5].
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>>[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-phenylpiperazine (193 mg, 1.2 mmol), and DIEA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.74 (m, 4H) 3.19 (m, 4H) 4.05 (s, 2H) 6.78 (t, J=7.29 Hz, 1H) 6.95 (d, J=7.80 Hz, 2H) 7.22 (m, 2H) 7.56 (dd, J=8.15, 4.75 Hz, 1H) 8.33 (dd, J=8.15, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 311 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:14]=[C:13]2[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:12]=32)[CH:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Br:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]3[N:7]([CH2:8][CH2:9][O:10][C:11]=2[CH:18]=1)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[N:14]=3
Reactant: COC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 45 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid methyl ester (1.000 g, 0.003095 mol) in tetrahydrofuran (7.50 mL) and water (4.5 mL) was added lithium hydroxide (0.2964 g, 0.01238 mol). The reaction was stirred at 45° C. for 2 h. The mixture was acidified to pH=1 with 2N HCl. The resulting precipitate was filtered and rinsed with cold water to obtain 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (860 mg) as an off-white solid. MS (ESI+) 309.0/311.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:13])[C:11]#[N:12].[CH3:14]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[C:11]#[N:12]
Reactant: CI
Reactant: COc1ccc(C(C)C#N)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)(C)C#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 2-(2-chloro-4-methoxy-phenyl)propionitrile (19 g, 0.097 mol) and methyliodide (7 mL, 0.11 mol) in dry DMF (100 mL) was flushed with argon for 2 min and cooled to 0° C. Sodium hydride (60% oil susp., 4.4 g, 0.11 mol) was added in small portions. The thick suspension was stirred for another 18 h at 25° C. and then poured into water (300 mL) and extracted with Et2O (3×100 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure leaving a yellow oil which was distilled. Bp: 103-106° C./0.06 mbar, clear oil that solidifies on standing. Yield: 17.5 g (83%). GCMS: >99%