Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H), 3.14 (s, 4H), 3.70 (s, 4H), 4.15 (s, 3H), 6.95-7.01 (m, 3H), 7.26-7.46 (m, 3H), 7.61-7.81 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][OH:21])=[CH:14][C:13]=1[F:22])C1C=CC=CC=1.O1CCCC1>CO>[CH2:27]([C:25]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][OH:21])=[CH:14][C:13]=2[F:22])=[C:9]([OH:8])[CH:26]=1)[CH3:28]
Reactant: CCc1ccc(Oc2ccc(NCCO)cc2F)c(OCc2ccccc2)c1
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(NCCO)cc2F)c(O)c1
Yield: 78.4 %

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for N-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-aminoethanol (350 mg, 0.92 mmol) and tetrahydrofurane for methanol (25 mL), the title compound (210 mg; 78%) was obtained as a yellow solid, after purification on silica gel (ethylacetate and petroleum ether: 5/5)
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37]O)[CH3:34].FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][O:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[CH:17]([C:27]([O:29][CH3:30])=[O:28])[N:16]([S:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=3)=[CH:12][CH:11]=1)(=[O:14])=[O:15])[CH2:25][CH2:24]2)[CH3:34]
Reactant: CCN(CC)CCO
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: CCN(CC)CCOc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(Oc3ccc(F)cc3)cc1)C2C(=O)OC

Procedure:
Methyl 2-[4-(4-fluorophenoxy)benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylate (3B) is reacted with 2-diethylaminoethanol by the method described under 3C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[CH2:9][CH2:8][N:7]([CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)C(C(O)=O)=[N:24]1.Cl.C(N=C=NCCCN(C)C)C>Cl.ClCCl>[CH3:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:10]1[CH2:11][CH:5]([NH:4][C:1]([C:2]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][N:24]=2)=[O:3])[CH2:6][N:7]([CH3:20])[CH2:8][CH2:9]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CC(=O)NC1CN(C)CCN(Cc2cccc(C)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(CN2CCN(C)CC(NC(=O)c3n[nH]c4ccccc34)C2)c1
Reaction time: 2 h
Yield: 32.4 %

Procedure:
A solution of 6-acetylamino-1-(3-methylbenzyl)-4-methyl-hexahydro-1H-1,4-diazepine (0.9 g) in 10% hydrochloric acid (20 ml) is refluxed with stirring for 2 hours. After cooling, the reaction mixture is basified with 48% aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is washed with water and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give an oil. A mixture of this oil, 1H-indazole-3-carboxylic acid (530 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (630 mg) and dichloromethane (20 ml) is stirred at 25° C. for 2 hours. The reaction mixture is washed successively with water and 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.4 g) as an oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]4)[N:21]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].O.Cl>C1COCC1.CO>[OH:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:26][C:22]2[N:21]=[C:20]([N:15]3[C:16]4[CH:17]=[CH:18][CH:19]=[C:11]([C:9]([OH:10])=[O:8])[C:12]=4[CH:13]=[CH:14]3)[CH:25]=[CH:24][N:23]=2)[CH2:28][CH2:29]1
Reactant: COC(=O)c1cccc2c1ccn2-c1ccnc(NC2CCC(O)CC2)n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c1ccn2-c1ccnc(N[C@H]2CC[C@H](O)CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
LAH (327 mg, 13.6 mmol) was added to a suspension of 1-[2-(4-hydroxycyclohexylamino)-pyrimidin-4-yl]-1H-indole-4-carboxylic acid methyl ester (1.0 g, 2.7 mmol) in a mixture of THF (4 mL), water (4 mL) and MeOH (1 mL). The reaction mixture was stirred at RT for 16 h, then evaporated under reduced pressure to give a beige solid. Aqueous HCl (1 M, 14 mL) was added to the residue, and the resulting mixture was stirred and evaporated under reduced pressure. The residue was triturated with MeOH to give trans-1-[2-(4-hydroxycyclohexylamino)-pyrimidin-4-yl]-1H-indole-4-carboxylic acid (700 mg) as an off-white solid. MS=353 [M+H]+; MP=259.0-261.0° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH:2]([CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:6][CH:5]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(CC=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 18 (20.0 g, 0.083 mole) in anhydrous dichloromethane (200 ml) was added pyridinium chlorochromate (PCC) (44.7 g, 0.207 mole) and the mixture was stirred at room temperature for two hours. Ether (500 ml) was then added to quench the reaction and the mixture was then filtered through C elite. (Trade Mark) Evaporation of the solvents in vacuo afforded the crude product which was purified by flash chromatography on silica gel using 20% ethyl acetate in hexane to give 19 (16.6 g, 80%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([N+:17]([O-])=O)[CH:5]=1.[CH3:21]O>[Pd]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:21]=[N:17][C:6]=2[CH:5]=1)=[O:20]
Reactant: CO
Reactant: COC(=O)c1ccc(NCCS(C)(=O)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Product: COC(=O)c1ccc2c(c1)ncn2CCS(C)(=O)=O
Reaction time: 2 h

Procedure:
4-(2-Methanesulfonyl-ethylamino)-3-nitro-benzoic acid methyl ester (1.63 g, 5.40 mmol) was dissolved in methanol, and 10% Pd/C (150 mg) was added to it under N2 atmosphere. The reaction mixture was then hydrogenated at 1 atmospheric pressure at room temp for 2 h. It was filtered through celite and the filtrate concentrated to yield the desired product. The crude material (1.32 g, 4.85 mmol) was taken in formic acid (10 mL) and allowed to stir at 50° C. for 4 h. The reaction mass was concentrated, diluted with water and extracted with EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give 1-(2-methanesulfonylethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (77%). 1H NMR (300 MHz, DMSO-d6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][CH2:16][C:17]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C=O.[CH:33](O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][CH2:16][C:17]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][N:25]([CH3:33])[CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(CCC(=O)N1CCC(c2ccc(Cl)cc2)CC1)c1ccc2c(c1)CCNCC2
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2ccc(C(=O)CCC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-butanone (0.3 g, 0.70 mmol) obtained in Example 15, formaldehyde (0.086 ml, 1.06 mmol) and formic acid (0.9 ml) was heated at 100° C. for 4 hours, then poured into water, made basic with 8 N aqueous sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, the residues were purified by alumina column chromatography (developing solvent; ethyl acetate-methanol=10:1), whereby 0.15 g of the title compound was obtained as colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:33]1[CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:33]2[CH2:36][CH2:35][CH2:34]2)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (400 mg, 1.18 mmol), anhydrous Cs2CO3 (769 mg, 2.36 mmol), and KI (40 mg, 0.24 mmol) in DMF (10 mL) is added bromo-cyclobutane (130 μL, 1.42 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (8) as white solid (320 mg, 69%).
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc1

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.751 g, 5.40 mmol), 4-methoxy phenol (715 mg, 5.76 mmol) and cuprous oxide (390 mg, 2.73 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 81.73° C. (DSC)
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C.CN(C=O)C>[ClH:7].[ClH:7].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=3)[C:33]=2[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:19])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCc1c(O)ccc2cc(C(=N)N)ccc12
Reactant: O=C(O)c1ccc(NC2=NCCN2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)CCc1c(OC(=O)c2ccc(NC3=NCCN3)cc2)ccc2cc(C(=N)N)ccc12
Reaction time: 2 h
Yield: 24.3 %

Procedure:
30 Milliliters of 20% hydrous pyridine was added to 1.12 g of 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid.hydrochloride, 1.5 g of 6-amidino-1-(2-ethoxycarbonylethyl)-2-naphthol.hydrochloride, 1.44 g of DCC and 56.7 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 48 hours at room temperature. Furthermore, 1.44 g of DCC, 5 ml of 20% hydrous pyridine and 10 ml of DMF were added, followed by stirring for 24 hours at room temperature. Then, the precipitate was filtered and the filtrate was concentrated rated under reduced pressure. To the residue was added 20 ml of DMF, and the resulting solution was added dropwise to 400 ml of ether, followed by stirring for 24 hours under cooling with ice. The supernatant was decanted to obtain a crude product. This was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 10 ml of ethanol and 1.55 ml of concentrated hydrochloric acid, followed by stirring for 1 hour under cooling with ice. Then, the precipitate was collected by filtration to obtain 307.9 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:30][CH:29]=[N:28][C:27]=1[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncsc1-c1ccccc1F
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3ccccc3F)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(2-fluoro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([N:16]=C=O)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.[OH-].[Na+].C(O)CO.Cl>C(OCC)C.O>[NH2:16][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]1
Reactant: O=C=NC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: OCCO
Product: NC1(c2ccccc2)CCC(=O)CC1
Reaction time: 0.08 h
Yield: 52 %

Procedure:
A reaction mixture consisting of 21.9 gm. (0.085 mole) 4-isocyanato-4-phenylcyclohexanone ethylene ketal (prepared as in Example 17, Part G), 10.9 gm. sodium hydroxide, and 210 ml. ethylene glycol is heated at the reflux temperature for sixty-six (66) hours. A solution results which is cooled in an ice-water bath. A small amount of ice is added to the solution followed by 23 ml. of concentrated hydrochloric acid which is added dropwise with stirring. After five minutes, the acidified solution is made strongly basic by adding 50% aqueous sodium hydroxide. The basic solution is diluted with 800 ml. water. The strongly basic, dilute aqueous solution is then extracted four times with 200 ml. portions of diethyl ether. The extracts are combined and washed with water and with brine, before removing the ether by evaporation under reduced pressure. The residue thus obtained is dissolved in 50 ml. of diethyl ether and the oily solution is treated with an equivalent of 3 N hydrogen chloride in diethyl ether. A precipitate forms which is collected on a filter and recrystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 15.2 gm. (52% yield) of 4-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride which has a melting point at 226° to 228° C. (with decomposition). A second crop of crystals weighs 1.60 gm. and has a melting range from 222° to 226° C. An analytical sample has a melting point at 248° to 249° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[NH2:25][C@H:26]([CH3:36])[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=1)[OH:28]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:25][C@H:26]([CH3:36])[C@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=3)[OH:28])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: C[C@@H](N)[C@@H](O)c1cccc(Br)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1cccc(Br)c1
Yield: 12 %

Procedure:
The title compound (7 mg, 12%) was obtained from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid and (1S,2R)-2-amino-1-(3-bromo-phenyl)-propan-1-ol hydrochloride salt as in Example 1, Part C. HPLC: RT=10.08 min. MS (ESI−): mass calcd. for C22H18BrClN4O4S2, 581.89; m/z found, 579/581 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.58 (s, 1H), 8.38 (dd, J=7.0, 0.9, 1H), 8.22 (dd, J=8.8, 0.9, 1H), 7.74-7.71 (m, 2H), 7.55-7.53 (m, 1H), 7.47-7.43 (m, 1H), 7.31-7.22 (m, 2H), 6.95 (dd, J=8.4, 2.0, 1H), 6.19 (d, J=8.5, 1H), 4.95 (d, J=2.7, 1H), 4.48-4.39 (m, 1H), 2.61 (s, 1H), 1.04 (d, J=6.9, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:11]=2[N+:22]([O-])=O)=[CH:4][C:3]=1[NH:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:30][CH:29]=1.C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>[Fe].C(O)C>[NH2:22][C:11]1[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:26][C:27](=[O:40])[C:28]2[CH:29]=[CH:30][C:31]([CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:32][CH:33]=2)[CH:4]=1)=[O:25]
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3[N+](=O)[O-])ccc2C)cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3N)ccc2C)cc1
Temperature: 95 °C
Yield: 72.2 %

Procedure:
A mixture of N-[2-methyl-5-(3-morpholino-2-nitrobenzamido)phenyl]-4-diethylaminomethylbenzamide (1.21 g), iron powder (1.24 g), glacial acetic acid (0.44 ml), water (2.2 ml) and ethanol (22.2 ml) was stirred and heated to 95° C. for 9 hours. The resultant mixture was cooled to ambient temperature and basified to pH9 by the addition of a saturated aqueous sodium bicarbonate solution. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated. There was thus obtained the title compound as a solid (0.826 g); Mass Spectrum: M+H+ 516.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH2:9](Br)[CH2:10][CH:11]([CH3:13])[CH3:12]>COCCOC>[CH2:9]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CCBr
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)CCOCCCCO
Temperature: 55 °C
Reaction time: 2 h

Procedure:
36.0 g (0.40 mol) of 1,4-butandiol are added over the course of 20 minutes of a suspension of 12.20 g (0.279 mol) of 55 % sodium hydride in 400 cc of absolute 1,2-dimethoxyethane. The mixture is stirred at 55° C for 2 hours. After this period, 40.2 g (0.266 mol) of isopentyl bromide are added dropwise at 55°, over the course of 20 minutes, and the mixture is then stirred at 60° for 48 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated at 40° /12 mm Hg. The residue is distilled at 0.9 mm Hg and for further purification the fraction, having a B.P. of 75° - 88°/0.09 mm Hg, is taken up in ether and washed with water. 4-Isopentyloxy-1-butanol is obtained as a gas-chromatographically pure oil.
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1)#[N:2].[H-].[Na+].C[N:13](C=O)C>>[NH2:13][N:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:3]1[C:1]#[N:2]
Reactant: N#Cc1c[nH]c(C#N)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(C#N)n(N)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a stirred solution of 2,4-dicyano-pyrrole (3.00 g, 25.6 mmol) in DMF (300 mL) was added sodium hydride (60% in mineral oil, 1.54 g, 38.4 mmol). The mixture was stirred for 15 min. Diphenylphosphinyl amino ester (8.96 g, 38.4 mmol) was added. The mixture was vigorously stirred while heating at 80° C. for 2 h and then cooled to rt. The mixture was filtered using DCM washings. The filtrate was concentrated to dryness to provide desired product (2.00 g, 59%). LTQ LC-MS: [M+H]+ 133.0, RT 0.96 min. The product was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[O:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:16])([C:12]([F:15])([F:13])[F:14])[O:7][CH2:6][CH2:5]2)(=[O:26])[CH3:25]
Reactant: CC1(C(F)(F)F)OCCc2cc(O)ccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2c(c1)CCOC2(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of 6-hydroxy-1-methyl-1-trifluoromethylisochroman (79 g, 0.34 mol) and triethylamine (120 mL, 0.88 mol) in THF (680 mL) was added acetyl chloride (31 mL, 0.44 mol) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction was quenched by adding aqueous 1 N-HCl (400 mL), and extracted with ethyl acetate (500 mL). The extracts were washed with aqueous saturated NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (Silica-gel, 15×20 cm, 6% ethyl acetate/hexane) to afford 6-acetoxy-1-methyl-1-trifluoromethylisochroman (83 g, 89%) as a colorless oil. 1H-NMR(CDCl3): 7.36 (d, J=7.2 Hz, 1H), 6.98 (dd, J=7.2, 2.5 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 4.18-4.08 (m, 1H), 3.92 (dt, J=11, 5.4 Hz, 1H), 2.86 (t, J=5.4 Hz, 2H), 2.30 (s, 1H), 1.66 (s, 3H).