Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-:3])O.[Na+].[C:6](=O)([O:14]C1C=CC=CC=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:6]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:1]([O:3][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1

Procedure:
400 parts of an aqueous solution of sodium hydrogencarbonate having a pH of 10 were added to 200 parts of diphenyl carbonate, obtained through the decarbonylation reaction of diphenyl oxalate using triphenyl phosphine oxide and oxalyl chloride as catalysts, the mixture was heated to 90° C. and stirred for 1 hour. To the obtained heavy solution (diphenyl carbonate layer) was further added 400 parts of distilled water, and the resulting mixture was heated to 90° C. and stirred for 1 hour to obtain diphenyl carbonate containing 10.3 ppm of hydrolyzable chlorine. An ester interchange reaction between this diphenyl carbonate and bisphenol A was carried out in the same manner as in Example 1 except that a disodium salt of bisphenol A was used in place of sodium hydroxide as an ester interchange catalyst in an amount of 2.0×10−6 mole, in terms of sodium, based on bisphenol A, to synthesize polycarbonate. The conditions and results are shown in Tables III-A and III-B below.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH:4]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][N:24]([C:26](=[O:39])[C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[CH3:25])[CH:19]=2)[C:14]=1[Br:40])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[Br:40][C:14]1[C:15]2[C:20](=[CH:19][C:18]([CH2:23][N:24]([C:26](=[O:39])[C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[CH3:25])=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:41])=[O:2]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CN(C)C(=O)c3ccc(C4CCCCC4)cc3)ccc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(Cc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1)C(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.6 %

Procedure:
A mixture of 2-(1-bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (445 mg, 0.68 mmol), prepared in the previous step, and 0.5 mL of 10% aqueous NaOH in THF was stirred at room temperature for 2.5 h. Aqueous 10% HCl was added until acidic and the reaction extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent removed under reduced pressure to give the title compound (419 mg, 95%), MS m/z: 600 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:50])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[C@@:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[C@@:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[N:18]=[C:17]2[C:37]2[CH:38]=[N:39][C:40]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][C:42]=2[O:43][CH2:44][CH3:45])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.[OH-].[Li+].Cl>CO.O1CCCC1>[ClH:28].[C:46]([C:40]1[N:39]=[CH:38][C:37]([C:17]2[N:16]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:50])=[O:5])[CH2:13][CH2:12]3)=[O:15])[C@@:20]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([CH3:21])[C@@:19]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([CH3:29])[N:18]=2)=[C:42]([O:43][CH2:44][CH3:45])[CH:41]=1)([CH3:47])([CH3:48])[CH3:49]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1

Procedure:
{4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid tert-butyl ester was either reacted with lithium hydroxide (2N solution) in methanol and tetrahydrofuran at 50° C. for 4 h or with 1N hydrochloric acid at 50° C. for 2.5 h to give the title compound. HR-MS (ES, m/z) calculated for C35H42Cl2N5O4 [(M+H)+] 666.2609, observed 666.2611.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[O:18]1CCCC1>C(O)(=O)C.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:17]=[O:18])=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1[nH]c(C)c(CCC(=O)O)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a mixture of 7 g 4-(2-carboxyethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester in 35 mL each of tetrahydrofuran (THF), acetic acid (AcOH) and water at −10° C. was added 70 g of ceric ammonium nitrate in portion over 20 minutes, the reaction temperature being maintained at about 5° C. The resulting mixture was them cooled to 0° C., stirred for another 2 hr and then diluted with 250 mL of brine. The mixture was then extracted with 2×300 mL 10% MeOH in dichloromethane (DCM). The organic extracts were combined and dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The residue was purified on silica gel column with hexanes(hex)/ethyl acetate (EtOAc)/AcOH (6:4:0.05) followed by crystallization in EtOAc to give 1.5 g of 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-amino-3-nitro-phenol (1.54 g, 0.01 mol), benzyl bromide (1.71 g, 0.01 mol) and K2CO3 (1.54 g, 0.011 mol) in DMF (5.0 mL) was stirred at room temperature. After 20 h, reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). Combined organic layers were washed with 2N NaOH (20 mL×3), water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated to afford 2-Benzyloxy-6-nitro-phenylamine, I-107 (2.01 g).
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:30][O:29]C(C)(C)[O:27]1)[CH2:3][NH:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:24])(=[O:23])[NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH:7]=1.Cl>C(O)C.O>[OH:1][CH:2]([CH:26]([OH:27])[CH2:30][OH:29])[CH2:3][NH:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:23])(=[O:24])[NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cccc(S(=O)(=O)Nc3c(F)cc(F)cc3F)c2)O1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(NCC(O)C(O)CO)c1cccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4.74 g (10 mmol) of 3-[N-(2,4,6-trifluorophenyl)sulfamoyl]-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in a mixture of 50 ml of ethanol and 20 ml of water and the solution is acidified to pH 1 with dilute hydrochloric acid. At this pH, it is stirred for 4 hours at 60° C. The solution is then adjusted to pH 6.6 with anion exchanger Amberlite IRA 67, filtered and evaporated to dryness in a vacuum. The solid amorphous residue is dried in a vacuum at 50° C. 3.61 g (8.32 mmol)=83.2% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [K].[C:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[C:2]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])#[N:3]
Reactant: N#Cc1cccc(O)c1
Reactant: BrCCCCCCBr
Agent: [K]
Product: N#Cc1cccc(OCCCCCCBr)c1

Procedure:
The intermediate 6-(3-cyanophenoxy)hexyl bromide was prepared from the potassium salt of 3-cyanophenol and 1,6-dibromohexane.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18][C:12]=2[CH:11]=[C:10]([CH:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]=[C:33]([CH3:35])[O:32][N:31]=3)=[CH:26][CH:25]=2)[C:20]([NH2:22])=[S:21])[CH:9]=1.[C:36](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:36][S:21][C:20](=[NH:22])[CH:19]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18][C:12]=2[CH:11]=1)[NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:28][CH:29]=1
Reactant: O=C([O-])O
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCCCO2
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCCCO2
Temperature: 25 °C

Procedure:
After adding 1.63 g of Me3O+BF4− to a solution of 4.7 g of 2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 50 ml of acetonitrile, the mixture was stirred at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester.
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.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:57]1([CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[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]([N:64]5[CH2:65][CH2:66][N:61]([CH2:60][CH:57]6[CH2:59][CH2:58]6)[CH2:62][CH2:63]5)=[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
Reactant: C1CN(CC2CC2)CCN1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCN(CC3CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-(cyclopropylmethyl)piperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.07 (br. s., 2 H) 0.47 (br. s., 2 H) 1.55 (br. s., 5 H) 1.68 (br. s., 2 H) 1.90 (br. s., 2 H) 2.21 (br. s., 1 H) 2.40-2.48 (m, 3 H) 3.31 (s, 4 H) 3.32 (br. s., 3 H) 3.88 (s, 3 H) 4.03 (t, J=13.89 Hz, 2 H) 4.64-4.76 (m, 1 H) 6.96 (d, J=8.84 Hz, 1 H) 7.04 (s, 1 H) 8.00 (s, 1 H) 8.15 (d, J=7.83 Hz, 1 H) 8.23 (s, 1 H). [M+H] calculated for C29H37F2N7O3, 570; found 570.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:35]([CH3:36])=[CH:34][C:15]2[N:16]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[N:23]=3)[S:18][C:14]=2[C:13]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O>[C:1]([O:5][C@@H:6]([C:12]1[C:35]([CH3:36])=[CH:34][C:15]2[N:16]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[N:23]=3)[S:18][C:14]=2[C:13]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(-c4ccc5c(cnn5C)c4)cs3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2nc(-c3nc(-c4ccc5c(cnn5C)c4)cs3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 40 °C
Reaction time: 17 h

Procedure:
In a 25 mL round bottom flask, (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-(1-methyl-1H-indazol-5-yl)thiazol-2-yl)benzo[d]thiazol-6-yl)acetate (74 mg, 0.117 mmol) was dissolved in THF (3 mL) EtOH (2 mL) and water (1 mL). Then aqueous NaOH (2N) (1.17 mL) was added. The reaction mixture was stirred at 40° C. in oil bath for 17 h. The resulting reaction mixture was concentrated and purified on Gilson reverse phase preparative HPLC with 0-95% acetonitrile (with 0.1% TFA) in water (with 0.1% TFA) to afford product as a TFA salt. LCMS-ESI+: calc'd for: C31H27ClN4O3S2: 603.1, 605.1, 604.1 (M+H+); found: 603.2, 605.2, 604.0 (M+H+).1H NMR (400 MHz, CD3OD) δ 8.36 (d, J=1.2 Hz, 1H), 8.06-7.98 (m, 3H), 7.82 (s, 1H), 7.70 (dd, J=7.9, 2.4 Hz, 1H), 7.66-7.52 (m, 4H), 5.28 (s, 1H), 4.05 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:8][C:7](=O)[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=O>B.C1COCC1>[CH3:1][C@H:2]1[NH:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][CH2:3]1
Reactant: C[C@H]1NC(=O)c2ccccc2NC1=O
Agent: B
Solvent: C1CCOC1
Product: C[C@@H]1CNc2ccccc2CN1
Yield: 67.7 %

Procedure:
(3R)-3-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (12.7 mmol) was allowed to react with 60 mL 1M BH3/THF to give (3R)-3-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine as a white foam/clear oil (8.6 mmol).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].C[O-].[Na+].[CH3:18][SH:19]>CO.C(Cl)Cl>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[C:6]([S:19][CH3:18])[N:5]=1)[CH3:2]
Reactant: CS
Reactant: CCNc1nc(Cl)cc(NC2CC2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCNc1nc(NC2CC2)cc(SC)n1

Procedure:
31.8 g (0.15 mol) of 2-ethylamino-4-cyclopropylamino-6-chloropyrimidine and 30.6 g of 30 percent strength methanolic sodium methylate solution (0.17 mol) in 25 g of methanol are first introduced into a bomb tube. 8.6 g of gaseous methylmercaptan (0.18 mol) are passed in, whilst cooling. The bomb tube is sealed and is heated to 100° for 24 hours. When the contents of the tube have cooled they are concentrated on a rotary evaporator to give an oil, the latter is taken up in methylene chloride and the solution is extracted with water. After drying over sodium sulphate, filtering and evaporating, the methylene chloride solution gives a yellow oil which crystallises slowly. When recrystallised from methanol-water, 27.3 g of colourless crystals of melting point 75°-6° are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]1.[H-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.Cl>CN(C)C=O.C(O)C>[ClH:18].[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][N:11]3[C:12](=[O:14])[CH2:13][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][C:10]3=[O:15])[CH2:23][CH2:24]2)=[O:36])=[CH:34][CH:33]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Reactant: O=C1CN(Cc2ccccn2)CC(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2C(=O)CN(Cc3ccccn3)CC2=O)CC1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.86 g of 4-(2-pyridylmethyl)piperazine 2,6-dione in 30 ml of dimethylformamide is added at 20° C. to a suspension of 0.36 g of sodium hydride. The mixture is brought to 60° C. for 30 minutes and 2.7 g of 1-(3-chloropropyl)-4-(4-fluorobenzoyl)piperidine, dissolved in 30 ml of dimethylformamide, are then added, again at 20° C. The mixture is kept stirring at 20° C. for approximately 15 hours and the reaction is completed by bringing to 70° C. for 2 hours. After concentration, the residue is taken up in water and the product is extracted with benzene. The oil obtained is purified by chromatography under pressure on 280 g of b 230-400 mesh silica, eluting with a mixture of dichloromethane and methanol (93.5:6.5 V/V). The base obtained is converted to the hydrochloride in ethanol. The precipitate obtained is then filtered off.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[OH-].[Na+].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>C1COCC1>[O:11]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17]
Reactant: O=C1NCCc2ccccc21
Reactant: C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)CCN1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
Dissolve 3,4-dihydroisoquinolin-1(2H)-one (500 mg, 3.40 mmol) in THF (20 mL) and add sodium hydroxide (274.5 mg, 6.79 mmol) followed by methyl acrylate (438.7 mg, 5.10 mmol) in THF (1 mL). Stir the mixture at ambient temperature for 3 hours; quench with water (20 mL); and then dilute with EtOAc (100 mL). Wash the resulting mixture with brine; dry the organic phase over Na2SO4; filter; and concentrate the filtrate under reduced pressure to provide the title compound as a yellow oil (530 mg, 66.9%). MS (m/z): 234 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH2:9][C@@H:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11]([OH:13])=O)[N:6]=[CH:5]1)[CH:2]=[CH2:3].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:50]([O:53][CH2:54][C@@H:55]([NH2:59])[CH:56]([CH3:58])[CH3:57])[CH:51]=[CH2:52]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[NH:14][C@@H:10]([C:11](=[O:13])[NH:59][C@H:55]([CH2:54][O:53][CH2:50][CH:51]=[CH2:52])[CH:56]([CH3:58])[CH3:57])[CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CCn1cnc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)c1
Reactant: C=CCOC[C@@H](N)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=CCOC[C@@H](NC(=O)[C@@H](Cc1cn(CC=C)cn1)NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the material from step A in 180 ml of DMF was mixed with 4.18 g (27.32 mmol) of N-hydroxybenzotriazole and 5.64 g (27.32 mmol) of N,N′-dicyclohexylcarbodiimide and stirred at RT for 2 h. Addition of 3.56 g (24.84 mmol) of (S)-1-allyloxymethyl-2-methylpropylamine (1-1B) was followed by stirring at RT for a further 24 h and then concentration, and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC. After washing with saturated NaHCO3 solution, 5.02 g of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:23])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:25][S:26][CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:23])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:28][CH2:27][S:26][CH3:25])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CSCCCl
Reactant: C/C(=C\c1ccc(O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCOc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 74.4 %

Procedure:
A mixture of 6 g of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol, 4.8 g of 2-chloroethyl methyl sulphide and 10.5 g finely powdered potassium carbonate in 100 ml of dimethylformamide is heated to 100° for 20 hours. The cooled reaction mixture is diluted with water and extracted several times with ethyl acetate. The crystalline residue obtained after drying and evaporating the organic phase is recrystallized from hexane and gives 5.5 g of methyl 2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]phenoxy]ethyl sulphide in colourless crystals, melting point 94°-96°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:16]([P:19](Cl)(Cl)=[O:20])([CH3:18])[CH3:17]>>[CH:16]([P:19]1(=[O:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([CH3:18])[CH3:17]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: Cc1ccc(NCc2ccccc2)cc1
Product: Cc1ccc(N2Cc3ccccc3P2(=O)C(C)C)cc1
Yield: 32 %

Procedure:
The procedure of Example 1 was employed utilizing N-(4-methylphenyl)-N-benzylamine and isopropyl phosphonic dichloride to yield 1-isopropyl-2-(4-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (5.4 g, 32% yield) as white crystals having a melting point of 135°-137° C. and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.FC1C=C2C(=CC=1)C=[N:17][CH:16]=[CH:15]2>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:15]=[CH:16][N:17]=[CH:5]2)=[CH:8][C:9]=1[F:10]
Reactant: Fc1ccc2cnccc2c1
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: Fc1cc2ccncc2cc1Cl

Procedure:
Starting from 3-chloro-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). Rt=0.77 min (Method A). Detected mass: 182.1/184.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]>[Fe].C(O)(=O)C>[N+:1]([C:4]1[C:13]([NH2:14])=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc2c(cc1[N+](=O)[O-])OCCO2
Yield: 28.4 %

Procedure:
To a mixture of 6,7-dinitro-2,3-dihydrobenzo[1,4]dioxin (Takakis, I. M.; Hadjimihalakis, P. M. J. Heterocyclic. Chem., 1991, 28, 625., 13 g, 57.8 mmol) and acetic acid (150 mL) was added iron powder (9.6 g, 172.5 mmol) at room temperature, then the mixture was refluxed for 30 min. After cooling, the mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 3.22 g (28%) of the title compound as orange solid:
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH:14]([OH:17])([CH3:16])[CH3:15].[O:18]=[C:19]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][C:26]([C:35](O)=[O:36])=[C:25]2[N:20]1[CH2:21][CH2:22][C:23]1[CH:40]=[CH:39][S:38][C:24]=12.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)Cl>[O:18]=[C:19]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][C:26]([C:35]([O:17][CH:14]([CH3:16])[CH3:15])=[O:36])=[C:25]2[N:20]1[CH2:21][CH2:22][C:23]1[CH:40]=[CH:39][S:38][C:24]=12
Reactant: CC(C)O
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
7.1 ml of tri-n-butylamine and 6.1 ml of isopropanol were added to a suspension of 2.0 g of 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid and 3.8 g of N-methyl-2-chloropyridinium iodide in 12.5 ml of methylene chloride, the reaction mixture was stirred under reflux for 24 hours, evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). After crystallization from methanol, there was obtained pure isopropyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 165.5°166°.