Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH:19]=O.O>CCCCCCC>[CH3:16][O:17][CH:18]([O:21][CH3:22])/[CH:19]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COC(C=O)OC
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Solvent: O
Solvent: CCCCCCC
Product: CCOC(=O)/C(C)=C/C(OC)OC
Temperature: 60 °C
Reaction time: 15 h
Yield: 121.4 %

Procedure:
To a stirred solution of ethyl 2-(diethoxyphosphoryl)propanoate (450 μL, 2.1 mmol) in heptane (5 mL) was added 2,2-dimethoxy acetaldehyde (60% in water, 1.0 mL, 4.2 mmol). The solution was stirred for 15 h at 60° C. After the reaction was cooled, water was added and the mixture was extracted with CH2Cl2 and filtered through a phase separator and a silica plug. Concentration under reduced pressure afforded (E)-ethyl 4,4-dimethoxy-2-methylbut-2-enoate (480 mg, >100%). The procedure was adapted from Tetrahedron 2002, 2533.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]([NH:12][C:13](=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:22](=[O:31])[C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:15]=1)([CH3:11])[CH3:10]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:24](=[C:23]2/[C:22](=[O:31])[N:21]([CH2:20][C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[C:13]([NH:12][CH:9]([CH3:11])[CH3:10])=[O:38])[C:32]3[C:33]/2=[CH:34][CH:35]=[CH:36][CH:37]=3)/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: CC(C)NC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: CC(C)NC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and N-isopropyl-3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzamide. 1H NMR (CDCl3, 300 MHz) δppm 7.74 (s, 1H), 7.60 (d, 1H), 7.26-7.43 (m, 10H), 7.07 (dt, 2H), 6.70 (t, 1H), 6.68 (d, 1H), 6.53 (d, 1H), 5.99 (d, 1H), 4.94 (s, 2H), 4.26 (m, 1H), 1.26 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[N:16]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:27][C:18]([C:14]2[N:15]([CH3:17])[N:16]=[C:12]([O:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH2:21][OH:22])[CH:13]=2)=[O:20])[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCC1
Reactant: CCCCc1noc(CO)c1COc1cc(C(=O)O)n(C)n1
Product: CCCCc1noc(CO)c1COc1cc(C(=O)NC2CCC2)n(C)n1
Yield: 78 %

Procedure:
As described for example 112h, 5-(3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 0.16 mmol) was converted, using cyclobutylamine instead of 2,2,2-trifluoroethylamine HCl, to the title compound (45 mg, 78%) which was obtained as a colorless oil. MS: m/e=363.3 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:30][C:31](O)=[O:32])[CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:30][C:31]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:32])[CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Product: CCCC(NC(=O)Cc1ccc(C(=O)OC)c(OC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:4][S:5][CH:6]=1.C([Li])CCC.[C:21](=[O:23])=[O:22]>C1COCC1>[Cl:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[C:4]([C:21]([OH:23])=[O:22])[S:5][CH:6]=1
Reactant: O=C=O
Reactant: O=C(Nc1ccccc1)c1cscc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1scc(Cl)c1C(=O)Nc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
4-Chlorothiophene-3-carboxanilide (14.6 g, 0.061 mol) is dissolved in 450 ml of THF and the solution is cooled to -70° C.; n-butyllithium (0.13 mol, 1.6N solution in n-hexane) is then added. After 30 minutes, carbon dioxide is gassed in until the solution was saturated, and the solution is allowed to heat up slowly to room temperature. It is then concentrated to dryness, the solid residue is taken up in a mixture of water, sodium hydroxide solution and ethyl acetate, the phases are separated and the aqueous phase is acidified with hydrochloric acid, thus precipitating the carboxylic acid. Yield: 13.5 g, 78%; m.p. 208°-210° C. (active ingredient no. 2.008).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)[CH:2]=[CH2:3].[NH2:14][C@H:15]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C@H:16]([OH:30])[CH2:17][NH:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:14][C@@H:15]([CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)[C@H:16]([OH:30])[CH2:17][NH:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20]1)=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCSc1cccc(C(=O)O)c1
Reactant: CCc1cccc(C2(NC[C@@H](O)[C@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCSc1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Yield: 176.8 %

Procedure:
3-(Allylthio)benzoic acid (717 mg, 3.69 mmol), (2R,3R)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethylphenyl)cyclopropyl]amino}butan-2-ol (247 mg, 0.685 mmol), and HATU (Aldrich, 2.1 g, 5.54 mmol) were dissolved in dichloromethane (35 mL), at ambient temperature, and treated with diisopropylethylamine (1.6 mL, 9.225 mmol). Upon completion, the reaction mixture was concentrated and chromatographed (SiO2, 2:1 to 1:1 Hexanes: EtOAc) to give the desired compound (650 mg). (LRMS (M+H) m/z=537.8)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@H:22]12[CH2:28][C@H:25]([NH:26][CH2:27]1)[CH2:24][O:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@@H:22]4[CH2:28][C@H:25]3[CH2:24][O:23]4)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@@H]2C[C@H]1CO2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (31560-06-2) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=366.5 [MH+].
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([F:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>ClCCl>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:24](=[O:25])[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([F:4])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(F)(F)c1cc(N)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
A mixture of 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-amine (528 mg, 2.37 mmol), potassium carbonate (979 mg, 7.10 mmol) and phenyl chloroformate (556 mg, 3.55 mmol) in anhydrous dichloromethane (20 mL) was stirred at rt for 15 h. Additional phenyl chloroformate (556 mg, 3.55 mmol) and potassium carbonate (979 mg, 7.10 mmol) was added and the mixture stirred for a further 4 h. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water, saturated aqueous sodium hydrogen carbonate solution, then dried over magnesium sulfate and filtered. Concentration under reduced pressure gave an oil which was purified via silica gel column chromatography (eluting with a gradient of 12% ethyl acetate in hexanes to 100% ethyl acetate) to afford phenyl 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (400 mg, 49%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.51-7.58 (m, 5H), 7.35-7.41 (m, 2H), 7.26 (m, 1H), 7.15 (m, 2H), 7.00 (brs, 1H), 6.80 (s, 1H), 2.04 (t, J=18 Hz, 3H); LC-MS (ESI) m/z 344 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29]C)=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([OH:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl-].[CH2:34]([NH+:41]([CH3:45])[CH2:42][CH2:43][Cl:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[Cl-:44].[CH2:34]([NH+:41]([CH3:45])[CH2:42][CH2:43][O:26][C@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:27]([OH:29])=[O:28])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[NH+](CCCl)Cc1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1ccccc1-3
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[NH+](CCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a suspension of methyl (7S)-14-cyclohexyl-7-hydroxy-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in International patent application WO2006/046030) in toluene (0.05 M), were added 10 eq of 30% w/w aq. NaOH followed by 0.25 eq of NBu4Br. After stirring for 30 min, 2.5 eq of N-benzyl-2-chloro-N-methylethanaminium chloride were added and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was concentrated in vacuo, and the residue purified by RP-HPLC (Waters Xterra prep. C18 column, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried in the presence of HCl to afford the title compound (25%) as a white powder. (ES+) m/z 539 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[C:12](=O)(OCC)[O:13]CC.Cl>C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[CH2:5]([C@H:2]1[CH2:3][O:4][C:12](=[O:13])[NH:1]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](Cc2ccccc2)CO1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of (2S)-2-amino-3-phenyl-1-propanol (0.649 g; 4.29 mmol) and diethyl carbonate (1.04 ml; 8.58 mmol), anhydrous potassium carbonate (20 mg; 0.14 mmol) was added, and the mixture was stirred at 120° to 130° C. for 3 hours. After cooling, to the resulting mixture 1N hydrochloric acid (1.5 ml) and ethyl acetate (about 50 ml) were added and stirred. The organic layer was separated and washed with brine, and dried over anhydrous magnesium sulfate. Distilling off the solvent under reduced pressure gave (4S)-4-benzyloxazolidin-2-one (0.760 g, quantitative yield) as a colorless solid. The sample for analysis was obtained by recrystallization from a mixed solvent of cyclohexane and toluene (1:1). Colorless crystals. M.P., 88°-89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[Cl:11][CH2:12][CH2:13][CH2:14][OH:15].[H-].[Na+]>CN(C=O)C>[Cl:11][CH2:12][CH2:13][CH2:14][O:15][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: OCCCCl
Reactant: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74170.5 %

Procedure:
A solution of 24.6 g (0.157 mmol) of 2-methoxybenzyl chloride and 26 ml (29.4 g,0.311 mmol) of 3-chloro-1-propanol in 150 ml of absolute DMF was treated portionwise at 10° C. within 2.5 hours with 8.4 g (0.196 mmol) of sodium hydride dispersion (55% in refined oil) and stirred at room temperature for 1 hour. Subsequently, a further 1.0 g (0.023 mmol) of sodium hydride dispersion was added at room temperature and the mixture was stirred for a further 3 hours. For the working-up, the reaction mixture was partitioned between 500 ml of water and 500 ml of ethyl acetate. The organic phase was separated. The aqueous phase was extracted four times with 250 ml of ethyl acetate each time. The combined organic phases were washed twice with 250 ml of water each time and finally the solvent was distilled off under reduced pressure. The crude product (44 g) was purified by chromatography on silica gel with a 1:2 mixture of methylene chloride and hexane as the eluent. There were obtained 25.0 g (74% of theory) of 2-methoxybenzyl 3-chloropropyl ether as a colourless oil; MS: 214. 216 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:20]=[C:21]([C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]([CH3:33])([CH3:34])[C:30]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH3:9])=[O:31])[CH:20]=[C:19]([C:18]([F:17])([F:35])[F:36])[CH:24]=1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 83.6 %

Procedure:
To the solution of 6-chloro-N-methyl-4-(o-tolyl)pyridin-3-amine (18.87 g, 81.3 mmol) and DMAP (29.8 g, 243.9 mmol) in 200 mL of anhydrous toluene was added the solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (28.5 g, 89.4 mmol) in toluene under N2 atmosphere. The solution was heated at 120° C. for 23 hrs. Cooled to room temperature, poured into 1 L of 5% aq. NaHCO3 solution, and extracted with EtOAc twice. The combined organic phases were washed by water and brine consecutively, dried over Na2SO4, filtered and purified by flash chromatography to afford 35 g 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide as a white solid (Yield: 83.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](OC(OCC)CBr)[CH3:17]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH:17]=[CH:16][S:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(S)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 155.3 %

Procedure:
A mixture of 3-methoxybenzenethiol (10 ml, 11.30 g, 80 mmole), K2CO3 (11.15 g, 80 mmole) and bromoacetaldehyde diethyl acetal (12 ml, 15.72 g, 80 mmole) in acetone (100 ml) was stirred at ambient temperature for 16 hours, then filtered. The filtrate was subsequently concentrated, in vacuo. The residue obtained was partitioned between H2O (150 ml) and Et2O (150 ml). The layers were separated and the aqueous phase was extracted with Et2O (150 ml). The combined organic extracts were washed with 0.5 M KOH (aq), H2O and brine, then dried over Na2SO4 and concentrated, in vacuo, to give 20.4 g of an amber oil which was used directly in the subsequent cyclization without any further purification.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C@H:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][C@@H:2]2[OH:1])=[CH:13][CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
A mixture of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (620 mg, 2.1 mmol, E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and benzyl bromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt for 16 h. The solvent was removed by evaporation and the residue was treated with 50 mL of water. The aqueous mixture was then extracted 4 times with 50 mL of chloroform. The combined organic phases were dried over anhydous Na2SO4, filtered, and evaporated to yield 750 mg of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate which was used without further purification. LCMS (method F) RT 2.28 min, m/z=310 (M+H+−t-butyl −water), 328 (M+H+−t-butyl).
Reaction SMILES: OS(O)(=O)=O.[CH3:6]C1C=CC(S(O)(=O)=O)=CC=1.[C:17]1([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH3:6][O:30][C:29]([C:23]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)=[O:31]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1

Procedure:
To a stirred solution of H2SO4 (16 mL) in MeOH (400 mL), 4-phenyl-4-piperidinecarboxylic acid 4-methylbenzenesulfonate (37.7 g, 0.1 mole) was added and the mixture was stirred and refluxed for 8 hours. Excess methanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6N NaOH. The pH was adjusted to 10-11 by adding more 6N NaOH and extracted with CH2Cl2 (3×150 mL). The combined CH2Cl2 extracts were dried (MgSO4) and the solvent evaporated to leave the desired product as a viscous oil. The 1H-NMR showed it to be pure (20.2 g, 92%) and was used without any further purification.
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=3[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]=2[N:28]=1)(=O)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.O>CN1C(=O)CCC1>[CH:29]1([NH:32][C:5]2[N:6]=[CH:7][C:8]3[C:17]4[CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=4[N:11]=[C:10]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:9]=3[N:28]=2)[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(S(C)(=O)=O)ncc12
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(NC3CC3)ncc12
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 77.9 %

Procedure:
methyl 3-(methylsulfonyl)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 117 mg, 0.298 mmol) was mixed in a vial with cylopropylamine (3.0 eq, 62 ul, 0.89 mmol) in NMP (2 ml). The mixture was stirred at 60° C. for 50 minutes. Water was added and the resulting solid filtered. The material was suspended in AcOEt/hexanes and filtered to afford methyl 3-(cyclopropylamino)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate as a yellow solid (86 mg, 78% yield). LCMS (ES): >95% pure, m/z 371 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[O:36][CH3:37]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=4[O:36][CH3:37])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C#N)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 68.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmoles), K2CO3 (2.8 g), 4-(3-bromopropoxy)-3-methoxybenzonitrile (4.0 gm, 14.8 mmoles) in acetonitrile (70 ml) was heated at reflux for 3 hr. At the end of the reaction, the solvent was removed on a rotary evaporator. The organic material was extracted into dichloromethane (250 ml) and the inorganics were filtered off. The dichloromethane solution was concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO2, 55 gm; eluted with dichloromethane, 600 ml; 1% methanol in dichloromethane, 600 ml). The material thus obtained was crystallized from a small amount of dichloromethane. Recrystallization from ethanol (25 ml) provided 3.8 gm (68%) of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]-3-methoxybenzonitrile as white crystals, m.p.=107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:6])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a solution of 3,4-dichlorobenzoyl chloride (295 mg, 1.41 mmol) in CH2Cl2 (4 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) and triethylamine (0.4 ml, 2.82 mmol) in CH2Cl2 (4 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (400 mg, 67%) as a colorless solid. Anal calcd for C20H18N2O4Cl2 : C, 57.02; H, 4.31; N, 6.65. Found: C, 57.05; H, 4.39; N, 6.50. MS M+1 calcd for C20H18N2O4Cl2 422, found 422.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=CC=CC=3)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O>[CH:13]1[C:14]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:12]=1
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: c1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
534 gm of anthracene and 326 ml of concentrated sulfuric acid were taken in a 2 liter round bottom flask fitted with a stirrer. The contents of the flask were heated to 140° C. for 90 minutes with continuous stirring. 1 ml of the mass was taken in a beaker and 3 ml water was added with shaking. It was observed to form a clear solution without free naphthalene smell, confirming the completion of sulfonation. The sulfonated mass was transferred to a reactor fitted with a thermometer, stirrer and a dropping funnel. The mass was stirred continuously for a period of 10 min. while maintaining the temperature at 80° C. A mixture of 5.4 gm oxalic acid, 4.14 gm salicylic acid and 10 gm phthalic acid dissolved in 50 ml water was added to the above sulfonated mass and stirring was continued at 80° C.