Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][NH:23]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH2:12][NH:13][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1sc2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(-c2c(CNc3ncnc4[nH]cnc34)sc3ccccc23)cc1
Temperature: 100 °C
Yield: 38.4 %

Procedure:
A mixture of C-(3-phenylbenzo[b]thiophen-2-yl)methylamine from Example 26 (230 mg, 0.961 mmol), 6-chloro-9H-purine (278 mg, 1.80 mmol) and DIPEA (0.34 mL, 1.92 mmol) in n-butanol (10 mL) was heated at 100° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) and then sonicated in diethyl ether. Further purification by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) afforded 165 as a white solid (132 mg, 38%). LCMS: RT 4.22 min [M+H]+ 358.1. 1H NMR (DMSO, 400 MHz): δ 12.96 (1H, s), 8.40 (1H, s), 8.23 (1H, s), 8.14 (1H, s), 7.94-7.85 (1H, m), 7.63-7.54 (4H, m), 7.51-7.43 (2H, m), 7.38-7.29 (2H, m), 4.94 (2H, s)
Reaction SMILES: [Na].N.BrC(Br)C[CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1([C:22]1[CH:27]=CC=[CH:24][CH:23]=1)[CH:14]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:31]([C:32]1[CH:33]=[CH:27][C:22]([C:7]2([CH:14]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:6]2)=[CH:23][CH:24]=1)#[CH:30]
Reactant: BrC(Br)CC1CCCCCCC1(c1ccccc1)C1CCCCCCC1
Reactant: C1CCOC1
Agent: N
Agent: [Na]
Product: C#Cc1ccc(C2(C3CCCCCCC3)CCCCCCC2)cc1
Reaction time: 0.54 h

Procedure:
Small pieces of sodium were added to liquid ammonia until a blue color persisted. Ferric nitrate (100 mg) was added and the solution was stirred. When the solution turned colorless, sodium (6 g) was added in small pieces. After about 30 to 35 minutes following the addition the blue color disappeared and a solution of the above dibromoethylphenyl bicyclooctane in tetrahydrofuran was added to the solution. The ammonia was allowed to evaporate overnight and the residue was partitioned between ether and ice/water. The organic layer was separated, dried over K2CO3 and evaporated to leave crude 1-(4-ethynylphenyl)bicyclooctane. This was purified by chromatography on alumina (made basic with NH3) and elution with dichloromethanehexane (1:4) and recrystallization from hexanedichloromethane. The compound was characterized by NMR (300 MHz, CDCl3): δ 0.9 (9H, s, (CH3)3C), 3.05 (1H, s, C≡CH), 4.15 (6H, s, (CH2O)3), 7.45 (2H, d, aromatic), 7.55 (2H, d, aromatic). The compound was also characterized by mass spectrometry (M+ 272) and was found to have a melting point of 167°-168 C.
Reaction SMILES: O=C1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]([O:15][CH3:16])[CH2:13][CH2:14][N:3]1[C:4]=23>[OH-].[Na+].CO>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:4]=1[NH:3][CH2:14][CH2:13][CH:12]2[O:15][CH3:16]
Reactant: COC1CCN2C(=O)OCc3cccc1c32
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC1CCNc2c(CO)cccc21
Yield: 63.3 %

Procedure:
6,7-Dihydro-3-oxo-7-methoxy-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (4.3 g) was dissolved in a mixture of 10% aqueous solution of sodium hydroxide and methanol (1:10 v/v, 55 ml), and the mixture was refluxed for 2 hours. After distilling off the solvent, the resulting residue was extracted with dichloromethane. The extract was washed with water and dried, the solvent was removed. The resultant residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (4:1 v/v)]to give 8-hydroxymethyl-4-methoxy-1,2,3,4-tetrahydroquinoline (2.4 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S(O[CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:23])(C)(=O)=O.[CH2:24]1[C:29]2[NH:30][C:31]3[C:36]([C:28]=2[CH2:27][CH2:26][NH:25]1)=[CH:35][CH:34]=[CH:33][CH:32]=3>C(#N)C>[CH2:24]1[C:29]2[NH:30][C:31]3[C:36]([C:28]=2[CH2:27][CH2:26][N:25]1[CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:23])=[CH:35][CH:34]=[CH:33][CH:32]=3
Reactant: CS(=O)(=O)OCCn1c(=O)oc2ccccc21
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1oc2ccccc2n1CCN1CCc2c([nH]c3ccccc23)C1

Procedure:
Potassium carbonate (0.828 g, 6 mmol), 3-(2-mesyloxyethyl)benzoxazolin-2-one (1.494 g, 5.814 mmol) and 1,2,3,4-tetrahydropyrido[3,4-b]indole (1 g, 5.814 mmol) in acetonitrile (30 ml) were heated under reflux under nitrogen for 16 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (80 ml) and water (30 ml). The water was separated and hydrochloric acid (0.5M, 40 ml) was added. The resultant white precipitate was collected by filtration and suspended in sodium hyroxide (2M, 60 ml) and washed with chloroform (3×50 ml). The combined chloroform extracts were washed with water (30 ml), dried (MgSO4), and the solvent filtered and evaporated in vacuo. The residue was treated with diethyl ether/ethyl acetate (3:1, 40 ml) and a fine flocculent precipitate resulted. The resultant filtrate was evaporated in vacuo and the residue chromatographed on silica (ethyl acetate 40-60 petrol 3:2) to give the title product, melting point 135°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][F:17].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](Cl)=[O:24]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][F:17])[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1
Reactant: FCCNc1cnccc1-c1ccccc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CCF)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-fluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification to give a first batch of compound (light yellow solid). A second chromatographic purification of the remaining impure fractions and mother liquor gave a second batch of compound. Yellow solid (25% overall). MS (ESI): m/z=491.08 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([NH2:10])[CH2:9][CH2:8]1.[I:11][C:12]1[C:13]([CH3:23])=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](O)=[O:18].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[I:11][C:12]1[C:13]([CH3:23])=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([NH:10][C:7]1([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][CH2:8]1)=[O:18]
Reactant: COc1cc(C)c(I)cc1C(=O)O
Reactant: NC1(c2ncccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(I)cc1C(=O)NC1(c2ncccn2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(pyrimidin-2-yl)cyclopropanamine (2.00 g, 14.8 mmol) and 5-iodo-2-methoxy-4-methylbenzoic acid (4.75 g, 16.28 mmol) in DMF (8 ml) in a 25 ml RB flask was cooled to 0° C., and then added with N,N-diisopropylethylamine (12.92 ml, 74.0 mmol) followed by HATU (6.75 g, 17.76 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was added ice water and extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with brine solution, dried over Na2SO4, filtered and concentrated. The crude product was purified by using a silica gel (60-120 mesh) column with 60% ethyl acetate in hexane as an eluent. Yield: 3.2 g, 48%. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J=4.8 Hz, 2H), 8.52 (s, 1H), 8.47 (s, 1H), 7.03 (t, 1H, J=5.0 Hz), 4.02 (s, 3H), 2.63 (s, 3H), 1.83-1.80 (m, 2H), 1.52-1.49 (m, 2H). LCMS: (ES+) m/z=410 (M+H)+; Column—Ascentis Express C8 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH; Flow=1 ML/MIN; Time: 0.0, 1.5, 3.2; % A: 100.0, 0.0, 0.0; % B: 0.0, 100.0, 100.0; RT: 1.904 min.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](/[CH3:20])=[CH:11]/[CH:12]=[CH:13]/[C:14](/[CH3:19])=[CH:15]/[C:16]([OH:18])=O)=[C:6]([CH3:21])[C:5]([CH3:22])=[C:4]([O:23][CH3:24])[CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH3:24][O:23][C:4]1[CH:3]=[C:2]([CH3:1])[C:7](/[CH:8]=[CH:9]/[C:10](/[CH3:20])=[CH:11]/[CH:12]=[CH:13]/[C:14](/[CH3:19])=[CH:15]/[C:16]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[O:18])=[C:6]([CH3:21])[C:5]=1[CH3:22]
Reactant: Nc1ccncc1
Reactant: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)c(C)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Nc2ccncc2)c(C)c1C
Yield: 64.1 %

Procedure:
Reaction of acitretin (0.10 g, 0.31 mmol) with 4-aminopyridine (0.03 g, 0.31 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a yellow solid (0.08 g, 61%). EIMS m/z: 403 ([M]+), 401 ([M]−).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:37](C(OC(C)(C)C)=O)[CH:38]=[CH:39][CH:40]=2)O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:36]3[NH:37][CH:38]=[CH:39][CH:40]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B1OC(C)(C)C(C)(C)O1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 6 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 22.1) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate to afford a grey solid. UPLC-MS (Condition 3) tR=1.06 min, m/z=449.2 [M+H]+, m/z=447.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.77 (m, 1H) 1.77-1.93 (m, 1H) 2.98 (d, J=12.23 Hz, 1H) 3.21-3.29 (m, 2H) 3.37-3.51 (m, 1H) 4.19 (d, J=2.20 Hz, 1H) 4.81 (d, J=3.42 Hz, 1H) 6.02-6.18 (m, 2H) 6.70-6.88 (m, 1H) 7.32 (d, J=9.05 Hz, 2H) 7.79-7.94 (m, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.70 (d, J=2.45 Hz, 1H) 10.15 (s, 1H) 11.10 (d, J=1.47 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:23]=[O:24]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:23]([NH:22][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3c(Br)cccc32)cc1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCc2c(Br)cccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 50 mL round-bottomed flask was added 5-bromo-1-(4-(trifluoromethyl)-phenyl)-1,2,3,4-tetrahydroisoquinoline (44 mg, 124 μmol, from step 3), CH2Cl2 (2 mL), 2-isocyanato-2-methylpropane (12 mg, 124 μmol, Aldrich). The reaction mixture was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes to give 5-bromo-N-tert-butyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 455 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 394A (1.8 g, 10.5 mmol) in CH2Cl2 (10 ml) was added dihydropyran (1.94 ml, 21.2 mmol) and PPTS (150 mg, 0.60 mmol). The reaction was stirred at rt overnight, washed with brine, concentrated, purified by silica gel flash column chromatography to give 394B (1.88 g, 70%) (100% CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][C:5]([O:16][CH3:17])=[C:6]([C:12](OC)=[O:13])[C:7]=1[C:8](OC)=[O:9].O.[NH2:25][NH2:26].Cl>O>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:26][NH:25][C:12](=[O:13])[C:6]=2[C:5]([O:16][CH3:17])=[N:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NN
Reactant: COC(=O)c1c(OC)nc(-c2ccccc2)c(N)c1C(=O)OC
Agent: Cl
Solvent: O
Product: COc1nc(-c2ccccc2)c(N)c2c(=O)[nH][nH]c(=O)c12
Temperature: 100 °C

Procedure:
To 0.8 g of 3-amino-4,5-dimethoxycarbonyl-6-methoxy-2-phenylpyridine was added 4 ml of hydrazine monohydrate. The mixture was heated at 100° C. in a stream of nitrogen for 1 hour. Under ice-cooling, water was added to the reaction mixture, followed by neutralization with hydrochloric acid for adjustment to pH 3. The resulting yellow crystalline precipitate was collected by filtration.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH:8]([C:20]([O:22]C)=[O:21])[O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15]C)=[O:14])(=O)C.[OH-].[Na+].Cl>C1COCC1>[C:20]([CH:8]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])[CH2:7][CH2:6][CH2:5][SH:4])([OH:22])=[O:21]
Reactant: COC(=O)c1cccc(OC(CCCSC(C)=O)C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(OC(CCCS)C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
A solution of methyl 3-(4-acetylthio-1-methoxy-carbonylbutoxy)benzoate XV (8.00 g, 23.5 mmol) in THF (60 mL) was deoxygenated by bubbling N2 through the solution for 1 hour. To the solution was added deoxygenated 3 N NaOH (47 mL, 141 mmol) and the mixture was stirred for 24 hours at room temperature under N2. The mixture was acidified with 1 N HCl and extracted with EtOAc (3×300 mL). The organic extracts were washed with water (300 mL) and brine (300 mL), dried over MgSO4, filtered, and concentrated. The residual oil was dissolved in ether and the solution was concentrated to afford 3-(1-carboxy-4-mercaptobutoxy)-benzoic acid 14 (4.40 g, 16.3 mmol, 69%) as a white solid: 1H NMR (CDCl3) δ 1.40 (t, J=7.9 Hz, 1H), 1.83–1.99 (m, 2H), 2.11–2.22 (m, 2H), 2.63 (m, 2H), 4.76 (dd, J=7.3, 5.0 Hz, 1H), 7.23 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.49 (m, 1H), 7.72 (d, J=7.7 Hz, 1H); 13C NMR (CDCl3) δ 24.1, 29.6, 31.2, 75.5, 114.8, 122.1, 123.9, 129.9, 130.5, 157.6, 171.8, 177.1. Anal. Calcd for C12H14O5S: C, 53.32; H, 5.22; S, 11.86. Found: C, 53.04; H, 5.38; S, 11.58.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:11])=[O:12])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of 2-amino-5-methoxy-benzenesulfonamide (2.73 g, 13.43 mmol) in pyridine (25 mL), 2,3-dichlorobenzenesulfonyl chloride (3.68 g, 15.0 mmol) was added slowly at 0° C. The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was then partitioned between ethyl acetate and 1N HCl. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:1) to afford the title compound (4.8 g, 87%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:19])([F:18])[C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:15]2[CH:14]=[C:13]([C:12]([F:19])([F:18])[F:11])[CH:17]=[N:16]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
A round bottom flask was charged with 2-chloro-5-nitropyrimidine (2.50 g, 15.7 mmol), 4-(trifluoromethyl)-1H-pyrazole (2.35 g, 17.2 mmol), K2CO3 (4.33 g, 31.3 mmol) and acetonitrile (39 mL). The reaction was heated at 80° C. for 2 hours. Potassium carbonate filtered off with a büchner funnel and acetonitrile removed under reduced pressure. The crude material was dissolved in ethyl acetate and transferred to a separatory funnel. Organics washed with water (3×), with brine (1×), dried over sodium sulfate, filtered and concentrated to afford the raw material. Purification by silica gel flash chromatography (ethyl acetate/heptane) provide 5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (1.95 g, 49%) as a yellow solid. MS (M+1): 259.2.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][N:30]=[C:31]=[O:32]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:30]([CH2:29][C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=NCc1ccco1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(Cc3ccco3)c(=O)n(C3CCCC3)c12
Yield: 53.7 %

Procedure:
1-Cyclopentyl-3-furan-2-ylmethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and (2-furyl)methyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 392 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.78 (d, 1H), 7.57 (t, 1H), 7.32 (d, 1H), 7.24 (d, 1H), 6.30 (d, 1H), 6.18 (d, 1H), 5.04 (p, 1H), 4.33 (s, 2H), 4.12 (s, 3H), 2.40 (m, 2H), 2.11 (m, 4H), and 1.16 (m, 2H) ppm.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCC(=O)O
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 140 °C
Yield: 90 %

Procedure:
A mixture of crushed phthalic anhydride (18.53 g, 0.125 mol) and 4-aminobutyric acid was heated for 30 minutes at 140° C. The reaction mixture was cooled, and resulting precipitate was recrystallized from methanol-water to give 26.26 g (yield 90%) of the titled compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([CH2:25]Cl)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:25][C:1]#[N:2])[C:19]=3[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: [C-]#N
Reactant: ClCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5.0 g of sodium cyanide and 120 ml of dimethylsulfoxide was added 11.7 g of 1-(4-chlorophenyl)-5-chloromethylisoquinoline little by little. The mixture was stirred at room temperature for 2 hours, and poured into a mixture of ethyl acetate and 1% sodium bicarbonate aqueous solution. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried. The solvent was distilled off. Recrystallization of the residue from dichloromethane-hexane afforded 1-(4-chlorophenyl)isoquinoline-5-acetonitrile as slightly yellow prisms having a melting point of 131.5° to 132.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:20]3=[C:21]([CH2:23][CH2:24][N:19]3[CH2:18][C@@H:17]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@H:16]23)[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:20]3=[C:21]([CH2:23][CH2:24][N:19]3[CH2:18][C@@H:17]3[CH2:25][NH:26][CH2:27][C@H:16]23)[CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(Br)cc(c43)[C@H]2C1
Product: Clc1ccc(-c2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)c(Cl)c1

Procedure:
Using 2,4-dichlorobenzeneboronic acid and following the procedures described in EXAMPLE 20, (±)-cis tert-butyl 2-bromo-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±)-cis-2-(2,4-dichlorophenyl)-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline, trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 112 as the free base. 1H NMR (CDCl3) δ: 7.46 (d, 1H, J=2.2 Hz), 7.29-7.20 (m, 2H), 7.05 (d, 1H, J=1.1 Hz), 6.93 (d, 1H, J=0.8 Hz), 3.58 (dd, 1H, J=10.9, 7.7 Hz ), 3.50-3.30 (m, 4H), 3.15-2.95 (m, 5H), 2.90-2.77 (m, 2H). LRMS (ES)+: 345.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([CH3:12])[C:2]([Cl:1])=[CH:7][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(Cl)ccc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Cl)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
A mixture of 1.50 g (8.00 mmols) of 4-chloro-3-methyl-2-nitrophenol, 1.50 g (8.80 mmols) of benzyl bromide, 2.43 g (17.6 mmols) of potassium carbonate and 70 ml of acetone was refluxed for 2 hours. Thereafter insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 2.22 g (>99%) of 3-benzyloxy-6-chloro-2-nitrotoluene.