Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([CH2:20][CH2:19][N:18]([CH3:31])[CH3:17])(=[O:23])=[O:22])=[CH:29][CH:28]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN(C)CCS(=O)(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCS(=O)(=O)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 37.7 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and 4-(2-dimethylamino-ethanesulfonyl)-phenylamine (0.14 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-{[(4-{[2-(dimethylamino)ethyl]sulfonyl}-phenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.11 g, 36%) as a golden powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]=1[CH2:10]Br)=[O:4].[OH2:27]>CN(C=O)C>[OH:27][CH2:10][C:9]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[S:6][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(SC)cc2)c1CBr
Reactant: O
Solvent: CN(C)C=O
Product: CSc1ccc(-c2c(-c3ccc(F)cc3)sc(C(=O)O)c2CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 249 mg of the product of Step 2 in 5 mL of DMF was added 237 mg of n-Bu4NOAc. The reaction mixture was stirred at r.t. for 15 min. Water (20 mL) was added and the product was extracted with 50 mL of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in 4 mL of THF and 2 mL of MeOH and treated with 1 ml of 1N LiOH. After 12 h, the reaction mixture was treated with 0.2 ml of HOAc and 10 mL of brine. The product was extracted with 40 mL of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo to provide 120 mg of title compound as a white solid.
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:16][C@H:17]([C:32]([O:34][CH3:35])=[O:33])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([C@@H:17]([C:32]([O:34][CH3:35])=[O:33])[O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:15][CH2:14]3)[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=1
Reactant: COC(=O)[C@@H](O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]-(methoxycarbonyl)methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 70; 735 mg, 1.27 mmol) was dissolved in ethyl acetate (10 ml) with glacial acetic acid (0.5 ml) and 10% palladium hydroxide (40 mg) added. The mixture was hydrogenated on a Parr™ at 40 psi overnight. The mixture was filtered through Celite™, then concentrated in vacuo and the residue basified with saturated sodium hydrogen carbonate solution. The solution was then extracted with ethyl acetate (×3) and the extracts dried (MgSO4) and concentrated in vacuo. The obtained oil was purified by flash column chromatography [10% methanol in dichloromethane) to give the title compound as a yellow oil. (5:1 desired:undesired). (323 mg, 52%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:17]=1[C:18]#[N:19])([O-])=O>CS(C)=O>[N+:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]=1[C:18]#[N:19])([O-:26])=[O:25]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1c(OCCOc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2-Phenoxyethanol (4.15 ml, 0.033 mole) is added to dimethylsulfoxy sodium prepared from 1.39 g of 57 percent sodium hydride and 40 ml dimethylsulfoxide, giving a mixture of the solid salt of the alcohol after about 20 minutes. This mixture is added to a solution of 5.8 g (0.030 mole) 2,6-dinitrobenzonitrile in 20 ml of dimethylsulfoxide at 30°-40°C., and the resulting purple solution is stirred over night at room temperature. The solvent is removed at 70°C. on a rotary evaporator, and the residue is triturated with water. A solid is filtered off and it is dissolved in ethylacetate. The ethylacetate solution is washed twice with H2O, brine, and dried with calcium sulfate. Evaporation of the ethylacetate, gives 8.5 g of 2-nitro-6(2-phenoxyethyoxy)-benzonitrile, which is crystallized from 200 ml ethyl alcohol, giving 6 g, m.p. 129°-137°C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH2:22])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:27](=N)[CH2:28][Cl:29])C>C(O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]2[NH:21][C:27]([CH2:28][Cl:29])=[N:22][C:17]=2[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(N)c1
Reactant: CCOC(=N)CCl
Agent: Cl
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Yield: 59.9 %

Procedure:
A mixture of 3′,4′-diamino-biphenyl-2-sulfonic acid tert-butylamide (1.0 g, 3.13 mmol), 2-chloroacetimidic acid ethyl ester hydrochloride salt (591 mg, 3.76 mmol) (prepared according to the procedure described in J. Med. Chem., 1986, 29, 2280) in anhydrous ethanol (100%, 20 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to afford the title compound as an off-white solid (708 mg, 60% yield). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.14 (dd, 1H, J=8.1 Hz, J=1.5 Hz), 7.79 (m, 1H), 7.74 (dd, 1H, J=8.5 Hz, J=1.1 Hz), 7.65 (td, 1H, J=7.5 Hz, J=1.6 Hz), 7.57 (td, 1H, J=7.8 Hz, J=1.6 Hz), 7.50 (dd, 1H, J=8.3 Hz, J=1.6 Hz), 7.39 (dd, 1H, J=7.3 Hz, J=1.2 Hz), 5.05 (s, 2H), 1.02 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C18H20ClN3O2S: 378.89 (M+H), Found 378.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[N:5]=[CH:4][N:3]=1)=[O:31]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of 4-amino-6-(4-nitrophenoxy)pyrimidine (560 mg, 2.41 mmol) and DIPEA (630 μL, 3.62 mmol) in DCM (15 mL) under nitrogen at 0° C. was added 2-methoxyacetyl chloride (330 μL, 3.62 mmol) dropwise over 5 min. The mixture was warmed to RT for 1 hr and the reaction was quenched by addition of a 1% solution of NH3 in MeOH (10 mL) and then evaporated in vacuo. The residue was partitioned between DCM (50 mL) and water (25 mL) and the organic layer was separated and washed with brine (25 mL) and was then dried (MgSO4). Evaporation of the volatiles in vacuo gave the title compound as a beige solid (730 mg, 97%): Rt 1.87 min (Method 2); m/z 305 (M−H)+ (ES+).
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1.O>[CH:19]1([C:25]([N:9]2[CH2:10][CH:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:12]3)[CH2:8]2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(C1CCCCC1)N1CC2CC2(c2ccccc2)C1

Procedure:
A 6.4 g. portion of 1-phenyl-3-azabicyclo[3.1.0]hexane is added to 60 ml. of benzene. A 4.2 g. portion of sodium carbonate in 40 ml. of water is added with stirring. A 5.9 g. portion of cyclohexylcarbonyl chloride in 40 ml. of benzene is added and the mixture is stirred overnight. The oily solid in the aqueous layer is extracted with chloroform. The extracts are washed with water and dilute hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The oily residue is extracted with ether giving a white solid as the product, mp 81°-82° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.O=[C:28]([CH2:34][C:35](=O)[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:34]=[C:35]([CH3:36])[N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: CCOC(=O)c1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 170 °C
Yield: 62.3 %

Procedure:
A mixture of N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (371 mg, 1.0 mmol), ethyl 2,4-dioxo-pentanoate (158 mg, 1.0 mmol) and potassium carbonate (69 mg, 0.5 mmol) in ethanol (2 mL) was heated in a sealed tube in a microwave oven to 170° C. for 0.5 h. The mixture was cooled, diluted with ethyl acetate (50 mL), and then washed with water (20 mL) and with brine (20 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% methanol as eluent to give the title compound (229 mg, 62%) as a yellow solid. MS ISP (m/e): 368.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.04 (d, 1H), 7.64 (s, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 7.17 (d, 1H), 6.98 (dd, 1H), 6.87 (s, 1H), 4.46 (q, 2H), 3.91 (s, 3H), 2.54 (s, 3H), 2.30 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[CH3:30])[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[CH3:30])[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(F)ccc1-c1cc(C(Oc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Reactant: CCOC(=O)CCNC
Product: Cc1cc(F)ccc1-c1cc(C(Oc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)o1
Yield: 76 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{cyclohexyl[5-(4-fluoro-2-methylphenyl)-2-methyl-3-furyl]methoxy}benzoic acid (139 mg) as well as ethyl 3-(methylamino)propanoate (52 mg) to give the title compound (127 mg, 76%) as an amorphous compound.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CC(C)=O>[N:14]([CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 36 h
Yield: 90.2 %

Procedure:
To a solution of 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (20.6 g, 103 mmol) in acetone (513 mL) was added an aqueous solution of sodium azide (7.01 g, 108 mmol in 32 mL water). Reaction was stirred at room temperature for 36 h. Mixture was split into three equal volumes and each was diluted with dichloromethane (500 mL) and brine was added (100 mL) and the layers were separated. The aqueous fractions were combined and extracted with dichloromethane (5×100 mL). The combined organic layers were concentrated in vacuo. The resulting residue was taken up in dichloromethane (200 mL) and evaporated to dryness three times to yield 19.25 g of a yellow-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (t, J=5.56 Hz, 2H) 3.85 (t, J=5.56 Hz, 2H) 4.28 (s, 2H) 4.36 (s, 2H) 12.58 (br. s., 1H)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([O:18][C@@H:19]([C@H:21]3[CH2:25][NH:24][C:23](=[O:26])[CH2:22]3)[CH3:20])[C:12]3[S:16][CH:15]=[N:14][C:13]=3[CH:17]=2)O1.Cl[C:29]1[N:34]=[C:33]([O:35][CH3:36])[C:32]([N:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:31][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:36][O:35][C:33]1[C:32]([N:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:31][CH:30]=[C:29]([C:9]2[CH:10]=[C:11]([O:18][C@@H:19]([C@@H:21]3[CH2:22][C:23](=[O:26])[NH:24][CH2:25]3)[CH3:20])[C:12]3[S:16][CH:15]=[N:14][C:13]=3[CH:17]=2)[N:34]=1
Reactant: COc1nc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncsc12)[C@H]1CNC(=O)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
(R)-4-((R)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one (4.05) (43 mg, 0.11 mmol), tert-butyl 4-(6-chloro-2-methoxypyridin-3-yl)piperazine-1-carboxylate 7.10 (50 mg, 0.15 mmol), K3PO4 (70.5 mg, 0.33 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.8 mg, 0.003 mmol) were taken up in 1,4-dioxane (1.6 mL) and water (0.16 mL) under Ar. The reaction mixture was stirred at 100° C. for 1.5 h and was then partitioned between EtOAc, water, and brine. The phases were separated, and the aqueous phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified to afford tert-butyl 4-(2-methoxy-6-(7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)benzo[d]thiazol-5-yl)pyridin-3-yl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H36N5O5S: 554.2; found: 554.5.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(c4ccccc4)CC3)cc2)nc1
Yield: 12.9 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.302 g, 1.25 mmol), 1-phenyl-piperazine (0.192 mL, 1.26 mmol), and sodium borohydride (0.110 g, 2.91 mmol) in methanol (12 mL) provides 0.0627 g (13%) of the title compound as a white solid Chromatography solvent: 25:1 methylene chloride:methanol. High resolution mass spectrum (electrospray): m/z calc for C23H25N4O2 389.1978, found 389.1993; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.9, 8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 7.27 (dd, 2H, J=7.3, 8.8 Hz), 7.20-7.15 (m, 2H), 7.05 (d, 1H, J=8.3 Hz), 7.03-6.99 (m, 2H), 6.88 (t, 1H, J=7.3 Hz), 3.67 (s, 2H), 3.27-3.21 (m, 4H), 2.74-2.69 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([OH:22])[C:6]=1[OH:23])([O:3][CH3:4])=[O:2].[CH2:24]1[O:26][CH2:25]1.[ClH:27]>CC(C)=O.C(OCC)(=O)C.C(O)C>[ClH:27].[C:1]([C:5]1[C:15]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:25][OH:26])[CH2:11][CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[CH:8]=[C:7]([OH:22])[C:6]=1[OH:23])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1
Reactant: C1CO1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)c(O)cc2c1CCN(CCO)CC2c1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A 4.2 g sample of 6-carbomethoxy-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is slurried in 25 ml of acetone and 0.7 g (0.016 mol, 10% excess) of ethylene oxide is added. The mixture is placed in a pressure bottle and stirred at ambient temperature for about 40 hours. The reaction mixture is then heated to 60°-80° for 30 minutes, cooled and filtered. Concentration of the filtrate gives a solid which is taken up in ethyl acetate and reprecipitated with ether. The solid thus obtained is dissolved in ethanol and treated with ethereal hydrogen chloride to give 6-carbomethoxy-7,8-dihydroxy-3-(2-hydroxyethyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [CH2:1]([NH:3][C:4](=S)[NH:5][NH2:6])[CH3:2].[Cl:8][CH:9]([C:15]([CH3:17])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>Cl>[ClH:8].[CH2:1]([NH:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([CH3:17])[NH:6][N:5]=1)[CH3:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCNC(=S)NN
Agent: Cl
Product: CCNc1n[nH]c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.1 %

Procedure:
A mixture of 47.68 g (0.4 mole) of 4-ethyl-3-thiosemicarbazide and 65.8 g (0.4 mole) of ethyl 2-chloracetoacetate was stirred under nitrogen atmosphere for 1.5 hr at ambient temperature then treated with 200 mL of 2N ethanolic hydrogen chloride. The mixture was stirred for ~72 hr, filtered to remove the amorphous sulfur, and the solvent was removed in vacuo to give a deep amber oil which solidified. Recrystallization from acetone gave 27 g of crude product which was recrystallized from benzene/petroleum ether to give 23.5 g of fine white crystals, mp 140°-148° C. Rework of the filtrate gave an additional 17.5 g of crude product.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>ClCCl.C(O)CCC>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:21]=[C:22]([NH:23][S:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][NH:4][CH2:5]3)=[CH:10][CH:9]=2)(=[O:15])=[O:16])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Agent: Cl
Solvent: CCCCO
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(C(F)(F)F)c1)c1ccc2c(c1)CNCC2

Procedure:
2-Acetyl-7-chlorosulphonyl-1,2,3,4-tetrahydroisoquinoline was reacted with 3-trifluoromethylaniline in dichloromethane according to the method generally described in EP No. 0038177-A. The resulting product was deacetylated by heating with aqueous hydrochloric acid in butanol to give 7-(3-trifluoromethylphenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline as the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:27]#[N:28])[N:12]3[C:17]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:16][C:15]([CH3:26])=[N:14][C:13]=23)=[C:4]([CH3:29])[CH:3]=1.C(=O)([O-])[OH:31].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([C:9]2[CH:10]=[C:11]([C:27]([NH2:28])=[O:31])[N:12]3[C:17]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:16][C:15]([CH3:26])=[N:14][C:13]=23)=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C([O-])O
Reactant: CCCC(CCC)Nc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C#N)n12
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCC(CCC)Nc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Temperature: 55 °C

Procedure:
8-(4-Bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (10.0 g) was added into conc. H2SO4 (50 mL) and heated for 55° C. for 5 hours. The reaction mixture was cooled to room temperature, poured into ice-water and then a saturated aqueous sodium hydrogencarbonate was added to make the aqueous mixture alkaline (pH=8) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate/chloroform=10:3:1) to give a solid. The solid was recrystallized from ethyl acetate to provide 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (5.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:28])([OH:27])[CH3:26])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1.[CH:32](=O)[CH3:33].C(O)(=O)C.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([CH2:32][CH3:33])[CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:26])([OH:27])[CH3:28])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1
Reactant: CC=O
Reactant: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CNCCO3)c21
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCO[C@H](COc2cnc(C#CC(C)(C)O)c3nc(-c4nonc4N)n(CC)c23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of the compound of Example 4 (0.13 g, 0.30 mmol) in MeOH (4 mL) at 0° C. was added acetaldehyde (0.034 mL, 0.61 mmol) and acetic acid (0.052 mL. 0.90 mmol). This was followed by the addition of NaCNBH3 (0.048 g, 0.76 mmol). The reaction was allowed to warm to RT. After 18 h, the reaction was poured into 50% aq. NaHCO3. The solution was cooled to 0° C. and the resultant precipitate was collected to give 0.10 g of the desired compound. MS (ES+) m/z 456.4 (M+H)+.