Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]([CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:27][C:28]1[C:29]([NH:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][C:45]#[N:46])[CH2:40][CH2:39]2)=[C:30]2[S:36][CH:35]=[CH:34][C:31]2=[N:32][CH:33]=1>O1CCCC1.C(O)C.CCOC(C)=O>[C:45]([CH2:44][C@H:41]1[CH2:40][CH2:39][C@H:38]([N:37]2[C:29]3=[C:30]4[S:36][CH:35]=[CH:34][C:31]4=[N:32][CH:33]=[C:28]3[N:27]=[C:2]2[CH:4]2[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5]2)[CH2:43][CH2:42]1)#[N:46]
Reactant: CC(C)(C)OC(=O)N1CC(C(N)=O)C1
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2nc3cnc4ccsc4c3n2[C@H]2CC[C@H](CC#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 3-(aminocarbonyl)azetidine-1-carboxylate (156 mg, 0.779 mmol) and triethyloxonium tetrafluoroborate (280 mg, 1.5 mmol) in tetrahydrofuran (0.4 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (39 mg, 0.14 mmol) and the above made reagent in ethanol (0.70 mL) was heated at reflux for 2 h. The mixture was cooled to room temperature, diluted with EtOAc, washed with sat. NaHCO3 solution, dried over MgSO4, concentrated and purified on silica gel column (0-5% MeOH in methylene chloride) to give the desired product. LCMS calculated for C24H30N5O2S (M+H)+: m/z=452.2. Found: 452.1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]([CH3:27])[CH2:10][CH2:11][CH:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1C=CC=CC=1>[CH3:27][N:9]([CH3:8])[CH2:10][CH2:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:1](=[O:3])[CH3:2])=[CH:22][CH:21]=1
Reactant: CN(C)CCC(Oc1ccc(N)cc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(OC(CCN(C)C)c2ccccc2)cc1
Reaction time: 0.75 h

Procedure:
2.8 ml of 98% acetic acid anhydride were added under an inert atmosphere to a solution of 7.6 g of N,N-dimethyl-γ-(4-amino-phenoxy)-benzene-propanamine in 80 ml of benzene and the mixture was stirred for 45 minutes. 50 ml of 2 N sodium hydroxide were added thereto and the decanted organic phase was washed with aqueous sodium chloride solution and was dried, treated with activated carbon and filtered. The filtrate was evaporated to dryness to obtain 9 g of N-[4-(3-dimethylamino-1-phenyl-propyloxy)-phenyl]acetamide.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][C:17]=3[CH3:24])[N:12]=2)=[CH:7][C:6]=1[C:25]([F:28])([F:27])[F:26])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.C1COCC1.[OH2:42].[Cl-].[Na+].[OH2:45]>[Os](=O)(=O)(=O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([OH:45])[CH2:23][OH:42])=[CH:18][C:17]=3[CH3:24])[N:12]=2)=[CH:7][C:6]=1[C:25]([F:26])([F:27])[F:28])([CH3:3])[CH3:2]
Reactant: O
Reactant: C=Cc1ccc(-c2noc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)n2)c(C)c1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(C(O)CO)ccc1-c1noc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 215 mg (0.55 mmol) of 5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-3-(2-methyl-4-vinylphenyl)-1,2,4-oxadiazole and 78 mg (0.66 mmol) of 4-methylmorpholine N-oxide in 12 mL of 3:1 v:v THF/H2O mix solvent was added 347 μL (0.03 mmol) osmium tetraoxide (2.5 wt %). After stirring at rt overnight, the mixture was poured into brine and extracted with EtOAc (3×20 mL). Organic layers were combined, dried over Na2SO4, and concentrated. Chromatography on Biotage 40S cartridge using 7:3 v/v EtOAc/hexanes as the eluant afforded 143 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.43 (d, J=5.9, 6H), 2.30 (br. s, 2H), 2.67 (s, 3H), 3.68 (dd, J=8.1, 11.4, 1H), 3.80 (dd, J=3.6, 11.3, 1H), 4.78 (m, 1H), 4.86 (dd, J=3.5, 8.0, 1H), 7.13 (d, J=8.7, 1H), 7.32-7.34 (m, 2H), 8.05 (d, J=8.0, 1H), 8.29 (dd, J=2.2, 8.8, 1H), 8.41 (d, J=2.1, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CO>O>[CH3:20][O:19][C:3]([O:2][CH3:1])([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][N:13]([S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:12]=1)=[O:7])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(C)(OC)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(C)(OC)OC(=O)N[C@@H](Cc1cn(S(=O)(=O)c2ccc(C)cc2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[(1,1-Dimethoxyethoxy)carbonyl]-L-histidine (12.7 g, 50 mmol) was dissolved in a solution of sodium carbonate (10.6 g, 100 mmol) in 150 ml water and cooled to 10°. p-Toluenesulfonylchloride (12.8 g, 67 mmol) was added in very small portions over a period of 30 minutes while maintaining vigorous stirring and controlling the temperature between 10°-15°. After the addition was complete, the reaction mixture was warmed to room temperature and stirring continued for an additional 4 hours. The reaction mixture was extracted twice with ethyl ether (75 ml) and the organic portions were discarded. The aqueous layer was acidified with 1N hydrochloric acid, extracted twice with ethyl acetate (150 ml) and the combined organic extracts were dried and concentrated to give an oily residue. Crystallization from ethyl acetate afforded 9.42 grams of the title A compound. m.p.=120°, [α]D =15.3° (c=1.66, CH3OH).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][CH:38]=1)[C:13]([NH:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:14])#[N:9]>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][CH:38]=1)[C:13]([NH:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:17]=1[C:18]([OH:20])=[O:19])=[O:14])#[N:9]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
0.5 mL of trifluoroacetic acid was added to 0.5 mL of methylene chloride solution containing 10 mg of tert-butyl 2-(3-cyanobenzamido)-4-phenoxybenzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 5.0 mg of 2-(3-cyanobenzamido)-4-phenoxybenzoic acid as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][C:20]([CH3:26])([CH3:25])[C:19]5[C:27]([C:31]([O:33]CC)=[O:32])=[N:28][N:29]([CH3:30])[C:18]=5[C:17]=4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[K+:37]>C(O)C>[K+:37].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][C:20]([CH3:26])([CH3:25])[C:19]5[C:27]([C:31]([O-:33])=[O:32])=[N:28][N:29]([CH3:30])[C:18]=5[C:17]=4[N:16]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(Nc3ncc4c(n3)-c3c(c(C(=O)[O-])nn3C)C(C)(C)C4)cc2)CC1

Procedure:
To a suspension of ethyl 8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (11.60 g, 24.390 mmol) in anhydrous ethanol (450 mL), 1.5 M potassium hydroxide in 95% ethanol (63 mL) was added under good stirring and the mixture was heated to reflux for 3 hours. After cooling in an ice bath, a solid was formed, that was filtered washing with ethanol, dried at 40° C. under vacuum to yield 11.8 g (quantitative yield) of white solid title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.OB(O)[C:33]1[CH:44]=[CH:43][C:36]([CH2:37][C@@H:38]([C:40]([OH:42])=[O:41])[NH2:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[NH2:39][CH:38]([CH2:37][C:36]1[CH:43]=[CH:44][C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:16]4[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]5[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=5)=[N:15]4)=[C:10]([CH3:30])[N:9]=3)[CH:3]=2)=[CH:34][CH:35]=1)[C:40]([OH:42])=[O:41]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(-c5ccc(CC(N)C(=O)O)cc5)c4)n3n2)cc(OC)c1OC
Temperature: 130 °C
Yield: 42.2 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 4-(dihydroxyboryl)phenylalanine (57.6 mg, 0.275 mmol), tetrakis(triphenylphosphine) palladium (0) (15.0 mg, 0.013 mmol) and potassium carbonate (52.8 mg, 0.382 mmol) was added DME (1.8 mL) and distilled water (0.6 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 130° C. for a total time of 1.5 hours. After cooling to room temperature, removed solvent under reduced pressure, dissolved residue in methanol (25 mL), and added silica gel (1 g). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using dichloromethane:methanol (100:0 to 65:35) followed by ethyl acetate:methanol (80:20) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 2-amino-3-(3′-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}-1,1′-biphenyl-4-yl)propanoic acid (0.0199 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.55 (s, 1H), 8.45 (d, J=7.9 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.61-7.21 (m, 5H), 7.09 (s, 2H), 3.65 (s, 6H), 3.63 (s, 3H), 3.43-3.12 (m, 1H), 2.92-2.80 (m, 2H). MS m/z 555 (M+1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([N:15]1[CH:20]=[C:19]([C:21]([OH:23])=O)[C:18](=[O:24])[C:17]2[CH:25]=[C:26]([I:28])[S:27][C:16]1=2)[CH3:14].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.CC(O)=O>CN(C=O)C>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:21]([C:19]2[C:18](=[O:24])[C:17]3[CH:25]=[C:26]([I:28])[S:27][C:16]=3[N:15]([CH2:13][CH3:14])[CH:20]=2)=[O:23])=[CH:32][CH:31]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(I)sc21
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
Carbonyldiimidazole (0.290 g) is added to a solution of 7-ethyl-2-iodo-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (Eur. J. Med. Chem. 1987, 22, 139) (0.520 g) in DMF (13 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (0.22 mL) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (50 mL), and the resulting off-white solid is filtered off. This material is recrystallized twice from methanol to yield 0.372 g (53%) of the title compound as an off-white, crystalline solid.
Reaction SMILES: [CH3:1][N:2]([CH:16]1[C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19][NH:18][CH2:17]1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[N:4]=1.[C:25](O)(=[O:28])[CH:26]=[CH2:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[N:4]=1)[CH:16]1[C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19][N:18]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:17]1
Reactant: C=CC(=O)O
Reactant: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CNCC12CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CC(N(C)c2ccnc(Nc3cnn(C)c3)n2)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.1 %

Procedure:
To a suspension of N4-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.4]nonan-4-yl)pyrimidine-2,4-diamine (0.10 g, 0.31 mmol) in DCM (8.0 mL) was added acrylic acid (55 mg, 0.76 mmol), HATU (0.14 g, 0.37 mmol) and Et3N (62 mg, 0.61 mmol). The mixture was stirred at room temperature for 4 h, then diluted with DCM (50 mL), and washed with water (20 mL) followed by brine (20 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by preparative-TLC (DCM/MeOH (v/v)=12/1) to give the product as a light yellow solid (25 mg, 21%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH:14]1([N:19]2[C:23]([NH2:24])=[C:22]([C:25]#[N:26])[C:21]([CH2:27][CH3:28])=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([N:19]2[C:23]([NH:24][C:9]([CH2:8][C:5]3[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=3)=[O:11])=[C:22]([C:25]#[N:26])[C:21]([CH2:27][CH3:28])=[N:20]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C#N
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccncc2)c1C#N
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a mixture of 4-pyridine acetic acid hydrochloride (4.3 g, 25 mmol) and DMF (50 ml) cooled in an ice bath was added NaH (1.0 g, 25 mmol, 60% dispersion in mineral oil). The resulting mixture was stirred for 30 minutes and then N,N'-carbonyldiimidazole (4.0 g, 24.6 mmol) was added followed 30 minutes later by 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carbonitrile (4.1 g, 20 mmol). The reaction mixture was stirred as such for 4 hours, then at room temperature for about 2 days, and then finally was heated on a steam bath for 2 hours. The reaction mixture was concentrated to dryness and water (50 ml) and acetic acid (5 ml) were added. The mixture was extracted with CH2Cl2 (300 ml), the organic layer was concentrated in vacuo and the resulting oil was crystallized from ether and purified by column chromatography on silica gel eluting with ether to afford 2.8 g (35%) of 1-cyclopentyl-3-ethyl-4-cyano-5-[(4-pyridinylmethyl)carbonylamino]-1H-pyrazole, as a viscous oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>>[NH2:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: CC(C)(N)CN
Reactant: N#Cc1ccc(Cl)nc1
Product: CC(C)(N)CNc1ccc(C#N)cn1
Temperature: 120 °C

Procedure:
A mixture of 1,2-diamino-2-methylpropane (3.14 ml, 30 mmol), and 6-chloronicotinonitrile (2.77 g, 20 mmol) were heated to 120° C. for 2 days. The reaction mixture was filtered, and the inorganic salt was rinsed with EtOAc. The filterate was concentrated under reduced pressure to provide the titled compound as a pale yellow solid. MS (DCI) m/z 191 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=3)[NH:18]2)=[CH:13][C:12]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:7][S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[O:30])[CH:23]=3)[NH:18]2)=[CH:13][C:12]=1[N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (190 mg, 1.55 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (62 mg, 1.55 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.31 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h. Then the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (38 mg, 25%) as a white solid: LC/MS m/e calcd for C25H30FN3O4S (M+H)+: 488.6, observed: 488.5.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[C:15]=2[CH:14]=[CH:13][N:12]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH:11]1[C:20]2[C:15](=[C:16]([S:21]([O:5][C:4]3[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 5-isoquinolinesulfonyl chloride (2.64 g, 10.0 mmol), as prepared in the preceding step, were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was triturated from ether/hexane to give the title compound as a pale yellow solid (1.15 g, 37%). 1H-NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 9.60 (s, 1H), 8.86 (d, J=6.1 Hz, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.37 (t, J=6.1 Hz, 2H), 7.86 (t, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.23 (s, 1H), 5.97 (s, 1H), 2.08 (s, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[C:3]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:2]=1.Cl.Cl.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=N)OCC.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.O>[OH:7][C:5]1[CH:4]=[C:3]([CH:8]2[O:11][C:19]([C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)=[N:10][CH2:9]2)[CH:2]=[CH:1][CH:6]=1
Reactant: CCOC(=N)c1cccs1
Reactant: NCC(O)c1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1cccc(C2CN=C(c3cccs3)O2)c1
Yield: 81.5 %

Procedure:
A mixture of (±) norphenylephrine hydrochloride (10 g, 0.05 mol), ethyl thiophene-2-imidate hydrochloride (10 g, 0.05 mol) and triethylamine (5 g, 0.05 mol) in tetrahydrofuran (300 ml) is heated to reflux for 8 hours. The mixture is dissolved in ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The combined ethyl acetate solutions are washed twice with dilute aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to dryness to obtain a viscous, partly crystalline material (10 g). This material is triturated with ether to obtain crystals (5 g) of m.p. 150°. These crystals are dissolved in hot acetonitrile and the solution is filtered and allowed to cool. The crystals (3.4 g) are filtered off, washed with acetonitrile and dried in vacuo; m.p. 156°-158° C.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:15])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([S:1][C:2]1[N:3]([CH3:15])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: Cn1c(S)nc2cnc3ccccc3c21
Product: Cn1c(SCc2ccccc2)nc2cnc3ccccc3c21

Procedure:
Using the method of Example 162, 2-mercapto-1-methyl-1H-imidazo[4,5-c]quinoline (from Example 165 below) was reacted with benzyl chloride to provide 2-benzylthio-1-methyl-1H-imidazo[4,5-c]quinoline. Recrystallization first from isopropanol then from ethanol provided solid product, m.p. 160°-163° C. Analysis: Calculated for C18H15N3S: %C, 70.8; %H, 5.0; %N, 13.8. Found: %C, 70.3; %H, 4.7; %N, 13.7.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][CH2:22][N:14]3[C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)[CH2:2]C.Br.Br.O[C:28]1C=CC(C2N=C3CCCN3C=2C2C=CN=CC=2)=CC=1.[H-].[Na+].CC(I)C>CN(C)C=O>[CH3:28][CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][CH2:22][N:14]3[C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CCCOc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 0.90 g (2.0 mmoles) of 2 (4 hydroxyphenyl) 3 (4-pyridyl) 6,7 dihydro-[5H]pyrrolo[1,2 a]imidazole dihydrobromide of Example 10 in 20 ml of dry dimethylformamide cooled in an ice bath was treated with 267 mg (6.67 mmoles) of 60% sodium hydride dispersion and allowed to warm to room temperature. A solution of 374 mg. (2.22 mmoles) of 2-propyl iodide in 2 ml of dimethylformamide was added dropwise and the reaction mixture heated at 100° C. for 4 hours. Another 35 mg (0.88 mmole) of 60% sodium hydride suspension was added at room temperature, followed by 113 mg (0.67 mmole) of 2-propyl iodide and the mixture heated at 100° C. for an additional 3 hours. After stirring overnight, the mixture was poured into 10 volumes of ice water and extracted three times with ethyl acetate. The organic phase was washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo. The residue was flash chromatographed on silica and the fraction eluting with 2% methanol in chloroform, concentrated in vacuo, and recrystallized from ethyl acetate to afford the titled compound, mp 148-150° C. Anal. Calcd. for C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C, 75.38; H, 6.58; N, 13.26.