Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@@H:45]([C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=4)[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:53][C:49]1[CH:48]=[C:47]([C@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]2[C@@H:25]2[C@@:20]([CH3:54])([CH2:21][CH2:22]3)[C@@:19]3([CH3:55])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:46])[CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2cccc(Cl)c2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2cccc(Cl)c2)CC1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((R)-1-(3-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (400 mg, 0.489 mmol) in DCM (10 mL) that was stirred at room temp was then added TFA (5 mL, 64.9 mmol). The reaction mixture was stirred at 30° C. for 2 h. The mixture was evaporated to dryness then diluted with 200 mL DCM. The organic phase was washed with saturated NaHCO3, water and brine. The organics were dried and concentrated under reduced pressure to afford crude product which was purified by preparative-HPLC to afford the title compound (100 mg, 27%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.38-7.14 (m, 4H), 6.96 (d, J=15.8 Hz, 1H), 6.25 (d, J=7.8 Hz, 1H), 5.73 (d, J=15.6 Hz, 1H), 5.23-5.08 (m, 1H), 4.50 (dd, J=5.4, 10.7 Hz, 1H), 3.27-3.11 (m, 1H), 2.82-2.49 (m, 3H), 2.33-2.19 (m, 1H), 2.19-2.00 (m, 2H), 2.00-0.71 (m, 47H); LC/MS: m/z calculated 761.4. Found 762.2 (M+1)+.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=O)[O:5]C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[C@H:24]([CH3:25])[O:23]3)=[N:16]2)=[CH:11][CH:10]=1.O>CS(C)=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:23][C:4](=[O:5])[N:3]([O:2][CH3:1])[CH:24]3[CH3:25])=[N:16]2)=[CH:13][CH:14]=1
Reactant: CONC(=O)OC
Reactant: C[C@@H]1O[C@@H]1COc1ccn(-c2ccc(Cl)cc2)n1
Solvent: CS(C)=O
Solvent: O
Product: CON1C(=O)OC(COc2ccn(-c3ccc(Cl)cc3)n2)C1C
Temperature: 25 °C

Procedure:
To 1.08 g (10.0 mmol) methyl N-methoxycarbamate in 17 ml DMSO have been added with stirring at ambient temperature 1.00 g (8.9 mmol) potassium tert.-butylate. Stirring has been continued for 5 min before 2.00 g (7.56 mmol) 1-(4-chloro-phenyl)-3-[[(2R,3S)-3-methyloxiran-2-yl]methoxy]pyrazole have been added. The mixture was stirred at 90° C. for 20 h. After cooling to ambient temperature the reaction mixture was poured into 150 ml of water, extracted thrice with 30 ml ethyl acetate each, the combined extracts have been dried with sodium sulfate and the solvent removed in vacuo. The crude product (2.5 g) was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:4][CH:3]=1.[N:19]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C:22](=O)[CH2:21][CH2:20]2>>[F:16][C:13]1[CH:14]=[CH:15][C:10]2[N:8]([CH2:7][CH2:6][C:5]3[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:23]4[CH2:26][CH2:27][N:19]([CH2:20][C:21]=3[C:11]=2[CH:12]=1)[CH2:25][CH2:24]4
Reactant: NN(CCc1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C1CCN2CCC1CC2
Product: Fc1ccc(CCn2c3c(c4cc(F)ccc42)CN2CCC3CC2)cc1

Procedure:
General procedure C was used to convert 1-(4-fluorophenethyl)-1-(4-fluorophenyl)-hydrazine (276 mg, 1.1 mmol; Example 85A) and 1-azabicyclo[3.2.2]nonan-4-one (144 mg, 1.1 mmol; Example 2A) into the title compound as the trifluoroacetic acid salt: 1H NMR (300 MHz, CDCl3) δ ppm 1.60-1.77 (m, 2H) 1.96-2.15 (m, 2H) 2.92 (s, 1H) 3.05 (t, J=6.54 Hz, 2H) 3.24 (d, J=28.16 Hz, 2H), 3.51-3.74 (m, 2H) 4.31 (t, J=6.35 Hz, 2H) 4.57 (s, 2H) 6.81-6.89 (m, 2H) 6.89-6.95 (m, 2H) 6.99-7.07 (m, 2H) 7.21-7.34 (m, 1H); MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([OH:12])([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])[C:3]#[CH:4].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][C:2]([OH:12])([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])[CH2:3][CH3:4]
Reactant: [H][H]
Reactant: C#CC(C)(O)CCC(C)=C(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CCC(C)(O)CCC(C)=C(C)C
Temperature: 45 °C

Procedure:
383.0 g of 3,6,7-trimethyl-6-octen-1-in-3-ol and 0.3 g of Lindlar catalyst (5% Pd+3.5% Pb on CaCO3) are put in an autoclave and heated under nitrogen to a temperature of 45° C. Nitrogen is exchanged by hydrogen (H2) and the reaction mixture put at an absolute pressure of 2 bar. After the calculated amount of hydrogen has been consumed the reaction mixture is filtered and distilled (2 mbar, 115° C.) to obtain 3,6,7-trimethyl-6-octen-3-ol (=compound of formula (Ia)).
Reaction SMILES: [ClH:1].C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:36][O:37][CH2:38][CH2:39][CH2:40][NH:41]C(OC(C)(C)C)=O)[C:11]([NH:13][CH:14]2[C:34](=[O:35])[N:16]3[C:17]([C:31]([OH:33])=[O:32])=[C:18]([CH2:21][S:22][C:23]4[N:27]([CH2:28][CH:29]=[CH2:30])[N:26]=[N:25][N:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[ClH:1].[ClH:1].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41])[C:11]([NH:13][CH:14]2[C:34](=[O:35])[N:16]3[C:17]([C:31]([OH:33])=[O:32])=[C:18]([CH2:21][S:22][C:23]4[N:27]([CH2:28][CH:29]=[CH2:30])[N:26]=[N:25][N:24]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCCN)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C

Procedure:
Conc. hydrochloric acid (0.5 ml.) was added to a solution of 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.) in methanol (20 ml.) and stirred at room temperature for an hour. After evaporating the solvent in vacuo, methanol was added to the residue and evaporated again. The residue was dried over phosphorus pentoxide in vacuo to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 0.89 g.).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][CH:3]=1.[I:11]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(O)(=O)C>[I:11][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(C#N)cc1I
Yield: 85.8 %

Procedure:
A mixture of 13.4 g (0.1 mole) of 1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 22.5 g (0.1 mole) of N-iodosuccinimide and 5 mL of trifluoroacetic acid in 250 mL of acetic acid was heated to reflux under argon for 4 hrs. The reaction was cooled and filtered to remove the crystalline precipitated product which was washed with water and ether and air dried to give 22.3 g (86%) of the 5-iodopyridinone as dense, light yellow needles, mp 260-264.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:48][C@H:49]([C:57]([CH:59]1[CH:66]2[CH2:67][CH:62]3[CH2:63][CH:64]([CH2:68][C:60]1([NH2:69])[CH2:61]3)[CH2:65]2)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:48][C@H:49]([C:57]([CH:59]1[CH:66]2[CH2:67][CH:62]3[CH2:63][CH:64]([CH2:68][C:60]1([NH2:69])[CH2:61]3)[CH2:65]2)=[O:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 1.88 g of Boc-L-tyrosyl-D-methionyl-glycine and 0.45 ml of N-methylmorpholine in 25 ml of dry tetrahydrofuran under nitrogen is cooled to -45° C. with stirring. To the cooled solution is added 0.52 ml of isobutylchloroformate. The reaction mixture is allowed to warm to -20° C. over a 10 minute period and is then cooled to -35° C. Following the addition of 1.9 g of L-phenylalanyl-1-aminoadamantane the reaction mixture is warmed to room temperature and allowed to stand overnight. The reaction mixture is filtered and the tetrahydrofuran is removed under reduced pressure. The residue is dissolved in methylene chloride and washed with cold 1 M potassium bisulfate solution and saturated sodium chloride solution. Removal of the solvent and purification by chromatography on silica gel gives Boc-tyrosyl-D-methionyl-glycyl-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR39##
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)=[O:34]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1Cl)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.5 %

Procedure:
A mixture of 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.340 g (1.8 mmol) of 2-chlorophenylacetyl chloride, 0.20 g of triethylamine and 9 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 48 hours. An additional 0.27 g of 2-chlorophenylacetyl chloride is added and the mixture stirred at room temperature for 2.5 hr. The mixture is washed with 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the solid recrystallized from dichloromethane to give 0.27 g of crystals;, m.p. 191°-194° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:24]4([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:31].[CH3:32]I>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:24]4([O:30][CH3:32])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:31]
Reactant: CI
Reactant: Cn1c(=O)ccc2cc(COc3cc(C(F)(F)F)cc(C4(O)CCOCC4)c3)ccc21
Product: COC1(c2cc(OCc3ccc4c(ccc(=O)n4C)c3)cc(C(F)(F)F)c2)CCOCC1
Yield: 95 %

Procedure:
Using the procedure described in Example 11, 4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)-5-trifluoromethylphenyl]-4-hydroxytetrahydropyran was reacted with methyl iodide to give 4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)-5-trifluoromethylphenyl]-4-methoxytetrahydropyran in 95% yield, m.p. 103° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(Cl)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccc(Cl)cc3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.96 min; [M+H]+=411.11.
Reaction SMILES: C([O:3][C:4](=[O:7])[CH:5]=[CH2:6])C.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[CH2:8]([O:15][CH2:6][CH2:5][C:4]([OH:7])=[O:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a stirred solution of ethylacrylate (0.5 mol, 50.0 g) in benzylalcohol (2 mol, 216 g), KtBu (5 mmol, 0.61 g) was added at room temperature. After standing overnight, NaOH (0.55 mol, 22 g) in water (100 ml) was added. The solution was stirred for 2 hrs. at 50° C. and cooled to room temperature. Water (300 ml) was added and the mixture extracted with CH2Cl2 (1×500 ml, 4×150 ml). The aqueous layer was evaporated and the residue washed with diethylether (4×100 ml). The white solid was dissolved in water (300 ml) and acidified with 33% HCl up to a pH of 2. On cooling (0° C.), the acid solidified. It was filtrated, rinsed with cold water, and dissolved in diethylether. After drying over MgSO4, the ether was evaporated. The acid was recrystallized from pentane/toluene and dried in a stream of nitrogen, resulting in 64.3 g (71%) of product.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.O>CN(C=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:10][CH:11]=1
Reactant: OCC1CC1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of cyclopropylmethanol (0.890 mL) in DMF (30 mL) was added sodium hydride (oil, 60%, 440 mg), and the mixture was stirred at room temperature for 10 min. To this mixture was added 2,5-dibromopyridine (2.00 g), and the mixture was stirred at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.88 g).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[CH:1]1([C:4]([NH:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccsc1N
Reactant: O=C(Cl)C1CC1
Product: COC(=O)c1ccsc1NC(=O)C1CC1

Procedure:
Cyclopropanecarbonyl chloride and methyl 2-aminothiophene-3-carboxylate (Aldrich) were processed using method analogous to that described in Example 13A to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:11]=1[S:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(O)cc1
Product: O=S(=O)(Nc1ccc(O)cc1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide was synthesized (98%) from 4-aminophenol (Aldrich) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride in a similar manner as described in Example 421. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.39 (s, 1H), 8.12 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 6.89 (m, 2H), 6.61 (m, 2H). MS (EI): m/z 384 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([O:23][CH3:24])[CH:5]=1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:33][C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=2)=[O:13])=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(OC)c1
Reactant: Cc1cnc(N)cn1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-methoxy-4-(4-nitro-phenoxycarbonylamino)-benzoic acid methyl ester (11.7 g, 33.8 mmol) in 34 mL NMP at room temperature under nitrogen was added 5-methyl-2-aminopyrazine (3.69 g, 33.8 mmol) and the reaction was immersed in an 85° C. oil bath. After 6 hours the reaction was allowed to cool to room temperature and a precipitate formed. EtOAc (200 mL) was added and the precipitate was isolated by filtration (4.7 g, 44%). 1H-NMR (400 MHz, d6-DMSO) 6 8.79 (br s, 1H), 8.36 (d, 1H), 8.23 (s, 1H), 7.60 (d, 1H), 7.52 (s, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([NH:18][C:19](=[O:22])[CH:20]=[CH2:21])[CH2:16][CH3:17].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:21][CH2:20][C:19]([NH:18][CH2:15][CH2:16][CH3:17])=[O:22])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C=CC(=O)NCCC
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: Cl
Product: CCCNC(=O)CCN1CCC2=C(C)c3ccccc3C2C1

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-propyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 20 hours. M.P. of the hydrochloride of the title compound 196°-197° from ethanol (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:8]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH:8]1([NH:14][C:15]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C=NC1CCCCC1
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)NC1CCCCC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
4-Aminopyridine (100 mg, 1.06 mmol) and cyclohexyl isocyanate (146.3 mg, 1.17 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][NH:27][CH2:28][CH3:29])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>>[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][N:27]([C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[CH2:28][CH3:29])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4]
Reactant: CCNCc1nc2ccccc2cc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(2-ethylaminomethyl-quinolin-3-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, dihydrochloride and cyclopropanecarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:20].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]([NH2:14])=[O:20])=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(Br)c2)c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Br)c1

Procedure:
A 14 g. portion of ethyl 1-(3-bromophenyl)-5-cyano-4-pyrazolecarboxylate was hydrolyzed by stirring under reflux in 200 ml. of ethanol with 6 g. of potassium hydroxide for 2 hours. The mixture was then poured over ice, acidified and filtered, and the solids were crystallized from ethanol/water and dried at 168° to obtain 10 g. of the desired product, m.p. 215°-217° dec. The product was identified by NMR analysis in CDCl3 /DMSOd6. δ7.06 (s,1), carboxamide; 7.30-7.64 (m,4), aromatic; 8.08 (s,1), pyrazole; 9.10 (s,1), carboxamide.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:31]=[CH:30][C:8]2[NH:9][C:10]([C:12]3[CH:13]=[C:14]([C:27](O)=[O:28])[CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[OH:26])[C:17]=3[OH:18])=[N:11][C:7]=2[CH:6]=1)(=[NH:4])[NH2:3].Cl.CN(C)CCCN=C=NCC.[NH2:44][CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1>CN(C)C=O>[ClH:1].[C:2]([C:5]1[CH:31]=[CH:30][C:8]2[NH:9][C:10]([C:12]3[CH:13]=[C:14]([C:27]([NH:44][CH2:45][C:46]4[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=4)=[O:28])[CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[OH:26])[C:17]=3[OH:18])=[N:11][C:7]=2[CH:6]=1)(=[NH:4])[NH2:3]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)O)cc(-c4cc(F)ccc4O)c3O)nc2c1
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)NCc4ccncc4)cc(-c4cc(F)ccc4O)c3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carboxylic acid hydrochloride (100 mg, 0.226 mmol), prepared as in Reference 23, O-(7-azabenzotrizol-1-yl)-1,2,3,3-tetramethyluroniumhexafluorophosphate monohydrate (37 mg, 0.242 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (46 mg, 0.237 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL). The mixture was stirred at room temperature for 1 hour and then 4-aminomethylpyridine (27 mg, 0.248 mmol) was added to the mixture. The mixture was stirred at ambient temperature for 18 hours and then concentrated to a gum under high vacuum. The residue was dissolved in 5% acetonitrile/95% 20 mM hydrochloric acid (10 mL) and product purified via preparative C18 reverse phase HPLC (5% to 35% acetonitrile gradient, 20 mM HCl aqueous to give 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-N-pyridin-4-ylmethyl-biphenyl-3-carboxamide hydrochloride (50 mg) as a tan powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.[Mg].Br[CH2:15][CH2:16][CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:15][CH2:16][CH3:17])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1
Reactant: CCCBr
Reactant: Cc1cc2c(cc1C=O)OCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1cc2c(cc1C)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of 5.0 g of (6-methyl-1,3-benzodioxol-5-yl)-carboxaldehyde in 20 ml of tetrahydrofuran was dropwise added at a room temperature to a Grignard reagent prepared from 0.86 g of magnesium ribbon, 10 ml of tetrahydrofuran and 4.4 g of 1-bromopropane. The obtained mixture was stirred at a room temperature for one hour, followed by the addition of a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with ether. The organic layer was washed with an aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. 5.6 g of (6-methyl-1,3-benzodioxol-5-yl)-butan-1-ol was obtained.