Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](O)=[O:17].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CCN=C=NCCCN(C)C>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)=[O:17])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(CO)cc1)c1ccccn1
Yield: 91.9 %

Procedure:
Using General Procedure F: Reaction of (4-Amino-phenyl)-methanol (200 mg, 1.63 mmol), picolinic acid (217 mg, 1.79 mmol), 1-hydroxybenzotriazole (242 mg, 1.79 mmol), 4-methyl morpholine (269 uL, 2.45 mmol) and EDCI (343 mg, 1.79 mmol) for 24 h at room temperature, gave the title compound (342 mg, 92%) as a red solid. 1H NMR (300 MHz, CDCl3) δ 4.70 (d, 2H, J=3.9 Hz), 7.41 (d, 2H, J=8.4 Hz), 7.50 (ddd, 1H, J=7.5, 4.8, 1.3 Hz), 7.79 (d, 2H, J=8.4 Hz), 7.92 (ddd, 1H, J=7.5, 7.5, 4.5 Hz), 8.31 (d, 1H, J=6.0 Hz), 10.06 (br s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:25]=[CH:26][C:27]1[CH:35]=[CH:34][C:32]([OH:33])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C)C=O>O>[CH:26]([C:27]1[CH:35]=[CH:34][C:32]([O:33][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:25]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of methyl 4-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate (0.80 g), potassium carbonate (0.40 g), vanillin (0.44 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 4-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (1.02 g, 92%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 185-186° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Cl[CH2:11][C:12](=O)[CH3:13].C([O-])(O)=O.[Na+]>C(O)C.O>[Cl:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]2[N:3]([CH:11]=[C:12]([CH3:13])[N:1]=2)[CH:4]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cn2cc(Cl)cc(Cl)c2n1

Procedure:
A mixture of 30 g 2-amino-3,5-dichloropyridine and 39 ml chloroacetone dissolved in 260 ml ethanol is heated under reflux for 64 hours. The volatile components are stripped off in vacuum and the residue suspended in 200 ml water. This is brought to pH 7-8 by means of saturated aqueous NaHCO3 -solution. A filtrate is obtained under suction and dried to constant weight in vacuo and recrystallized from cyclohexane. 17.8 g of the title compound of m.p. 156°-158° C. is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[C@H:14](C(O)=O)C>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:14])[CH3:5]
Reactant: C[C@H](N)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 12 h

Procedure:
Site-specific mutagenesis was carried out according to standard techniques described by Kunkel (Kunkel T A. Rapid and efficient site-specific mutagenesis without phenotypic selection; Proc Natl Acad Sci, USA 1985, 82:488-492). Sequencing of the cDNA was carried out for assurance that the mutation was correct and that any new mutations had not been introduced. Expression of the recombinant FIX was obtained using “human embryonic kidney cell line 293” and the methods already reported in the literature (Chang J L, Jin J P, Lollar P, et al. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J. Biol. Chem. 1998; 273:12089-12094). The recombinant FIX was isolated from the supernatant (culture medium) by means of an immunoaffinity column, as aforedescribed. Briefly, the supernatant of the cell culture was collected every 24 hours for 10 days and conserved at −20° C. For the purification the supernatant was thawed out and benzamidine and EDTA were added to a final concentration of 5 milliMoles and 4 milliMoles respectively. After filtration through a Millipore filter, the supernatant was incubated with fast-flow Sepharose Q resin for 12 hours at 4° C. The resin was then re-equilibrated in Tris, NaCl and benzamidine buffer and loaded onto the column. Elution was undertaken with a 0-60 nM calcium gradient. The eluate was then dialyzed in a Tris-NaCl buffer. The preparation was then applied to the immunoaffinity column following the method described in example 2 (in the “in vitro” expression of the recombinant protein). Starting from the culture medium, the procedure was the same as for the plasma, except for the precipitation procedure using BaCl. The culture medium was centrifuged at 4000 g for 20 minutes then subjected to dialysis in Tris-NaCl and loaded onto the immunoaffinity column at a rate of 0.5 ml/min. The remaining steps were the same as those taken for the plasma.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3)c2c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)O
Temperature: 0 °C
Yield: 99.4 %

Procedure:
To a solution of ethyl 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 36a, 110 g, 0.335 mol) in EtOH (450 mL) was added a solution of NaOH (33.5 g, 0.837 mol) in water (200 mL) at room temperature. The reaction mixture was then refluxed overnight. The reaction solution was cooled down to 0° C. and carefully neutralized with 4N HCl to pH 7. The resultant solution was concentrated under reduced pressure to remove most of the EtOH. The precipitate was collected by filtration, and re-dissolved in EtOH (4 L) at 65° C. and treated with activated charcoal (5 g) for 0.5 h. The charcoal was removed by filtration over celite, and the filtrate was concentrated. The precipitate was collected by filtration, washed with cold water, and dried under vacuum at 60° C. overnight to give the title compound as a white solid (100 g, 99%). M.p.: 220.0-221.5° C. 1H NR (400 MHz, DMSO-d6) δ 1.28-1.72 (m, 8H), 2.00-2.04 (m, 2H), 2.75 (s, 3H), 4.69-4.71 (m, 1H), 7.10-7.12 (d, J=8.0 Hz, 1H), 7.24-7.26 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 12.80 (brs, 1H). MS 301 (MH+). Elemental Analysis Calculated (Found) for C17H20N2O3: C, 67.98% (67.74%); H, 6.71% (7.01%); N, 9.33% (9.40%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:22](#[N:25])[CH:23]=[CH2:24]>N1C=CC=CC=1.O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:24][CH2:23][C:22]#[N:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC#N
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCC#N
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of Example 109A (65 mg, 0.200 mmol) in pyridine (1 mL) and water (1 mL) was added acrylonitrile (0.185 ml, 3.00 mmol) and the reaction heated at 90° C. for 7 hr. The reaction was concentrated and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexane) to afford the title compound (65 mg, 86%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.36 (s, 9H) 3.05 (t, J=6.44 Hz, 2H) 3.90 (s, 3H) 4.40 (t, J=6.44 Hz, 2H) 6.74 (s, 1H) 6.92 (d, J=8.81 Hz, 1H) 7.35 (dd, J=8.81, 3.05 Hz, 1H) 7.90 (d, J=3.05 Hz, 1H); MS (DCI/NH3) m/z 378 (M+H)+. Anal. calcd C18H20ClN3O2S: C, 57.21; H, 5.33; N, 11.12. Found: C, 56.93; H, 5.42; N, 10.92.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH2:10]([S:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(SCc2ccccc2)cc1
Temperature: 120 °C
Yield: 30.6 %

Procedure:
Mix under argon atmosphere 4-fluorobenzonitrile (1.21 g, 10 mmol), benzyl mercaptan (1.86 g, 15 mmol), and cesium carbonate (6.5 g, 20 mmol) in anhydrous NMP (20 mL). Degas the flask and fill with argon. Heat at 120° C. for 3 h. Cool to ambient temperature, dilute with EtOAc, filter and wash with 1N aqueous HCl. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate (689 mg, 31%). GC-MS m/z: 225 (M+).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][CH:54]=[O:55])[N:10]=2)[N:5]=1)[CH3:3].N1CC[O:59][CH2:58][CH2:57]1.C([BH3-])#N.[Na+]>C(O)C.CO>[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][C:54]([O:59][CH2:58][CH3:57])=[O:55])[N:10]=2)[N:5]=1)[CH3:3]
Reactant: C1COCCN1
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCC=O)ccc2n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)COc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Reaction time: 20 h
Yield: 23.9 %

Procedure:
A saturated solution of hydrogen chloride in ethanol (0.1 ml) was added to a solution of compound B (600 mg) and morpholine (450 mg) in methanol (10 ml) containing 3A molecular sieves (1 g). Sodium cyanoborohydride (53 mg) was added and the mixture was stirred for 20 hours. Volatile material was removed by evaporation and the residue purified by flash chromatography, eluting with methanol/ethyl acetate (1:9 v/v). to give 2-ethyl-6-[2-(4-morpholino)ethoxy]-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A) (152 mg), m.p. 135°-137° C. (after trituration with hexane); NMR (d6 -DMSO): 1.3(t, 3H), 2.3-2.45(m, 4H), 2.6-2.8(m, 2H), 2.85(q, 2H), 3.4-3.55(m, 4H), 4.45-4.6(m, 2H), 5.4(s, 2H), 6.8-6.9(m, 6H), 7.1-7.7(complex m, 18H), 7.8(dd, 1H), 8.15(d, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)(=[O:3])[CH3:2].[Cl:46][C:47]1[N:55]=[C:54]2[C:50]([N:51]=[CH:52][N:53]2[CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][O:57]2)=[C:49](Cl)[N:48]=1.C(N(CC)C(C)C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:49]2[N:48]=[C:47]([Cl:46])[N:55]=[C:54]3[C:50]=2[N:51]=[CH:52][N:53]3[CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][O:57]2)[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](NC(=O)OC(C)(C)C)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6nc(Cl)nc7c6ncn7C6CCCCO6)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Temperature: 60 °C

Procedure:
(2R,3R,4R,5R)-2-(2-Chloro-6-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydrofuran-3,4-diyl diacetate (Intermediate 1) (5.2 mmol) was treated with 1:1 trifluoroacetic acid/dichloromethane (20 ml) for ca. 2 h. This was concentrated in vacuo and the residue was purified by SPE (SCX, 50 g), eluting sequentially with dichloromethane, methanol, 40% (2M ammonia in methanol): dichloromethane and 2M ammonia in methanol. The appropriate fraction was concentrated in vacuo and suspended in propan-2-ol (60 ml). To this was added N,N-diisopropylethylamine (4 m. eq.) and 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (prepared according to the method disclosed in WO2003080604A1) (1 m. eq.) and this was heated at 60° C. overnight. After cooling to room temperature, further 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.5 m. eq.) and N,N-diisopropylethylamine (4 ml) were added and this was heated at 60° C. for a further ca. 5 h. After cooling to room temperature, the reaction mixture was then concentrated in vacuo and the residue was partitioned between dichloromethane (ca. 60 ml) and water (ca. 60 ml). The organics were washed with water (ca. 60 ml), dried over magnesium sulfate and concentrated in vacuo to yield the title compound as an off-white crystalline solid, 4 g.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH:12]([O:31][C:32](=[O:34])[CH3:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]2[CH2:28][O:27]C(C)(C)[O:25]2)=[CH:15][CH:14]=1)(=[O:10])[CH3:9]>CO.C(OCC)(=O)C>[C:32]([O:31][CH:12]([O:11][C:8](=[O:10])[CH3:9])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[CH2:28][OH:27])=[CH:17][CH:18]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(OC(C)=O)c1ccc(OCCCCC2COC(C)(C)O2)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(=O)OC(OC(C)=O)c1ccc(OCCCCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a solution of 7 (5.8 g, 15.26 mmol) in 20% aqueous methanol. The solution was stirred for 40 min at room temperature and then diluted with 400 ml of ethyl acetate and washed with 400 ml of 5% sodium bicarbonate solution followed by 400 ml of water. The organic solution was dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 50% hexane in ethyl acetate to 100% ethyl acetate to 5% methanol in ethyl acetate. The pure product fractions were evaporated affording an oil: 1.1 g (20%) yield; TLC (5% methanol in ethyl acetate), Rf=0.64; 1H NMR (CDCl3) 7.62 (1H, s, acetal CH), 7.44 (2H, d, J=8.7 Hz, aromatic), 6.90 (2H, d, J=8.6 Hz, aromatic), 3.98 (2H, t, J=6.3 Hz, CH2), 3.68 (1H, m, CH), 3.46 (2H, m, CH2), 2.11 (6H, s, Acetyl), 1.82 (2H, m, CH2), 1.55 (4H, m, CH2). Anal. Calcd for C17H24O7: C, 59.99; H, 7.11. Found: C, 60.26; H, 7.08
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[S:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[S:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)sc2Cl)n1
Temperature: 150 °C
Yield: 36.8 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2,5-dichloro-3-thiophenecarbonyl chloride (0.265 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.055 g (37% yield) of pure product: MS (ES) m/z 485 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:28])[C:8]([C@H:13]([OH:27])[C:14]([O:16][C@@H:17]3[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]3[CH:24]([CH3:26])[CH3:25])=[O:15])=[C:9]2[OH:12])=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.O>C(OC(C)=O)(C)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:28])[C:8]([C@H:13]([O:27][C:5]([CH3:10])([CH3:6])[CH3:4])[C:14]([O:16][C@@H:17]3[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]3[CH:24]([CH3:25])[CH3:26])=[O:15])=[C:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: Cc1cc2ccc(Br)cc2c(O)c1[C@H](O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: O
Product: Cc1cc2ccc(Br)cc2c(O)c1[C@H](OC(C)(C)C)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reaction time: 3 h

Procedure:
To a solution of (S)-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2-(7-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate in t-BuOAc (150 mL) was added 70% perchloric acid (HClO4) (3.0 mL). After 3 h, water was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes). Upon sitting, crystals formed in the resulting oil that were the desired diastereomer. 1H-NMR: 400 MHz, (CDCl3) δ: 9.11 (s, 1H), 8.39 (s, 1H), 7.48 (m, 2H), 7.10 (s, 1H), 5.46 (s, 1H), 4.66 (m, 2H), 2.53 (s, 3H), 1.71 (m, 2H), 1.62 (m, 2H), 1.36 (m, 2H), 1.32 (s, 9H), 0.80 (m, 7H), 0.60 (d, J=6 Hz, 3H).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][N:30]=[C:31]([NH2:33])[CH:32]=2)=[CH:24][CH:23]=1>O1CCCC1>[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[NH:29][N:30]=[C:31]([NH:33][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[CH:32]=2)=[CH:26][CH:27]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: COC(=O)c1ccc(-c2cc(N)n[nH]2)cc1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(NC=C3C(=O)Nc4ccccc43)n[nH]2)cc1

Procedure:
The named compound is prepared by substituting 4-(5-amino-2H-pyrazol-3-yl)-benzoic acid methyl ester for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2847 gms. of 4-(5-amino-2H-pyrazol-3-yl)-benzoic acid methyl ester by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:11](=O)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:13])C.Cl.[C:15]([NH:19]N)([CH3:18])([CH3:17])[CH3:16]>C(O)CCC.C(O)(=O)C>[C:15]([N:19]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:13])[C:5]=2[CH:4]=[N:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C)C=C1C(=O)CCCCC1=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCO
Product: CC(C)(C)n1ncc2c1CCCCC2=O

Procedure:
A solution of 1,3-cycloheptadione (2 g, mmol) was heated to reflux for 1 hour with dimethylforamide dimethylacetal (15 mL). The reaction mixture was concentrated and triturated with ether to yield 1.8 g of 2-dimethylaminomethylene-cycloheptane-1,3-dione. A solution of 2-dimethylaminomethylene-cycloheptane-1,3-dione (0.52 g, 2.9 mmol) and t-butylhydrazine hydrochloride (0.44 g, 3.5 mmol) in n-butanol (25 mL) and 0.3 mL of acetic acid was heated to reflux for 16 hours. The solvents were evaporated and the residue was chromatographed, eluting with 30% ethyl acetate/hexane to yield the title compound: 1H NMR (300 MHz, CDCl3) δ 7.85 (s, 1 H), 3.17 (m, 2 H), 2.68 (m, 2 H), 1.98 (m, 2 H), 1.89 (m, 2H) 1.68 (s, 9 H); MS (DCI/NH3) m/z 207 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[O:6][CH2:5][CH2:4][O:3]1.[O-2].[Ca+2].S1C=CC=C1>O1CCCC1.[Pt]>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2ccccc2[N+](=O)[O-])OCCO1
Agent: [Pt]
Agent: [Ca+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: CC1(c2ccccc2N)OCCO1
Yield: 78.2 %

Procedure:
2-methyl-2-(2-nitrophenyl)-1,3-dioxolane (0.132mol) was dissolved in tetrahydrofuran (600 ml) and this solution was hydrogenated with platinum on activated carbon (4 g) as a catalyst in the presence of calcium oxide (10 g) and thiophene (3 ml). After uptake of H2 (3 equiv), the catalyst was filtered on celite and washed with tetrahydrofuran. The tiltrate was evaporated. The residue was recrystallized from n-hexane. The crystals were filtered off and dried, yielding 18.5 g (78%) of 2-(2-methyl-1,3-dioxolan-2-yl)benzenamine (interm. 27).
Reaction SMILES: FC1C=NC2C=CC=C(N)C=2C=1.Cl.[F:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[C:22]([CH2:25][C:26]([OH:28])=O)[CH:21]=[CH:20][CH:19]=2.[Br:29][C:30]1[C:31]([C:36]2[NH:40][CH:39]=[N:38][N:37]=2)=[C:32]([NH2:35])[S:33][CH:34]=1>>[Br:29][C:30]1[C:31]([C:36]2[N:40]=[CH:39][NH:38][N:37]=2)=[C:32]([NH:35][C:26](=[O:28])[CH2:25][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]=2[CH:24]=[C:15]([F:14])[CH:16]=[N:17]3)[S:33][CH:34]=1
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Reactant: O=C(O)Cc1cccc2ncc(F)cc12
Agent: Cl
Agent: Nc1cccc2ncc(F)cc12
Product: O=C(Cc1cccc2ncc(F)cc12)Nc1scc(Br)c1-c1nc[nH]n1

Procedure:
The title compound was prepared by converting 3-fluoroquinolin-5-amine (850 mg, 5.24 mmol) into 2-(3-fluoroquinolin-5-yl)acetic acid hydrogen chloride (76 mg, 315 umol) and reaction with 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (34 mg, 139 umol) as outlined in Example 1.68., above. Method [8] retention time 2.46 min by HPLC (M+206). 1H NMR (300 MHz, CDCl3) δ 12.35 (s, 1H), 8.89 (d, J=2.7 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.07 (dd, J=9.3 and 2.7 Hz, 1H), 7.83 (m, 1H), 7.74 (d, J=6.9 Hz, 1H), 7.59 (s, 1H), 6.93 (s, 1H), 4.33 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=1[CH3:21])=[O:8].[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=2[CH3:21])=[O:8])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35]
Reactant: COc1c(C)c(C)c(C(=O)CCCCCBr)c(C)c1OC
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)c2c(C)c(C)c(OC)c(OC)c2C)ccc(C(=O)OC)c1O
Yield: 83 %

Procedure:
A mixture of 0.194 g (2.6 mmol) of 6-bromo-1-(3,4-dimethoxy-2,5,6-trimethylphenyl)-1-hexanone, 0.55 g (2.6 mmol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 1.10 g (7.8 mmol) of potassium carbonate in 20 mL of acetone and 2 mL of DMF was stirred at reflux for 17 hours. After workup as in Example 16, the crude product was purified by chromatography on 100 g of silica gel. Elution with 10% ethyl acetate-hexane gave 1.05 g (83% yield) of 4-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid methyl ester. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 486 (C28H28O7).