Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[N:34]1([CH:40]2[CH2:44][O:43][C:42](=[O:45])[CH2:41]2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:27])[N:37]3[CH2:36][CH2:35][N:34]([CH:40]4[CH2:41][C:42](=[O:45])[O:43][CH2:44]4)[CH2:39][CH2:38]3)[N:9]=2)[CH:7]=1
Reactant: O=C1CC(N2CCNCC2)CO1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CC(N2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (200 mg, 0.43 mmol) in DMF (10 mL) was added 4-(piperazin-1-yl)oxolan-2-one hydrochloride (250 mg, 1.21 mmol), HATU (247 mg, 0.65 mmol), DIEA (167 mg, 1.29 mmol). The resulting solution was stirred at room temperature overnight. Water (50 mL) was added. The resulting solution was extracted with DCM (×3) and the organic layers combined. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (32.0% MeCN up to 60.0% in 10 min); Detector, 254/220. 37 mg product was obtained. This resulted in 36.7 mg (14%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(5-oxooxolan-3-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 28) [M+H]+=615.0, RT=0.99 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (d, 1H, J=6.9 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 9.0 Hz), 7.56 (s, 1H), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.44-4.38 (m, 1H), 4.26-4.18 (m, 1H), 3.49 (t, 4H, J=5.1 Hz), 3.40-3.37 (m, 1H), 2.78-2.68 (m, 1H), 2.60-2.55 (m, 1H), 2.47-2.35 (m, 4H).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](/[CH:15]=[CH:16]/[C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)=[N:7][CH2:6][CH2:5]1>CO>[C:21]([OH:23])(=[O:22])[CH3:20].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)=[N:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(/C=C/C2=NCCN(C)c3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)O
Product: CN1CCN=C(/C=C/c2ccc(C(=O)O)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2.2 ml of 2M potassium hydroxide solution were added to a solution of 770 mg (2.41 mmol) of methyl (E)-4-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]benzoate in 22 ml of methanol. The temperature was raised to 60° C. and the solution was stirred for 3 hours. A further 2 ml of 2M potassium hydroxide solution was added and the solution was stirred for a further 16 hours. The solvent was removed by evaporation and the residue dissolved in water and washed with diethyl ether. The aqueous layer was acidified with acetic acid and extracted three times with ethyl acetate. The organic phases were combined, dried over magnesium sulphate, filtered and evaporated to dryness. There was obtained (E)-4-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]benzoic acid acetate as a red oil, MS: m/e 307.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[CH:53]([OH:56])[CH2:52][CH2:51]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH:53]([OH:56])[CH2:52][CH2:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC1CCNCC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCC(O)CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and piperidin-4-ol and isolated as light-yellow gum (12.6 mg, 67%). MS (m/e): 401.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.OO.C(OCC)(=[O:24])C.CCCCCC>O>[Cl:19][C:14]1[CH:13]=[C:12]([CH:9]2[O:8][C:5]3=[N:6][CH:7]=[C:2]([OH:24])[CH:3]=[C:4]3[CH2:11][CH2:10]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(C)=O
Reactant: Clc1ccc(C2CCc3cc(Br)cnc3O2)cc1Cl
Agent: OO
Solvent: O
Solvent: CCCCCC
Product: Oc1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: -75 °C
Reaction time: 2 h

Procedure:
6-Bromo-2-(3,4-dichlorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine (1.5 g) was converted to the corresponding lithio intermediate according to the procedure described in Example 23 and then quenched at -90° C. with 1.3 ml of tri-n-butyl borate. The resulting dark solution was stirred at -75° C. for 2 hours and then allowed to warm to 0° C. The mixture was then acidified with 3N hydrochloric acid, the organic phase was separated, and the aqueous layer was extracted with ether. The combined organic layers were concentrated to give a light brown, tacky solid. To this material was added 25 ml of 30% hydrogen peroxide and the resulting mixture was warmed at 60° C. for 30 minutes. The mixture was then cooled and diluted with 75 ml of water and the resulting mixture was extracted with two 50-ml portions of methylene chloride. The methylene chloride extracts were combined, washed with aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated to give a yellow solid. Column chromatography (silica gel, 3% ethyl acetate/hexane) gave 2-(3,4-dichlorophenyl)-3,4-dihydro-6-hydroxy-2H-pyrano[2,3-b]pyridine melting at about 218°-219° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH3:14])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:15]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:18][O:17][C:15](=[O:16])/[CH:19]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH3:14]
Reactant: CC/C(=C\C=O)c1ccc(OC)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-pentenal (7.1 g) was treated with (carbomethoxymethylene)triphenylphosphorane (14 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) overnight at room temperature. The ester was isolated in the normal fashion to afford 8 g of (E,E)-5-(4-methoxyphenyl)-2,4-heptadienoic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:31]([F:34])([F:33])[F:32])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:69]1[CH2:73][C:72](=[O:74])[NH:71][CH2:70]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:31]([F:34])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:69]4[CH2:73][C:72](=[O:74])[NH:71][CH2:70]4)=[O:22])=[C:19]([CH2:26][C:27]([F:28])([F:30])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1CC(F)(F)F
Reactant: O=C1CNCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2CC(F)(F)F)CN1
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)benzoic acid (200 mg, 0.38 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), HATU (292 mg, 0.77 mmol, 2.00 equiv), DIEA (99 mg, 0.77 mmol, 1.94 equiv), imidazolidin-4-one hydrochloride (94 mg, 0.77 mmol, 1.98 equiv). The resulting solution was stirred for 2 h at r t. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with ethyl acetate/petroleum ether (2:1). This resulted in 150 mg (60%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)phenyl)carbonyl]imidazolidin-4-one as yellow oil.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].Cl[CH2:15][CH2:16][CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22]>>[CH3:5][N:4]1[C:6]2[N:7]=[CH:8][N:9]([CH3:10])[C:11]=2[C:12](=[O:13])[N:1]([CH2:15][CH2:16][CH2:17][CH2:18][P:19](=[O:23])([O:24][CH2:25][CH3:26])[O:20][CH2:21][CH3:22])[C:2]1=[O:3]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOP(=O)(CCCCCl)OCC
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.075 mol of theobromine and 0.09 mol of diethyl 4-chlorobutanephosphonate analogously to Example 23 and crystallized from diisopropyl ether.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:12])([CH:10]=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC(=CC)C.Cl([O-])=[O:19].[Na+].P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[CH:1]([CH:4]1[CH2:5][CH2:6][C:7]([CH3:12])([C:10]([OH:19])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCC(C)(C=O)CC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)C1CCC(C)(C(=O)O)CC1
Yield: 100.4 %

Procedure:
A flask was charged with 10 g of 4-isopropyl-1-methyl cyclohexane carbaldehyde, 200 mL of tert-butanol and 100 mL of 2-methyl-2-butene. While stirring the contents of the flask, a solution prepared by dissolving 13 g of sodium chlorite and 11 g of sodium dihydrogenphosphate in 80 mL of water was added to the flask at 0° C. After stirring the contents of the flask at room temperature for 40 min, a part of tert-butanol in the flask was distilled off, and then a small amount of sulfuric acid was added to the flask. The resulting reaction mixture was extracted with an ether, and the thus obtained extract solution was concentrated and then purified by a silica gel column, thereby obtaining 11 g of 4-isopropyl-1-methyl cyclohexanecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12]([NH2:19])=[N:13][NH:14]3)[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]1[CH:26]=[C:25](C)[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30].O1CCC[CH2:32]1>>[NH2:19][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[CH:18][C:10]=2[C:9]#[C:8][C:4]2[CH:3]=[C:2]([NH:1][C:29]([NH:28][C:22]3[CH:23]=[C:24]([CH3:32])[CH:25]=[CH:26][C:21]=3[F:20])=[O:30])[CH:7]=[CH:6][CH:5]=2)[NH:14][N:13]=1
Reactant: Nc1cccc(C#Cc2cccc3[nH]nc(N)c23)c1
Reactant: Cc1ccc(N=C=O)c(F)c1
Reactant: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2cccc(C#Cc3cccc4[nH]nc(N)c34)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-((3-aminophenyl)ethynyl)-1H-indazol-3-amine (50 mg, 0.2 mmol) was taken in 2 ml of tetrahydrofuran, reaction was set under nitrogen atmosphere. 2-fluoro-1-isocyanato-4-methylbenzene was taken in 1 ml of tetrahydrofuran and added dropwise to the solution of 4-((3-aminophenyl)ethynyl)-1H-indazol-3-amine in tetrahydrofuran. The reaction was stirred at room temperature for 30 min, loaded onto silica and columned to give 1-{3-[(3-amino-1H-indazol-4-yl)ethynyl]phenyl}-3-(2-fluoro-5-methylphenyl)urea.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7]1=[O:20])[CH3:4].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>>[ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8][C:7]1([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[OH:20])[CH3:4]
Reactant: COc1cccc(Br)c1
Reactant: CN(C)CC1CC(CCc2ccccc2)CCC1=O
Agent: Cl
Product: COc1cccc(C2(O)CCC(CCc3ccccc3)CC2CN(C)C)c1
Yield: 40 %

Procedure:
The base of compound (48) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified firstly with 7:1 ether/methanol via a silica gel column and subsequently via HPLC. It was taken up in 2-butanone and trimethylchlorosilane/water was added, with the addition of ether if necessary. Compound (45) was obtained in a yield of 40% theoretical.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[CH3:18][C:19]1([O:22][CH2:21]1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Yield: 70.1 %

Procedure:
2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 200 mg, 0.884 mmol), isobutylene oxide (0.196 mL, 2.21 mmol) and cesium carbonate (460 mg, 1.40 mmol) in N,N-dimethylformamide (2.5 mL) were stirred at 100° C. under microwave irradiation for 10 min. The volatiles were removed in vacuo then the crude residue was adsorbed onto silica gel using methanol and purified by silica gel chromatography (5-10% methanol in methylene chloride gradient) to afford the title compound (43, 185 mg, 70%). NH4OAc standard conditions. DAD Retention time=5.93 min. M+H=299. 1H NMR (300 MHz, MeOD-d4): 8.64 (d, J=4.9 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.34 (dd, J=7.6, 7.3 Hz, 1H), 7.20 (dd, J=7.8, 7.3 Hz, 1H), 5.49 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1C=CC(C2CCNCC2)=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:29][C:17]=34)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Product: Cc1ccc(N2CCN(CCCc3[nH]nc4c3CCCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 5 and 1-(4-methylphenyl)piperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 2,4,5,6,7,8-hexahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)cycloheptapyrazole is obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][C:3]=1C(C)(C)C.C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2oc3c(Cl)cc(C(C)(C)C)c(O)c3c2C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: COc1ccc(Cc2oc3c(Cl)ccc(O)c3c2C)cc1
Reaction time: 1 h

Procedure:
To a cold solution (0° C) of 4-hydroxy-7-chloro-5-t-butyl-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran(165) (Example 43) (10 g, 27.8 mmol) in 500 mL dichloromethane was added 5 mL of anisole followed by aluminum chloride (13 g, 0.1 mol) in portions. The mixture was allowed to stir for 1 h and then poured onto ice. The mixture was extracted with dichloromethane, the organic extracts were dried, concentrated and chromatographed to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:32]1(C)[CH:37]=CC=[CH:34][CH:33]=1>O>[CH2:2]([O:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:37][CH2:32][CH2:33][CH3:34])=[CH:8][CH:9]=2)=[CH:15][CH:16]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Reactant: CCCCBr
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(Sc2ccc(OCCCC)cc2)cc1
Reaction time: 16 h
Yield: 99.1 %

Procedure:
A solution was prepared by combining 107 g of bromobutane, 76 g of bis(4-hydroxyphenyl) sulfide, 108 g of potassium carbonate, and 230 g of DMF. The solution was aged at 90° C. for 16 hours. The aged solution was cooled to room temperature, to which 600 g of water was added to quench the reaction. To the solution was added 300 g of toluene. The organic layer was separated, washed with water, and concentrated in vacuum, obtaining 114 g of the target compound, bis(4-butoxyphenyl) sulfide as amorphous solid. Yield 99%.
Reaction SMILES: N[C@@H](CCC(N[C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=O)C(O)=O.N[C@H:22]([C:25](O)=O)[CH2:23]S.N[CH:29](C(O)=O)CCS.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C.C(N[C@H](C(O)=O)CS)(=O)C>>[CH3:29][C@@H:11]([C:14]([N:16]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:25][CH2:22][CH2:23]1)=[O:15])[CH2:12][SH:13]
Reactant: NC(CCS)C(=O)O
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Product: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Glutathione, L-cysteine, DL-homocysteine, D-penicillin, hemoglobin (bovine), methylene blue and Medium 199 sets were purchased from Sigma Chemical Co., St. Louis, Mo. N-acetylcysteine was obtained from Aldrich Chemical Co., Milwaukee, Wis. Captopril was kindly provided by Dr. Victor Dzau. Sodium nitrite, histamine and methacholine were purchased from Fisher Scientific, Fairlawn, N.J. Leukotriene D4 was purchased from Anaquest, BOC Inc., Madison, Wis. Antibiotic/antimycotic mixture (10,000 U/ml penicillin G sodium, 10,000 mg/ml, streptomycin sulfate, 25 mg/ml amphotericin B) was purchased from Gibco laboratories, Grand Island, N.Y. Radioimmunoassay kits for the determination of cyclic GMP were purchased from New England Nuclear, Boston, Mass.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>O1CCCC1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:17][CH:16]=[CH2:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Cl
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=CCC(O)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To 29 g of benzophenone in 150 mL of tetrahydrofuran (THF) at 0° C. was added 88 mL of 2M allyl magnesium chloride. After 16 hrs, the starting material was completely consumed as indicated by thin layer chromatography (TLC). To the reaction mixture was added 1 mL of methanol to quench the excess Grinard reagent. The THF was distilled in vacuo and the residue was shaken with dilute aqueous hydrochloric acid and chloroform. The layers were separated and the aqueous phase was extracted with chloroform. The combined organic layers were dried with sodium sulfate and concentrated to give 37 g of 1,1-diphenyl-3-buten-1-ol which is characterized by:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[NH:21][C:20](=[O:22])[C:19](=[CH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:18][C:17]2=[O:31])=[N:13][CH:14]=1)C1C=CC=CC=1.[OH-].[Na+].O>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[NH:21][C:20](=[O:22])[C:19](=[CH:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:18][C:17]2=[O:31])=[N:13][CH:14]=1
Reactant: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=CCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Yield: 69.1 %

Procedure:
Compound B (0.5 g) and NaOH (0.5 g) were dissolved in 100 mL of methanol. The mixture was hydrogenated in the presence of 0.5 g of palladium/charcoal under 1 atmospheric pressure. After the completion of the reaction as monitored by TLC, the catalyst was removed by filtration and the filtrate was evaporated in vacuo to produce a residue, which was dissolved with 50 mL of water. The obtained aqueous solution was adjusted to PH=7. A precipitate was formed and collected to give a 0.27 g (70%) of 3-[(5-hydroxypyrid-in-2-yl)methylidene]-6-(benzylmethylidene)piperazine-2,5-dione (Compound C). 1H-NMR (400 MHz, CDCl3): 6.758 (s, 1H), 7.087 (s, 1H), 7.290-7.580 (m, 7H, aromatic), 8.328 (s, 1H), and 12.289 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][NH2:14].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:14][CH3:13])(=[O:11])=[O:10]
Reactant: CN
Reactant: O=S(=O)(Cl)Cc1ccccc1Br
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To a solution of (2-bromophenyl)methanesulfonyl chloride (2 g, 7 mmol) in THF (15 mL) was added CH3NH2/H2O (25%, 2 g, 20 mmol) at 0° Celsius. The resulting mixture was warmed up to rt, stirred for 16 hours, concentrated to dryness and purified by HPLC to give the title compound (0.8 g, 41%). MS (ESI): mass calcd. for C8H8BrO2S, 262.96; m/z found, 264.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 7.65-7.54 (m, 2H), 7.35 (m, 1H), 7.22 (dd, J=7.6, 1.7, 1H), 4.53 (s, 2H), 4.10 (s, 1H), 2.72 (s, 3H).
Reaction SMILES: C1(CBr)CC1.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.[C:15]([C:18]1[S:22][C:21]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])=[N:20][C:19]=1[CH3:29])(=[O:17])[CH3:16]>>[C:15]([C:18]1[S:22][C:21]([N:23]2[CH2:27][CH2:26][N:25]([CH2:11][C:10]3[CH:13]=[CH:14][C:7]([F:6])=[CH:8][CH:9]=3)[C:24]2=[O:28])=[N:20][C:19]=1[CH3:29])(=[O:17])[CH3:16]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: BrCC1CC1
Product: CC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as describe in Preparation 19, making variations as required to replace cyclopropylmethyl bromide with 4-fluorobenzyl bromide to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 98% yield (3.27 g): 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.07-6.97 (m, 2H), 4.45 (s, 2H), 4.10-4.04 (m, 2H), 3.48-3.37 (m, 2H), 2.67 (s, 3H), 2.38 (s, 3H); MS (ES+) m/z 334.1 (M+1).