Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[C:21]=3[CH3:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41].CO>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:40]([NH:39][C:33]4[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=4[F:31])=[O:41])=[C:22]([CH3:27])[C:21]=3[CH3:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc(N)c(C)c3C)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3C)ccnc2cc1OCc1ccccc1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylaniline (260 mg) was dissolved in N,N-dimethylformamide (5 ml). 2,4-Difluorophenyl isocyanate (121 mg) was then added to the solution, and a reaction was allowed to proceed at room temperature overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was washed with methanol and was collected by filtration to give 219 mg (yield 61%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([B:16]([OH:21])[OH:17])[S:7][C:6]=2[CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc2ccsc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2cc(B(O)O)sc2c1
Temperature: 0 °C
Yield: 88.5 %

Procedure:
To a solution of 6-methyl-benzo[b]thiophene (0.16 g, 0.001 mol) in 10 mL of anhydrous THF at −60° C. is added n-BuLi (0.8 mL, 0.0012 mol) dropwise via syringe. After stirring for 30 minutes triisopropyl borate (0.3 mL, 0.0012 mol) is added dropwise. The reaction mixture is allowed to warm to 0° C. and then partitioned between 1.0N HCl and EtOAc. The organic layer is separated, dried, filtered and concentrated to produce a white solid that is triturated from ether/hexane. Filtration provides 0.17 g of 6-Methyl-benzo[b]thiophene-2-boronic acid as white solid. MS m/z 193 [M+1]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]([C@H:15]1[N:18]([CH:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:17](=[O:38])[C@@H:16]1[C@H:39]([O:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[CH3:40])=[CH2:14].Cl>ClCCl.O.C(N(CC)CC)C>[CH:12]([C:13]([C@H:15]1[N:18]([CH:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[C:17](=[O:38])[C@@H:16]1[C@H:39]([O:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[CH3:40])=[CH2:14])=[O:11]
Reactant: C=C(CO)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C=O)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (8.5 ml) in dry dichloromethane (212 ml) was added dropwise a mixture of dimethylsulfoxide (14.5 ml) and dichloromethane (42.5 ml) at -50° C., and the resultant mixture was stirred for 10 minutes at the same temperature as above. A solution of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (45 g) in dry dichloromethane (400 ml) was added dropwise thereto at -50° C. or less over a period of 15 minutes, followed by stirring for 15 minutes. Triethylamine (64 ml) was then dropwise added thereto, and the reaction mixture was warmed to room temperature, diluted with cold water (480 ml) and acidified with 6 N hydrochloric acid (65 ml). The organic layer was washed successively with brine (200 ml×3), 2% sodium bicarbonate (200 ml) and then brine (200 ml) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-formylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[C:5]([CH2:17][CH2:18][CH3:19])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:4][CH2:3]1>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[C:5]([CH2:17][CH2:18][CH3:19])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:4]=[CH:3]1
Reactant: CCCC1(c2cccc(OC)c2)CCN(C)CC1C
Solvent: CC(=O)O
Product: CCCC1(c2cccc(OC)c2)C=CN(C)CC1C

Procedure:
Following the procedure set forth in Example 1, 43 g. of 1,5-dimethyl-4-n-propyl-4-(3-methoxyphenyl)piperidine was reacted with 276 g. of mercuric acetate in 717 ml. of five percent aqueous acetic acid to provide, after purification by distillation, 30.2 g. of 1,5-dimethyl-4-n-propyl-4-(3-methoxyphenyl)-1,4,5,6-tetrahydropyridine. B.P. 126°-138° C. at 0.15 torr.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:28]([N:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[C:28]([N:35]1[CH2:36][CH:37]=[C:38]([C:2]2[CH:3]=[C:4]([N:8]3[CH:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[CH2:11][C:10]([C:21]([F:26])([F:27])[C:22]([F:25])([F:23])[F:24])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:39][CH2:40]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(Br)c2)c(F)c1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 204, except for using 1-(3-bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole prepared in Step 4 of Preparation 14; and using 1-BOC-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine instead of 3-(methylthio)phenylboronic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][OH:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][O:17][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 90.8 %

Procedure:
A solution of D1 (9.70 g, 0.04 mol), imidazole (1.05 eq., 2.95 g) and tert-butyldimethylsilyl chloride (1.1 eq., 6.22 g) in DMF (dry, 50 ml) was stirred overnight at ambient temperature. Solvent was removed under reduced pressure and the residue partitioned between Et2O and water. The aqueous phase was separated and the organic phase washed with dilute HCl (0.5M, 2×100 ml), followed by water (2×100 ml) and the organic phase was then dried (anhydrous MgSO4), filtered and concentrated under reduced pressure to afford an oil (12.70 g). This was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:9][Br:11])=[O:10]
Reactant: CC(=O)c1ccccc1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1C(=O)CBr
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
A solution of 13.42 g of ortho-methylacetophenone in 15 ml of acetic acid was treated with 15.98 g of bromine in 15 ml acetic acid. After being kept at ca 100° C. for 90 minutes, the mixture was poured into 300 ml water and extracted with ether. Removal of solvent from the dried (MgSO4) extract provided 19.70 g of residual oil, which by GLC was 75% pure. This crude product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Li]CCCC.Cl[Si:21]([CH3:32])([CH3:31])[CH:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]1[CH3:30]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[C:5]([NH:6][Si:21]([CH3:31])([CH3:32])[CH:22]2[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]2[CH3:30])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C(C)C)cc(Br)cc2C(C)C)C(C)=C1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of 13.8 g (53 mmol) of 4-bromo-2,6-diisopropylaniline in 170 ml of THF, 21.0 ml of 2.5 M (53 mmol) of nBuLi in hexanes were added dropwise at −80° C. This mixture was additionally stirred for 30 minutes at ambient temperature and then added to a solution of 11.4 g (53 nimol) of chloro(dimethyl)(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane in 70 ml of THF. The resulting mixture was stirred overnight and then evaporated to dryness. The residue was suspended in 100 ml of toluene. This suspension was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow oil, b.p. 156-162° C./0.15 mm Hg. Yield 12.8 g (55%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:36]1[C:44]2[C:39](=[C:40](B3OC(C)(C)C(C)(C)O3)[C:41]([F:45])=[CH:42][CH:43]=2)[CH:38]=[CH:37]1)(C(C)(C)C)(C)C>>[F:45][C:41]1[C:40]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([CH:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:39]2[C:44](=[CH:43][CH:42]=1)[NH:36][CH:37]=[CH:38]2
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1

Procedure:
Crude 4-(2-chloro-6-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.1 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 49 mg of 111 following reverse phase HPLC purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH2:16][F:17])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH2:16][F:17])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)[C@H](F)CO1
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]3(CF)N=C(N)OC[C@H]3F)c2)nc1

Procedure:
The condensation of (4S,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.6) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=390.4 [M+H]+.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25](Br)[CH:26]=O)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]2=[O:37])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([NH2:46])(=[S:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CS(Cl)(=O)=O.Cl>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:45][C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:46][CH:26]=1)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]2=[O:37])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccccc4)s3)CSC12
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (a mixture of the bromoaldehyde epimers) (5.87 g) and thiobenzamide (1.5 g) in dry tetrahydrofuran (60 cc) is stirred at 20° C. for 1 hour 20 minutes, and thereafter there are added to the reaction mixture, cooled to 2° C., methanesulphonyl chloride (0.85 cc) followed, in 5 minutes, by triethylamine (5.6 cc). After having been stirred for 2 hours at 2° C., the reaction mixture is poured into a mixture of ethyl acetate (100 cc) and 1N hydrochloric acid (50 cc). The organic phase is washed with a saturated sodium bicarbonate solution (100 cc) and then with a saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is chromatographed on a column (height: 25 cm; diameter: 5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with an 80:20 (by volume) mixture of cyclohexane and ethyl acetate, and 125 cc fractions being collected. Fractions 17 to 22, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-phenyl-thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1 g) is obtained in the form of a yellow froth.
Reaction SMILES: [Br-:1].[Br-:2].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]1([CH3:33])[CH2:31][C:30]2[NH:29][N:28]=[CH:27][C:26]=2[C:25](=[O:32])[CH2:24]1>C(O)(=O)C>[Br:1][C:24]1([Br:2])[C:23]([CH3:33])([CH3:22])[CH2:31][C:30]2[NH:29][N:28]=[CH:27][C:26]=2[C:25]1=[O:32]
Reactant: [Br-]
Reactant: CC1(C)CC(=O)c2cn[nH]c2C1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CC1(C)Cc2[nH]ncc2C(=O)C1(Br)Br
Yield: 100 %

Procedure:
According to Scheme 2 Step 3: Pyridinium tribromide (15.2 mmol, 4.87 g) was added to a solution of 6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (6.09 mmol, 1.00 g) in acetic acid (9 mL) and the reaction mixture was heated under reflux for 3 hours. After evaporation of the solvent, the crude residue was partitioned between DCM and a saturated solution of Na2CO3. The organic phase was washed with water, was dried over Na2SO4 and concentrated to yield 5,5-dibromo-6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (6.09 mmol, 1.96 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[N:11]#[C:12][NH2:13].O1CCOCC1.[ClH:20]>CCOCC>[ClH:20].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12](=[NH:11])[NH2:13])[CH:10]=1)=[O:5])[CH3:2]
Reactant: N#CN
Reactant: CCOC(=O)c1cn[nH]c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1cnn(C(=N)N)c1
Temperature: 100 °C
Yield: 93 %

Procedure:
To a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (5.00 g, 35.7 mmol), cyanamide (1.50 g, 35.7 mmol), and dioxane (25 mL) was added a solution of 4M HCl in dioxane (9.80 mL, 39.3 mmol). The reaction mixture was heated to 100° C. for 3 h. The reaction was cooled to 23° C. and Et2O (20 mL) was added. The resulting white precipitate was filtered to yield the titled compound (7.26 g, 93%). 1H NMR (400 MHz, DMSO-d6): 9.65 (br m, 4H), 9.29 (s, 1H), 8.43 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: S([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C@H:20]2[C@H:25]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:24]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:23]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@@H:22]([CH2:50][O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[O:21]2)=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>CCO.C1COCC1>[CH2:27]([O:26][C@@H:25]1[C@@H:24]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@H:23]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:22]([CH2:50][O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[O:21][C@H:20]1[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][CH:12]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: c1ccc(COC[C@H]2O[C@@H](c3c[nH]c4ccccc34)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
To a solution of compound 84 (740 mg, 0.93 mmol) in a mixture of EtOH (20 mL) and THF (10 ml) was added KOH (250 mg). The reaction mixture was stirred at 50° C. for 1 d. After reaction complete, the resulting solution was quenched with 1.0 M HCl and organic layer was extracted with EtOAc. After evaporating volatile material under reduced pressure, the residue was purified with normal phase column chromatography to afford titled compound 85 (370 mg, 62%) as off-white solid.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[CH3:9]S(C)=O.[Cl:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][O:19][C:20]([CH3:33])([CH3:32])[C:21](=[O:31])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[N:25]=2)=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20]([C:21]2([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[N:25]=3)[CH2:9][O:31]2)([CH3:32])[CH3:33])=[CH:34][CH:35]=1
Reactant: CS(C)=O
Reactant: CC(C)(OCc1ccc(Cl)cc1)C(=O)COc1cccc(Cl)n1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: O
Product: CC(C)(OCc1ccc(Cl)cc1)C1(COc2cccc(Cl)n2)CO1
Temperature: 60 °C

Procedure:
1.5 g (0.05 mol) of 80% pure sodium hydride are added in portions to a mixture of 11 g (0.05 mol) of trimethylsulphoxonium iodide and 60 ml of dimethylsulphoxide at 10° C., with stirring. The reaction mixture is stirred for 15 minutes, 17.7 g (0.05 mol) of 3-(4-chlorobenzyloxy)-(6-chloropyridin-2-yloxy)-3-methyl-2-butanone in a little dimethylsulphoxide are then added dropwise and the mixture is warmed at 60° C. for 1 hour. It is subsequently poured into water, under a nitrogen atmosphere, and extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated. The crude 2-[2-(4-chlorobenzyloxy)-prop-2-yl]-2-(6-chloropyridin-2-yloxymethyl)-oxirane thus obtained is further reacted directly. ##STR13##
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[CH:13]1([CH2:16][O:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]1>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH:13]1([CH2:16][O:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20](=[NH:22])[O:21][CH2:6][CH3:7])[CH2:15][CH2:14]1
Reactant: NC(=O)c1ccccc1OCC1CC1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)c1ccccc1OCC1CC1
Reaction time: 18 h
Yield: 66 %

Procedure:
A solution of triethyloxonium fluoroborate (99.1 g., 0.522 mole) in methylene chloride (225 ml.) was added to a stirred solution of 2-cyclopropylmethoxybenzamide (99.2 g., 0.518 mole) in methylene chloride (450 ml.). The mixture was stirred at 22° for 18 hours. The solution was concentrated to about one-fifth volume and then diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride - diethyl ether to give ethyl 2-cyclopropylmethoxybenzimidate fluoroborate (104.7 g., 65.7%), m.p. 120°-121°. To a stirred, cooled (ice-water) mixture of the fluoroborate (104.7 g.) in ethanol (100 ml.) was added 400 ml. of 6% ethanolic ammonia. The mixture was stirred for 18 hours at 20°. The mixture was concentrated and the residue partitioned between diethyl ether and 3N sodium hydroxide. The ether layer was washed with brine and dried over sodium sulfate. The dried solution was treated with hydrogen chloride. The precipitate was recrystallized from methylene chloride-diethyl ether to give 2-cyclopropylmethoxybenzamidine hydrochloride (71.5 g., 92.5% from fluoroborate), m.p. 166°-171°.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[CH:31]([N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]1=[O:22])[CH2:32]2
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC1CN2CCC1CC2
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CN2CCC1CC2

Procedure:
(5Z)-3-(1-Azabicyclo[2.2.2]oct-3-yl)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 3-hydroxy-1-azabicyclo[2.2.2]octane following General Procedure J.