Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([CH3:36])[CH:35]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:32]3[CH:33]=[C:34]([CH3:36])[CH:35]=[C:30]([CH3:29])[CH:31]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: Cc1cc(C)cc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Yield: 84 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,5-dimethylphenyl boronic acid instead of phenyl boronic acid to obtain the title compound (84%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.[NH2:32][C:33]1[C:34]([C:40]([O:42][CH3:43])=[O:41])=[N:35][C:36](Br)=[CH:37][N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC#N>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CCOCC.O>[NH2:32][C:33]1[C:34]([C:40]([O:42][CH3:43])=[O:41])=[N:35][C:36]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:37][N:38]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (2 g, 4.431 mmol), methyl 3-amino-6-bromo-pyrazine-2-carboxylate (934.6 mg, 4.028 mmol) and K3PO4 (1.710 g, 8.056 mmol) with MeCN (14.09 mL)/water (3.133 mL). Degassed with vacuum/nitrogen over 5 cycles, treated with Pd[P(tBu)3]2 (114.9 mg, 0.2248 mmol), degassed further 5 cycles and stirred under nitrogen for 2 hours at 60° C. The reaction mixture was cooled to ambient temperature and poured onto icewater/ethylacetate. The organic layer was washed with aq NaHCO3, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50-70% EtAc/petrol. The relevant fractions were concentrated in vacuo to a solid. Trituration with ether/petroleumether gave methyl 3-amino-6-[4-[(1-tert-butoxycarbonyl-3-piperidyl)sulfonyl]phenyl]pyrazine-2-carboxylate as a colourless solid (1.728 g, 3.626 mmol, 90.02%). H NMR (400.0 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.3 (d, 2H), 8.0 (d, 2H), 7.7 (br s, 2H), 4.0-4.1 (m, 1H), 3.9 (s, 3H), 3.7-3.8 (m, 1H), 3.3-3.4 (m, 1H), 2.77-2.95 (m, 2H), 1.95-2.05 (m, 1H), 1.7-1.75 (m, 1H), 1.6-1.65 (m, 1H) and 1.20-1.40 (m, 10H) ppm; LC/MS m/z 421.1 [M−56+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH2:16]3)[C:12]3[C:11]4[CH:31]=[CH:32][CH:33]=[CH:34][C:10]=4[S:9][C:8]=3[NH:7][C:6]=2[CH:35]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClC(Cl)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:36])[C@@H:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[CH2:16]3)[C:12]3[C:11]4[CH:31]=[CH:32][CH:33]=[CH:34][C:10]=4[S:9][C:8]=3[NH:7][C:6]=2[CH:35]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cccc(CC[C@H]2CN(C3=Nc4ccc(F)cc4Nc4sc5ccccc5c43)CCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1cccc(CC[C@H]2CN(C3=Nc4ccc(F)cc4Nc4sc5ccccc5c43)CCN2C)c1
Yield: 80.6 %

Procedure:
Using a method similar to the method of Example 543, using (S)-9-fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.164 g, 0.337 mmol), sodium triacetoxyborohydride (0.107 g, 0.505 mmol), and aqueous formaldehyde (0.038 mL, 0.50 mmol) in dichloroethane gives the title compound (0.136 g): mass spectrum (APCI+, m/e): 501 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26][NH2:27]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:27][CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([CH3:21])[CH:30]=[CH:29][CH:28]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: Cc1cccc(CCN)c1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCc2cccc(C)c2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 78.9 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 3-methylphenethylamine (0.0248 g, 0.184 mmol) gives the title compound (0.0568 g, 78.9%): TOF MS ES+ 392.2 (M+H)+, HRMS calcd for C23H26N3O3 392.1974 (M+H)+, found 392.1975, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.7 min, 97.6% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[S:7])=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:47]=1[C:48]([NH:50][NH2:51])=[O:49]>CN(C)C=O>[Cl:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:47]=1[C:48]([N:50]([C:6](=[S:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]#[C:12][C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:4]=1)[NH2:51])=[O:49]
Reactant: Cc1cccc(Cl)c1C(=O)NN
Reactant: Cc1ccc(C(O)=S)cc1C#Cc1cnc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)N(N)C(=O)c2c(C)cccc2Cl)cc1C#Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-3-[(quinolin-3-yl)ethynyl]thiobenzoic acid (0.15 g, 0.5 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.15 g, 0.7 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) in N,N-dimethylformamide (15 ml) was stirred at ambient temperature for 1 hr. 2-Chloro-6-methylbenzohydrazide (0.125 g, 0.5 mmol) was added and the mixture stirred for 12 hrs at ambient temperature. Concentration and trituration of the residue with water produced a solid which was filtered, washed with water and finally purified by flash chromatography on silica gel (elution with 10% methanol in dichloromethane) to get 2-chloro-6-methyl-N-[4-methyl-3-[2-(3-quinolyl)ethynyl]thiobenzoyl]benzohydrazide as a white solid.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: COP(=O)(CCC(N)C(=O)O)Oc1cccc([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 62.5 %

Procedure:
Next, 1.09 g (2.01 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[methyl(3-nitrophenyl)phosphono]butanoate and 1.30 g (12.0 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.80 g (6.00 mmol) of aluminum trichloride and reaction was carried out at room temperature for 3 hours. Thereafter, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of ether three times and the water layer was removed, and methanol was added to adjust the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, 30 mL of the effluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out from water to obtain 2-amino-4-[methyl(3-nitrophenyl)phosphono]butanoic acid (0.40 g, yield 63%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:17][CH2:16][C:15]4[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=4[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[C:22](=[N:28][Si](C)(C)C)=[N:23][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]1)/[C:8]/2=[N:28]/[C:22]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1c2cc(Br)ccc2CC12CCc1ccccc1CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(Br)ccc2CC12CCc1ccccc1CC2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of 6′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-inden]-1′(3′H)-one (20 mg, 0.059 mmol) in DCM (2 mL) was added TiCl4 (44.7 mg, 0.235 mmol) dropwise, the mixture was stirred at 50° C. at Ar2 under microwave for 20 minutes, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (43.8 mg, 0.235 mmol) was added dropwise. The mixture was stirred at 60° C. at Ar2 under microwave for 10 minutes and repeated the same operation for one time and then poured into ice-water (10 mL). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude (Z)—N-(5′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-indene]-3′(1′H)— ylidene)cyanamide (20 mg, 4%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:25]([Cl:36])(=[O:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:36].[CH2:20]([C:17]([O:22][C:25](=[O:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:18][CH3:19])[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)[CH3:21]
Reactant: CCC(O)(CC)CCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC(CC)(CC)CCN1CCC(c2noc3cc(F)ccc23)CC1
Product: Cl
Reaction time: 96 h
Yield: 76.4 %

Procedure:
To a solution of 6-fluoro-3-[1-(3-hydroxy-3-ethylpentyl)-4-piperidinyl]-1,2-benzisoxazole (2.5 g, 7.48 mmol) in DCM (100 ml) was added decanoyl chloride (1.5 ml, 7.48 mmol) at 0° C., under nitrogen. The reaction mixture was stirred for 4 days at which time it was poured into NaHCO3 (sat., 50 ml). The layers were separated and the aqueous phase was extracted with DCM (2×). The combined organics were dried, filtered and concentrated to give the crude product which was purified via flash column chromatography (silica gel, 20-40% EtOAc/DCM). The product containing fractions were concentrated to give 3.0 g (81%) of the desired product as a yellow oil. The hydrochloride salt was prepared in anhydrous ether (60 ml) and isopropanol (1 ml) with ethereal HCl. The white salt was filtered and washed with anhydrous ether, m.p.=159-161° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([F:15])=[C:6]([Cl:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9](O)=[O:10])([O-:3])=[O:2].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[N+:1]([C:4]1[C:5]([F:15])=[C:6]([Cl:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([Cl:19])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reaction time: 14 h

Procedure:
An amount of 3.47 g (0.015 mole) of 5-nitro-3-chloro-2,4-difluorobenzoic acid and 2.03 g (0.016 mole) of oxalyl chloride are dissolved in 15 ml of dichloromethane then two drops of DMF are added. The reaction is stirred for 14 hours then the solvent is evaporated under vacuum to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].C(O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[C:7]([N+:14]([O-:16])=[O:15])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccc(Cl)cc2[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2c(O)c1[N+](=O)[O-]

Procedure:
A suspension of 7-chloro-4-hydroxycarbostyril (0.5g.) in glacial acetic acid (4 ml.) was nitrated with concentrated nitric acid (0.7ml.) at 100°C and worked up in the usual manner to give the title compound, m.p. (aqueous ethanol) 166°-167°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(N(CC)CC)C.N[CH2:25][C:26]([NH2:29])([CH3:28])[CH3:27]>CCO>[CH3:25][C:26]1([CH3:28])[CH2:27][NH:16]/[C:13](=[N:12]/[C:10]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=2)=[O:11])/[NH:29]1
Reactant: CC(C)(N)CN
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)CN/C(=N/C(=O)c2nc(Cl)c(N)nc2N)N1

Procedure:
A suspension of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (0.2 g, 0.517 mmol) in EtOH (2 ml) is treated with triethylamine (0.029 ml, 0.258 mmol) followed by 1,2-diamino-2-methylpropane (0.07 ml, 0.672 mmol) and stirred at reflux overnight. The resulting suspension is filtered under vacuum to afford the title compound as a pale yellow solid; [M+H]+ 284
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5](=[O:22])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[O:20][CH3:21])[CH2:12][CH2:11]CCC1)[CH3:2].[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C[N+](C)(C)C.Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([C:25]([F:27])([F:26])[F:24])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[O:20][CH3:21])[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C(=O)CC1(c2cccc(F)c2OC)CCCCC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC1(c2cccc(F)c2OC)CC1)C(F)(F)F
Temperature: -25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
1.05 g (3.3 mmol) of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate and 0.74 ml (5 mmol) of (trifluoromethyl)-trimethylsilane in 7 ml of THF are mixed with 62 mg of tetramethylammonium fluoride at −40° C. It is stirred for 2 hours at −25° C., and then another 0.35 ml (2.4 mmol) of (trifluoromethyl)-trimethylsilane and 62 mg of tetramethylammonium fluoride are added. After another 2 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-40%), 800 mg of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionate is obtained as a yellow oil. This oil is mixed in 40 ml of diethyl ether at 0° C. with 150 g (4 mmol) of lithium aluminum hydride, and it is stirred for 2.5 more hours at room temperature. 20 ml of saturated ammonium chloride solution is carefully added at 0° C. to the batch, and it is vigorously stirred for 15 more minutes. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 630 g of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diol is obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:4][C:5]([C:22](F)([F:24])[F:23])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([CH:14]([CH3:16])[CH3:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1.C1COCC1>O>[F:24][CH:22]([F:23])[C:5]1[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH:14]([CH3:15])[CH3:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:27])([F:1])[F:26])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1C(C)C
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C(C)C
Yield: 37.8 %

Procedure:
A mixture of 50.0 g (0.124 mole) of diethyl 2,6-bis(trifluoromethyl)-1,4-dihydro-4-isopropyl-3,5-pyridinedicarboxylate, 18.87 g (0.124 mole) of DBU and 200 ml of THF is held at reflux for 18 hours and poured into water and extracted with ether. The ether extract is washed with diluted hydrochloric acid, dried (MgSO4) and concentrated. The residue is kugelrohr distilled at 1 torr to give 17.97 g (37.8%) of the desired product which is a liquid, nD25 1.4465.
Reaction SMILES: [NH2:1][C:2]1[N:25]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>CN(C)C(=O)C.O>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[N:25]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 78.1 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}carbamate (10.5 g, 30.8 mmol) in N,N-dimethylacetamide (40 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (8.39 mL, 92.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, trifluoroacetic acid (50 mL) was added to the residue, and the mixture was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in water. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (7.44 g, 78%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.C(O)C.[CH3:19][NH2:20].Cl>C(O)C>[CH3:19][NH:20][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: CN
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Agent: Cl
Solvent: CCO
Product: CNc1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 2.26 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 30 ml of ethanol, 6.50 ml of 30%-methylamine ethanol solution was added, and the mixture was heated for 24 hours at 80°-90 ° C. in a sealed tube. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.57 g of the desired compound as pale yellow needles, m.p. 260° C. (decomp.).
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH:8]([CH2:12][N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])[CH2:7]2)[O:5][CH2:4][CH2:3]1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:28]([O:27][C:25]([N:9]1[CH2:10][CH2:11][C:6]2([O:5][CH2:4][CH2:3][O:2]2)[CH2:7][CH:8]1[CH2:12][N:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22])=[O:26])[CH3:29]
Reactant: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a suspension of the above 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.1 mmol) and ethyl chloroformate (0.24 ml, 2.5 mmol) in dry tetrahydrofuran (14 ml) cooled in an ice bath under nitrogen was added diisopropylethylamine (0.95 ml, 5.4 mmol) and the reaction mixture was stirred at ambient temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between dichloromethane (25 ml) and 1N hydrochloric acid (25 ml). The layers were separated, and the aqueous layer extracted with dichloromethane (20 ml). The combined organic extracts were washed with a saturated sodium bicarbonate solution (50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was triturated with n-butylchloride, filtered and dried with nitrogen which afforded 0.47 g (61%) of 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.Cl.[O-:13][Mn](=O)(=O)=O.[K+].[CH3:19][N:20]=[C:21]=[O:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[O:13])[S:11][N:20]([CH3:19])[C:21]2=[O:22])=[CH:7][CH:8]=1
Reactant: CN=C=O
Reactant: COc1ccc(N=C=S)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Product: COc1ccc(-n2c(=O)sn(C)c2=O)cc1

Procedure:
Reagents: 4-methoxyphenyl isothiocyanate (0.89 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), methyl isocyanate (0.38 ml, 6.5 mmol).
Reaction SMILES: [F:1][C:2]([F:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[F:1][C:2]([F:28])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOCC(F)(F)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCOCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of Intermediate 8 (6.41 g, 16.5 mmol) in ethanol (50 ml) was added hydrazine monohydrate (12 mL, 247 mmol). The mixture was stirred at room temperature overnight, concentrated, and the residue was triturated with isopropyl alcohol. The resulting solid was filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel, eluting with methylene chloride/ethanol/ammonium hydroxide (80:8:1) to give the title compound (2.31 g, 54%) as oil.