Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.[NH3:21]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([NH2:21])=[O:16])=[CH:9][CH:8]=1
Reactant: N
Reactant: O=C(Cl)C=Cc1ccc(OCc2cccc(F)c2)cc1
Solvent: ClCCl
Product: NC(=O)C=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 19 %

Procedure:
500 mg (1.72 mmol) of the crude 3-[4-(3-fluoro-benzyloxy)-phenyl]-acryloyl chloride as prepared in Example 8c) is dissolved in 2 ml dichloromethane and 4 ml of concentrated ammonia is added. The mixture is hold at reflux temperature for about 4 hours, cooled and filtered. The solid is subjected to column chromatography (silica gel, dichloromethane/methanol/ammonia 140:10:1) to give 89 mg (19%) of a colorless solid. MS: m/e=272.2 (M++H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][N:24]4[CH:27]=[C:28]([CH2:30][C:31]([O:33]CC)=[O:32])[N:29]=[C:23]4[CH:22]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[OH-].[Na+].[ClH:40].Cl.CCOC(C)=O>C1COCC1.CCOC(C)=O>[ClH:40].[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][N:24]4[CH:27]=[C:28]([CH2:30][C:31]([OH:33])=[O:32])[N:29]=[C:23]4[CH:22]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14]
Reactant: CCOC(=O)Cc1cn2ccc(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(-c2nc(-c3ccn4cc(CC(=O)O)nc4c3)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (7-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridin-2-yl)acetate (230 mg) in THF (2.0 ml) was added a 1M aqueous NaOH solution (1.0 ml), followed by stirring at 80° C. for 2 hours. After cooling to room temperature, a 1 M HCl aqueous solution (1.0 ml) was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=10:1 to 5:1) to obtain colorless powders. To a solution of this colorless powder in EtOAc was added a 4M HCl/EtOAc solution, followed by concentration. The resulting colorless powder was powdered/washed with IPE to obtain (7-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridin-2-yl)acetic acid hydrochloride (180.4 mg) as colorless powders.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:20]2[CH2:21][CH2:22][CH2:23][C:18]([CH3:24])([CH3:17])[CH2:19]2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: CC1(C)CCCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)CCCN(C(=O)c2csc(Br)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
5-Bromothiophene-3-carboxylic acid (0.5 g, 2.4 mmol) was dissolved in acetonitrile (10 mL) and triethylamine (7.1 mmol). 3,3-Dimethylpiperidine (2.4 mmol) and HATU (2.4 mmol) were added and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in DCM and washed with water. After drying with anhydrous magnesium sulphate, the solution was filtered and evaporated and the residue purified by flash chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a white crystalline solid (0.475 g). 1H NMR δ (ppm)(CHCl3-d): 7.4 (s, 1H), 7.1 (s, 1H), 3.6-3.1 (m, 4H), 1.7 (m, 2H), 1.4 (m, 2H), 0.9 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30](C)(C)C)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O.ClC(OC)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[1-tert-butyloxycarbonyl-4-piperidinylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid and subsequent reaction with methyl chloroformate. Melting point: 213°-215° C,; Rf : 0.24 (silica gel; petroleum ether/ethyl acetate/methanol=20:10:1)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([C:14]([OH:16])=O)[CH:3]=1.Cl.[F:18][C:19]([F:31])([F:30])[CH2:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([C:14]([NH:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([O:21][CH2:20][C:19]([F:31])([F:18])[F:30])=[CH:23][CH:24]=2)=[O:16])[CH:3]=1
Reactant: Cc1cc(C(=O)O)nc(Nc2ncco2)n1
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: Cc1cc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)nc(Nc2ncco2)n1

Procedure:
The title compound is prepared from 6-methyl-2-(oxazol-2-ylamino)pyrimidine-4-carboxylic acid (25 mg, 0.11 mmol, Step-1) and (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (28 mg, 0.11 mmol) by the similar manner in Example-2.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[C:5]([O:8][CH2:9][CH:10]=[CH2:11])(=[O:7])[CH3:6]>>[C:5]([O:8][CH2:9][CH2:10][CH2:11][Si:2]([Cl:4])([Cl:3])[Cl:1])(=[O:7])[CH3:6]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOC(C)=O
Product: CC(=O)OCCC[Si](Cl)(Cl)Cl

Procedure:
In a 4-liter flask with stirrer, reflux condenser, internal thermometer and 2 dropper funnels, one filled with 800 g of allyl acetate and the other with 1.355 kg of trichlorosilane, 200 ml of allyl acetate was heated to 65°C. Then the heat source was removed, 1 ml of an 0.01 molar solution of mesityl oxide-platinum dichloride complex in allyl acetate was added, and the reaction was allowed to complete itself within 8 minutes while stirring was performed and the two reactants were fed in simultaneously. During that period the temperature rose to 105°C due to self-heating. After that no more silane hydrogen was detected analytically. Distillation of the reaction product yielded 2.28 kg of 3-acetyloxypropyltrichlorosilane, BP20 : 98°-100°C; nD20 : 1.4359.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5]2.N12CCCN=C1CCCCC2.O=C1CCC(=O)N1[O:38][C:39](=O)[C@H:40]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH3:41]>CN(C)C=O.O>[C:45]([O:44][C:43]([NH:42][C@H:40]([CH3:41])[C:39]([O:19][CH2:18][CH2:17][CH2:16][NH:15][C:6]1[C:7]2[N:8]([CH:12]=[CH:13][N:14]=2)[C:9]2[C:4]([N:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)=[O:38])=[O:49])([CH3:48])([CH3:47])[CH3:46]
Reactant: OCCCNc1nc2cc(F)ccc2n2ccnc12
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCCCNc1nc2cc(F)ccc2n2ccnc12
Temperature: 60 °C
Reaction time: 65 h
Yield: 11.6 %

Procedure:
To a solution of commercially available (Peakdale) 3-[(7-fluoroimidazo[1,2-a]quinoxalin-4-yl)amino]propan-1-ol (20 mg, 0.08 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (12 μL, 0.08 mmol) in anhydrous dimethylformamide (600 μL) under argon was added dropwise a solution of tert-butyl {(1R)-2-[(2,5-dioxopyrrolidin-1-yl)oxy]-1-methyl-2-oxoethyl}carbamate (22 mg, 0.08 mmol) in anhydrous dimethylformamide (200 μL). The mixture was stirred at 60° C. for 65 h, then diluted with cold water and extracted four times with chloroform and once with chloroform/isopropanol (5:1). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC (silica, dichloromethane/methanol 20/1) to afford the title compound as a colorless oil (4 mg, 12%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22]([OH:24])=[O:23])=[C:9]1[CH:25]([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36]O>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)[C:10]([C:22]([O:24][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([F:41])=[C:33]([F:32])[CH:34]=2)=[O:23])=[C:9]1[CH:25]([CH3:26])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(C(=O)OCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure E,1-benzyl-6-(ethoxylcarbonyl)-2-isopropyl-1H-indole-3-carboxylic acid (Compound 39, 39 mg, 0.1 1 mmol) in CH2Cl2 (4 ml) was added EDC (35 mg, 0.22 mmol) and DMAP (16 mg, 0.15 mmol), followed by 3,4-difluorobenzyl alcohol (20 mg, 0.15 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7](=[O:18])[CH2:6][CH2:5]2.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[NH:26])=[CH:11][C:10]=2[F:12])[CH2:5][CH2:6][C:7]1=[O:18]
Reactant: CN(C)CCN1C(=O)CCc2cc(N)cc(F)c21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)CCN1C(=O)CCc2cc(NC(=N)c3cccs3)cc(F)c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6-Amino-1-(2-(dimethylamino)ethyl)-8-fluoro-3,4-dihydroquinolin-2(1H)-one (312 mg, 1.24 mmol) was stirred to dissolve in ethanol (15 mL). To this solution was added methyl thiophene-2-carbimidothioate hydroiodide (708 mg, 2.48 mmol). The resulting suspension was stirred for 2 days at room temperature. When TLC analysis showed that the reaction was finished, the mixture was diluted with water and aqueous sodium carbonate, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated and the crude product chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in ethyl acetate, then a second time using 20-80% MeCN in an aqueous buffer of ammonium carbonate and ammonium hydroxide adjusted to pH 10.6. Yield: 27 mg). 1H NMR (DMSO-d6) δ 2.14 (s, 6H), 2.44 (t, 2H, J=6.7 Hz), 2.49 (m, 2H, masked by DMSO peak), 2.80 (t, 2H, J=6.6 Hz), 3.95 (t, 2H, J=6.5 Hz), 6.61 (m, 4H), 7.09 (m, 1H), 7.62 (m, 1H), 7.75 (m, 1H). ESI-MS: 361 (MH+, 100), 316 (40), 158.6 (57), 136 (37).
Reaction SMILES: Cl[C:2]1[C:3]2[S:13][C:12]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH:16]=[C:17]([CH3:18])[C:11]=3[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCCC1>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:15]2[CH:16]=[C:17]([CH3:18])[C:11]3[C:4]4[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[C:3]=4[S:13][C:12]=3[N:14]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: C1CNCCN1
Reactant: CCCc1nc(Cl)c2sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c3c2n1
Solvent: C1CCOC1
Product: CCCc1nc(N2CCNCC2)c2sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c3c2n1

Procedure:
0.42 g (1.0 mmol) 4-chloro-7-(3,4-dimethoxyphenyl)-9-methyl-2-propyl-pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidine and 0.37 g (4.3 mmol) piperazine in 8 ml tetrahydrofuran are stirred at room temperature for 4 h. Having removed the solvent, the residue is suspended in 10 ml water and sucked off. The residue is suspended in about 50 ml dichloromethane and filtrated. The filtrate is washed with a total of 30 ml water, dried on sodium sulfate and the solvent is removed. The residue is recrystallized from ethyl acetate. 0.17 g (37%) of the title substance is obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:33])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[C:16]2[N:34]=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:36]=[CH:37][C:15]=2[C:14]1=[O:44]>CO>[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:33])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[C:16]2=[N+:34]([O-:9])[C:35]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:36][CH:37]=[C:15]2[C:14]1=[O:44]
Reactant: CN1CCN(CC(=O)N2c3ccccc3N(C)C(=O)c3cnc(-c4ccccc4)nc32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: CN1CCN(CC(=O)N2c3ccccc3N(C)C(=O)c3cnc(-c4ccccc4)[n+]([O-])c32)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 0.7 g (3.4 mmol) of m-chloroperbenzoic acid (85 percent) in 10 ml of methanol is slowly added at room temperature to a suspension of 1 g (2,3 mmol) of 6-methyl-11-[(4-methyl-1-piperazinyl)acetyl]-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 40 ml of methanol. After stirring for 3 hours at 20° C. and filtering, the filtrate is concentrated in vacuo and the residue is purified by chromatography on neutral silica gel using 20:1 chloroform/methanol as the eluant. Yield: 0.5 g (48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:16][CH2:15][C:14]3([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17]3)[CH2:13][CH2:12]1)[C:7](=[O:24])[C:6]([C:25](OCC)=[O:26])=[C:5]2[OH:30].Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][C:14]3([O:21][CH2:20][C:19]([CH3:22])([CH3:23])[CH2:18][O:17]3)[CH2:15][CH2:16]1)[C:7](=[O:24])[C:6]([C:25]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:26])=[C:5]2[OH:30]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC3(CC2)OCC(C)(C)CO3)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC2(CCC3(CC2)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2cc(Cl)ccc23)OC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A mixture of ethyl 6″-chloro-4″-hydroxy-5,5-dimethyl-2″-oxo-dispiro[1,3-dioxane-2,1′-cyclohexane-4′,1″-naphthalene]-3″-carboxylate (69 mg, 159 μmol) and tert-butyl 2-aminoacetate hydrochloride (53 mg, 317 μmol) in 1.5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (62 mg, 476 μmol). The mixture was warmed to 95° C. and stirred for 2 hours, M+1=420. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 66 mg of the title compound as a white yellow solid. MS (m/z)=520 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12](OC)=[O:13])[CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1
Reactant: COC(=O)c1cc(O)n2nc(C)nc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2nc(CO)cc(O)n2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
In 4 liters of ethanol was suspended 45.4 g of 7-hydroxy5-methoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine and 37.83 g of sodium borohydride was added little by little thereto, and the mixture was then stirred at room temperature for 3 hours. A residue obtained by removing ethanol was dissolved in 2 liters of water, and 500 ml of Amberlite IRC-50(H+) (trade name) was added thereto and stirred. Subsequently, the mixture was filtered and after removing water from the filtrate, 500 ml of methanol was added to the filtrate and the mixture was stirred. Then, methanol was removed from the mixture to obtain a residue. These procedures were repeated three times. Then, 500 ml of ethanol was added to the residue and the mixture was condensed. Precipitated crystals were collected by filtration, washed with ethanol and dried to obtain 39.35 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.Cl.[C:9](=[NH:20])(SCCC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH3:7][C:5]1[O:4][N:3]=[C:2]([NH:1][C:9](=[NH:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1
Reactant: Cc1cc(N)no1
Reactant: CCCSC(=N)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(NC(=N)c2ccccc2)no1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
In a 1 liter flask provided with a condenser, a thermometer and a stirring device are added 250 ml acetonitrile, 24.5 g 3-amino-5-methyl-isoxazole. This gives a solution to which are added 54 g propyl thiobenzimidate hydrochloride, and the resulting suspension is then refluxed. Dissolution is found to occur. Refluxing is maintained 2 hours. The material crystallizes and is left aside overnight, after which it is filtered, suction filtered and dried. Crystallization from isopropanol and reconversion to the base by addition of the suitable amount of sodium hydroxide solution give 28 g N-(5-methyl-isoxazol-3-yl)-benzamidine. (Yield: 56%). M.p. (capillary tube): 127°-129° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)OC(C)(C)C)C3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A solution of 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.1 mmol) in DCM (6.5 mL) was treated with TFA (6.5 mL). The reaction mixture was stirred at RT for 4 hours then concentrated in vacuo. The residue was azeotroped with DCM then dissolved in DCM and washed with an aqueous saturated sodium bicarbonate solution (×2) followed by brine. The mixture was passed through a phase separator cartridge and concentrated in vacuo to give 235 as a pale orange gum (397 mg, quant.). LCMS: RT=3.13 min, [M+H]+=368. 1H NMR δ (ppm) (DMSO-d6): 9.34 (1H, s), 9.05 (1H, s), 8.30 (1H, d, J=8.19 Hz), 8.06 (1H, d, J=0.58 Hz), 7.23 (1H, dd, J=8.24, 1.89 Hz), 7.13 (1H, d, J=1.84 Hz), 5.82-5.72 (1H, m), 4.36-4.30 (2H, m), 4.25-4.17 (2H, m), 4.13-3.97 (3H, m), 3.43-3.37 (2H, m), 1.50 (6H, d, J=6.59 Hz).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[P:6]([O:14][C:15]1[CH:20]=[CH:19][C:18](CO)=[CH:17][CH:16]=1)([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[P:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:1][Br:5])=[CH:17][CH:16]=1)([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOP(=O)(OCC)Oc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)Oc1ccc(CBr)cc1
Yield: 92 %

Procedure:
To the solution of carbon tetrabromide (5.73 g, 17.3 mmol) and diethyl 4-(hydroxymethyl)phenyl phosphate (3.74 g, 14.4 mmol) in 50 ml of methylene chloride was added triphenylphosphine (4.54 g, 17.3 mmol) at 0° C. The resultant mixture was stirred for 2 hours. The compound was purified by flash chromatography using heptane/ethyl acetate (80/20 to 70/30) as eluent in a yield 92%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21].C(N(CC)CC)C.O>O1CCCC1>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:21][C:12](=[O:13])[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH3:15]
Reactant: OCc1cccc(F)c1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2cccc(F)c2)cc1
Yield: 78.1 %

Procedure:
To a solution of 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.7 g of m-fluorobenzyl alcohol in 30 ml of tetrahydrofuran was added 3.7 g of triethylamine, dropwise under cooling, and the mixture was reacted at room temperature for 1.5 hours. After the reaction was complete, the crystals procuced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether. The ether extract was dehydrated and freed of ether by distillation. The oily residue thus obtained was distilled in vacuo to yield 5.9 g of 2-(4-isobutylphenyl)propionic acid-m-fluorobenzyl ester as a colorless oil, boiling at 143°-144° C./0.2 mmHg. Mass spectrum: parent ion 314 m/e.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([OH:13])[CH:3]=1>C1COCC1>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([OH:13])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(Br)cc1O
Solvent: C1CCOC1
Product: OCc1cc(F)c(Br)cc1O

Procedure:
Preparation according to Preparation 21, using methyl 4-bromo-5-fluoro-2-hydroxybenzoate (2.1 g, 8.4 mmol), borane tetrahydrofuran complex (31.0 ml, 31.0 mmol) and dry THF. Yield: 3.3 g (not pure). ESIMS: m/z 221 (M+H)+, 219 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:34])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:45][C:46]([F:57])([F:56])[CH2:47]OS(C(F)(F)F)(=O)=O>C1COCC1.C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:14]([Cl:34])=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH2:47][C:46]([F:57])([F:56])[F:45])[CH2:32][CH2:33]5)=[O:27])=[CH:24][CH:25]=4)=[CH:17][C:18]=3[Cl:19])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCN(CC(F)(F)F)CC1
Yield: 43.6 %

Procedure:
Treat a solution of 1-cyclohexyl-3-[3,5-dichloro-4′-(piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.182 g, 0.35 mmol) and N,N-diisopropyl ethyl amine (0.32 g, 2.47 mmol) in THF (10 mL) with trifluoromethane sulfonic acid 2,2,2-trifluoroethyl ester (0.41 g, 1.77 mmol) and heat to reflux for 3 hours under N2. Add more N,N-diisopropyl ethyl amine (0.13 g, 1.03 mmol) and trifluoromethane sulfonic acid 2,2,2-trifluoroethyl ester (0.24 g, 1.03 mmol) and continue to heat at reflux for 2 more hours. Cool the reaction to room temperature, dilute with ethyl acetate and wash with saturated sodium bicarbonate then water. Dry the organic layer with sodium sulfate and purify the crude product by reverse phase HPLC to afford 91 mg (43%) of the title compound: MS (m/z): 596 (M+).