Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.[CH3:21][C:22]([CH3:41])(O[CH2:30][O:31][C:32]([CH3:40])([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C(S(OS(C2C(C)=CC=CC=2)(=O)=O)(=O)=O)=CC=CC=1>O1CCOCC1>[CH3:21][C:22]([O:14][CH2:13][C@H:12]1[O:15][C@@H:8]([N:7]2[CH:16]=[C:3]([C:2]([F:1])([F:19])[F:20])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9][C@@H:10]1[OH:11])([CH3:41])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:40][C:32]([O:31][C@@H:30]1[C@@H:12]([CH2:10][OH:11])[O:15][C@@H:8]([N:7]2[CH:16]=[C:3]([C:2]([F:20])([F:1])[F:19])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9]1)([CH3:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(OCOC(C)(C)c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Agent: Cc1ccccc1S(=O)(=O)OS(=O)(=O)c1ccccc1C
Solvent: C1COCCO1
Product: CC(C)(OC[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O)c1ccccc1
Product: CC(C)(O[C@H]1C[C@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO)c1ccccc1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
1.00 Gram of 2'-deoxy-5-trifluoromethyluridine was dissolved in 15 ml of 1,4-dioxane. Thereto were added 2.50 g of bis-(α,α-dimethylbenzyloxy)methane and 38 mg of toluenesulfonic acid anhydride. They were heated to 60° C. and stirred for 3.5 hours. The reaction mixture was subjected to evaporation. The residue was subjected to silica gel column chromatography wherein a developing solvent of chloroform-methanol (20:1) was first used for preliminary separation and then a developing solvent of benzene-acetone (10:1) was used, to obtain 0.40 g (yield: 29.2%) of hygroscopic and amorphous 2'-deoxy-5'-O-(α,α-dimethylbenzyl)-5-trifluoromethyl uridine (compound 22) and 0.28 g (yield: 20.4%) of hygroscopic and amorphous 2'-deoxy-3'-O-(α,α-dimethylbenzyl)-5-trifluoromethyluridine (compound 23).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li]CCCC.CCCCCC.[CH3:22][O:23][C:24]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:25]=1[CH2:26][NH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=O)[O:32][CH2:31]2.Cl>C(COC)OC.CO>[CH3:22][O:23][C:24]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:25]=1[CH2:26][NH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:32][CH2:31]2
Reactant: COc1ccc(CNc2ccc3c(c2)COC3=O)c(OC)c1
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(CNc2ccc3c(c2)COC3=C2C(=O)Nc3ccccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
To a stirred solution of oxindole (555 mg, 4.17 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 2.5M n-BuLi solution in hexane (3.67 ml, 9.17 mmol), and the resulting mixture was stirred at room temperature for 10 minutes, followed by the addition of 5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-one (1.0 g, 3.34 mmol). After stirred at room temperature for 2.5 hours the mixture was poured into 1M HCl aqueous solution (100 ml). The resulting solid was separated, washed with water, and dried under vacuum to afford a crude product. Trituration of the crude product with MeOH produced 3-[5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (630 mg, 46%).
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22].Cl>C1COCC1>[CH:7]([CH:4]1[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2][CH:3]1[O:10][C:21](=[O:22])[CH2:20][Br:19])([CH3:8])[CH3:9]
Reactant: O=C(Br)CBr
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OC(=O)CBr)C1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (−) Menthol (2.75 mmoles) in anhydrous THF (5 ml), Et3N (2.75 mmoles) is added under stirring. The solution temperature is lowered to 0° C. and bromo-acetylbromide (2.5 mmoles) added. The solution temperature is then allowed to raise to room temperature and the reaction mixture is stirred for 2 hours. An HCl 1N (2 ml) aqueous solution is added and the organic phase is extracted with ethyl acetate (3×5 ml). The pooled organic phases are washed with a saturated aqueous NaCl solution (1×15 ml), dehydrated on Na2SO4 and filtered. The solvent is evaporated under a reduced pressure and the crude product is purified by flash chromatography in n-hexane/ethyl acetate 97/3 volume/volume. 388 mg of 2-isopropyl-5-methyl-cyclohexyl ester of the bromo acetic acid (51% yield) are recovered.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([S:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([S:24][C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:3]([CH3:27])[N:4]=1)[CH3:26]
Reactant: OB(O)c1ccccc1
Reactant: CCSc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCSc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 26.5 %

Procedure:
To a solution of 4′-{[5-bromo-2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.76 g) and phenylboronic acid (0.32 g) in 1,4-dioxane (10 mL) solution were added 2 M aqueous cesium carbonate solution (2 mL) and tetrakis(triphenylphosphine)palladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.2 g, 26%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][C:46]1[C:51]2[N:52]=[C:53]([NH2:55])[S:54][C:50]=2[C:49]([N:56]([CH3:58])[CH3:57])=[CH:48][CH:47]=1>C1COCC1>[CH3:57][N:56]([CH3:58])[C:49]1[C:50]2[S:54][C:53]([NH:55][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:52][C:51]=2[C:46]([O:45][CH3:44])=[CH:47][CH:48]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(N(C)C)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)C)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
To a stirred solution of 41 mg (0.29 mmol) 4-fluoro-benzoic acid in 1 ml THF were added 128 mg (0.34 mmol) HATU and 0.10 ml (0.56 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 2.5 h. 50 mg (0.22 mmol) 4-methoxy-N7,N7-dimethyl-benzothiazole-2,7-diamine was then added and stirring continued at room temperature for 16 h. The reaction mixture was then concentrated in vactio. Flash chromatography (ethyl acetate/hexane) afforded 64 mg (83%) N-(7-dimethylamino-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide as a white crystalline solid. ES-MS m/e (%): 346 (M+H +, 100).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1)[C:4]([O:6]C)=O)=O.[C:15]([O-:18])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]([NH2:40])=[NH:39])=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:45])([F:44])[F:43]>CN1C(=O)CCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]3[NH:40][CH:1]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][C:12]([O:18][CH3:15])=[N:13][CH:14]=4)[C:4](=[O:6])[N:39]=3)=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:43])([F:44])[F:45]
Reactant: COC(=O)C(C=O)Cc1cncnc1
Reactant: O=C([O-])[O-]
Reactant: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(N(C)CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 200 °C
Yield: 25.9 %

Procedure:
To the mixture of methyl 2-formyl-3-(5-pyrimidinyl)propanoate (67.9 mg, 0.350 mmol) and K2CO3 (149 mg, 1.076 mmol) in NMP (2 mL) was added neat N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol). The reaction mixture was heated with a microwave reactor at 200° C. for 3 h. Purification via MDAP then afforded the title compound as a white solid (38 mg, 22.4% yield). LCMS: rt=3.02 min, [M+H+]=516.0
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([C:16]#[N:17])[C:5](=O)[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:7]=1.[OH2:19].[NH2:20][NH2:21].O>C(O)C>[NH2:17][C:16]1[C:4]2[C:5](=[O:19])[N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[CH:7]=[C:2]([Br:1])[C:3]=2[NH:21][N:20]=1
Reactant: NN
Reactant: N#Cc1c(Cl)c(Br)cn(-c2ccccc2Cl)c1=O
Reactant: O
Solvent: CCO
Product: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 70 °C
Yield: 81.9 %

Procedure:
To a solution of 5-bromo-4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (20.9 g) in ethanol (122 mL) was added hydrazine monohydrate (6.08 g) at room temperature. The reaction mixture was heated at 70° C. for 2 hr. The reaction mixture was cooled to room temperature, and poured into water. The resulting solid was collected by filtration, and washed with water to give the title compound (16.9 g).
Reaction SMILES: ClC1N=[N:6]C(C(N)=[O:9])=C(NC2C=CC=C(C(C)C)N=2)C=1.N[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C.[C:36]([C:39]1[N:44]=[N:43][C:42]([NH:45][C@@H:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C@@H:47]2[NH:52]C(=O)OC(C)(C)C)=[CH:41][C:40]=1[NH:60][C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([CH3:69])[CH3:68])[N:62]=1)(=[O:38])[NH2:37].N[C@H]1CCCC[C@H]1NC1N=NC(C(N)=O)=C(NC2C=CC=C(C(C)C)N=2)C=1.C(O)(C(F)(F)F)=O>CN1CCCC1=O.ClCCl>[NH4+:6].[OH-:9].[NH2:52][C@H:47]1[CH2:48][CH2:49][CH2:50][CH2:51][C@H:46]1[NH:45][C:42]1[N:43]=[N:44][C:39]([C:36]([NH2:37])=[O:38])=[C:40]([NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([CH:67]([CH3:69])[CH3:68])[N:62]=2)[CH:41]=1
Reactant: CC(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Agent: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: CC(C)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: [NH4+]
Product: [OH-]
Temperature: 150 °C
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (102 mg, 350 μmol) in N-methyl-2-pyrrolidinone (6 ml) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) and the mixture heated to 150° C. for 3 d. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) was added and the reaction heated to 150° C. for an additional 2 d, then cooled, concentrated, and purified by chromatography (silica, 50 μm, 40 g, Analogix, 96:3.8:0.2 to 84:15.2:0.8; dichloromethane:MeOH:NH4OH) to give a mixture of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate and 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (33 mg). This mixture was dissolved in dichloromethane (2 mL) then TFA (370 mg, 250 μL, 3.24 mmol) was added. After 18 h, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (spherical silica, 20-45 μm, 25 g, Versaflash Supelco, 96:3.8:0.2 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 25 min gradient to afford 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (12 mg, 9%) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.35 (br. s., 1H) 8.33 (s, 1H) 7.96 (br. s., 1H) 7.44 (t, J=7.83 Hz, 1H) 6.70 (d, J=7.58 Hz, 1H) 6.61 (d, J=8.08 Hz, 1H) 5.61 (br. s., 1H) 5.31 (br. s., 1H) 3.75 (br. s., 1H) 3.19 (d, J=3.28 Hz, 1H) 2.89-3.01 (m, 1H) 1.32-1.80 (m, 8H) 1.27 (d, J=6.82 Hz, 6H). LCMS (EI/CI) m/z: 370 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:29]([S:33]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH:44]=[CH2:45])=[CH:39][C:38]=1[O:46][CH3:47])(=[O:35])=[O:34])[CH2:30][CH2:31][CH3:32].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:45]=[CH:44]/[CH2:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][S:33]([CH2:29][CH2:30][CH2:31][CH3:32])(=[O:34])=[O:35])=[C:38]([O:46][CH3:47])[CH:39]=2)[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1ccc(I)cc1OCc1ccccc1
Reactant: C=CCc1ccc(OS(=O)(=O)CCCC)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)Oc1ccc(C/C=C/c2ccc(/C=C/C(=O)OC)c(OCc3ccccc3)c2)cc1OC
Temperature: 80 °C
Yield: 90.6 %

Procedure:
71 mg (0.2 mmol) of 2-(dicyclohexylphosphino)biphenyl and 23 mg (0.1 mmol) of palladium acetate are added to a solution of 2 g (5.07 mmol) of methyl(E)-3-(2-benzyloxy-4-iodophenyl)acrylate, 1.1 ml (7.6 mmol) of triethylamine and 2.9 g (5.07 mmol) of 4-allyl-2-methoxyphenyl 1-butane-1-sulfonate in 20 ml of dimethylformamide. The reaction mixture is heated at 80° C. for 4 hours. The reaction is treated by addition of 50 ml of water and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate and filtered, and the solvents are then evaporated off. The residue is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 2.53 g (91%) of methyl(E)-3-(2-benzyloxy-4-{(E)-3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propenyl}phenyl)acrylate are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(C(C)C)C(C)C)C>CS(C)=O.O>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CN(c2ccc(Cl)nn2)C1
Temperature: 25 °C

Procedure:
tert-Butyl azetidin-3-ylcarbamate (500 mg, 2.90 mmol) and 3,6-dichloropyridazine (454 mg, 3.05 mmol) were combined in DMSO (5 mL) and N-ethyl-N-isopropylpropan-2-amine (563 mg, 4.35 mmol), and the mixture was heated overnight at 100° C. The mixture was cooled to room temperature and diluted with water. Filtration provided the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:65])[N:50]([C@@H:52]2[C@@H:56]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:55][NH:54][CH2:53]2)[CH3:51])=[CH:44][CH:43]=1>CN(C=O)C.C(OCC)(=O)C>[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:65])[N:50]([C@@H:52]2[C@@H:56]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:55][N:54]([C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[CH2:53]2)[CH3:51])=[CH:44][CH:43]=1
Reactant: O=C(O)C1CCOCC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCOCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.6 %

Procedure:
To a solution of tetrahydropyran-4-yl-carboxylic acid (51 mg, 0.39 mmol) in DMF (1 mL) was added ambient temperature 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.36 mmol) and N,N-diisopropyl ethyl amine (125 mg, 0.97 mmol). After stirring for 15 min at this temperature a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (124 mg, 0.32 mol) in DMF (1 mL) was added and stirred for 20 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with aqueous sodium carbonate (1 M, 10 mL), water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, ethyl acetate:methanol=98:2 to 85:15) afforded the title compound (92 mg, 57%) as a white oil. MS m/e: 495.3 [M]+.
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.C1COCC1.[OH-].[Na+].[F:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>C(O)C.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][S:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[CH3:14])[N:3]=3)=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(F)cc4)cc3)n(C)c(=O)c12
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 71.8 %

Procedure:
To a solution of 2-mercapto-3,5-dimethylquinazolin-4-one (0.492 g) as obtained in Reference Example 18-in ethanol (10.0 ml)-THF (10.0 ml) was added 1N-sodium hydroxide (2.50 ml). Then, 4-(4-fluorobenzoyl)benzyl bromide (0.700 g) was added and the mixture was stirred at 60° C. for 3.5 hours. This reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaCl solution and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to provide the title compound as colorless needles (0.717 g, yield 72%). 1H-NMR (CDCl3) δ: 2.85(3H,s), 3.55(3H,s), 4.60(2H,s), 7.10-7.20(3H,m), 7.46-7.63(4H,m), 7.72-7.87(4H,m).
Reaction SMILES: [CH3:1][C:2](C)=CCBr.[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11](O)=[CH:10][C:9]=2O1.CCCCC>[Cl-].[Cl-].[Zn+2].C1C=CC=CC=1>[O:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:1][CH2:7]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(C)=CCBr
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCCCC
Product: c1ccc2c(c1)CCCO2
Yield: 190.4 %

Procedure:
5.1 gm of 3-methyl-1-bromo-2-butene was combined with 4 gm of 3,4-methylenedioxyphenol and dissolved in 50 ml. of pentane and 50 ml. benzene. 2 gm of anhydrous ZnCl2 was added and the reaction mixture refluxed for 1 hour and cooled. The mixture was extracted with ether and washed successively with 100 ml. of water, 100 ml. 5% sodium carbonate and 100 ml. of saturated salt solution. After drying the extract over anhydrous sodium sulfate, the solvent was removed in vacuo leaving 7.4 g of crude chromane. The crude material was fractionated on a column of Florisil and eluted with increasing concentrations of ether in petroleum ether to yield 4.5 g of pure chromane.
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].BrN1C(=[O:24])CCC1=O.O>C(Cl)Cl>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([OH:24])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CN1c2ccccc2CCc2ccccc21
Solvent: O
Solvent: ClCCl
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
13.2 g (0.060 mols) of (I) are dissolved at room temperature in 80 ml of CH2Cl2 under stirring, then 11.8 g (0.066 mols) of N-bromosuccinimide of purity above 98% and 0.70 g (0.003 mols) of di-tert-butyl-peroxalate are added under stirring. The reaction mixture is subjected to mild nitrogen stream for 5 minutes, then heated to 45° C. and stirred at this temperature for 85 minutes. The resulting suspension is added with 100 ml of demineralized water and 3 grams of polyethylene glycol with average molecular weight 400, then refluxed for 5 hours under strong stirring. After decanting at 30° C., the organic phase is separated, dried over 4 g of Na2SO4, filtered and the resulting solution is concentrated to 20 ml, added with 10 ml of hexane, cooled to 0-5° C. for 2 hours and filtered to obtain 8.64 g (61%) of (VI), m.p. 110-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9](OCC)=[O:10])=[C:4]([O:16][CH3:17])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[CH2:9][OH:10])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1C(C)(C)CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a stirred solution of ethyl 2-(4-bromo-2-methoxyphenyl)-2-methylpropanoate (110 mg, 0.36 mmol) in THF (4 mL) was added 1 M solution of lithium aluminum hydride in THF (0.4 mL, 0.4 mmol) at −60° C. and the reaction mixture was warmed up to 0° C. in 40 min (the starting material is still present by TLC) and then allowed to stir at room temperature for 4 hours—now the starting material is consumed (TLC). A solution of sodium hydroxide (105 mg) in water (0.2 mL) was added and the mixture was stirred at room temperature for 30 min. Then 3 mL of methylene chloride (3 mL), silica gel (1 g), and anhydrous magnesium sulfate (1 g) were added and the mixture was stirred for 2 hours. Solids were filtered off and mother liquor was concentrated to give the title compound (85 mg). By GCMS, this is a mixture of the target primary alcohol and de-brominated primary alcohol (40% of the desired product by GCMS). This mixture was used for the next step without purification. GCMS (ES+) 258 (M+).