Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[C:36](O)([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.O>[C:36]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)O
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(4-hydroxyphenyl)propanoic acid (3.32 g, 20 mmol) in dry DMF (20 ml) is carefully added 1,1′-carbonyldiimidazole (3.24 g, 20 mmol) portionwise. The reaction mixture is stirred at 40° C. for 2 hours after which time DBU (6.02 ml, 40 mmol) and tert-butanol (4.78 ml, 50 mmol) are added and the reaction mixture is now stirred at 65° C. for 2 days. The reaction mixture is allowed to cool to room temperature and poured into water (50 ml) and the product is extracted with diethyl ether (3×30 ml). The organics are combined, dried (MgSO4) and the solvent removed in vacuo to give a yellow oil. Purification by flash chromatography (SiO2, EtOAc/iso-hexane) yields 3-(4-Hydroxy-phenyl)-propionic acid tert-butyl ester as a colourless oil. 1H NMR (DMSO-d6) 9.1 (1H, s), 7.0 (2H, d, J=8.45), 6.65 (2H, d, J=8.45), 2.7 (2H, t, J=7.28), 2.4 (2H, t, J=7.28), 1.4 (9H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=1)=[N+:15]=[N-:16]
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc2ccc(Cl)cc2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(bromomethyl)-7-chloroquinoline (50 mg, 0.195 mmol) in DMF (0.5 ml) was added sodium azide (19.01 mg, 0.292 mmol). Reaction mixture was stirred for 2 h at 90° C. Reaction mixture was diluted with ethyl acetate/water. Layers were separated and organic layer was washed twice with water and with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.990 min, MS (Method V) [M+H]+=219.1.
Reaction SMILES: N1C=CC=CC=1.P(Br)(Br)[Br:8].[CH2:11]([O:13][CH:14](O)[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12].O>C1C=CC=CC=1>[CH2:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:8])[CH3:12]
Reactant: CCCCC(O)OCC
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCOCCCCCBr
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 182 %

Procedure:
10 g of pyridine was added dropwise to a solution of 78 g (0.29 mol) of phosphorus tribromide in 130 ml of benzene. After the solution was stirred for 10 minutes and cooled to -5° C., a mixture of 102 g (0.77 mol) of pentane diol monoethyl ether and 5 g of pyridine was added dropwise. After maintaining the reaction temperature at 0° C. and stirring for 2 hours, the solution was stirred for 8 hours at the room temperature. 100 ml of water was added and extracted with diethyl ether. The organic layer was washed subsequently with 6N hydrochloric acid and an aqueous sodium hydrogen carbonate solution, then dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under the reduced pressure, to obtain 103 g of 5-bromopentyl ethyl ether. Boiling point; 47-48° C. (1 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][OH:16])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(N(CC)CC)C>[CH:9]([NH:10][CH:11]([CH3:12])[CH3:6])([CH3:13])[CH3:8].[CH3:17][S:18]([O:16][CH2:15][CH2:14][C:8]1[C:9]([CH3:13])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)(=[O:20])=[O:19]
Reactant: COc1ccc2cc(CCO)c(C)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)NC(C)C
Product: COc1ccc2cc(CCOS(C)(=O)=O)c(C)nc2c1

Procedure:
Compounds of formula (50), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 6. Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared using the procedures described in Synthetic Comm., 17(14):1647-1653 (1987). Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be treated with a reducing agent, such as, but not limited to, lithium aluminum hydride or sodium borohydride, to provide (7-methoxy-2-methyl-3-quinolinyl)methanol. (7-Methoxy-2-methyl-3-quinolinyl)methanol can be treated with a chlorinating reagent, such as, but not limited to, thionyl chloride to provide 3-(chloromethyl)-7-methoxy-2-methylquinoline. 3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodium cyanide or potassium cyanide to provide (7-methoxy-2-methyl-3-quinolinyl)acetonitrile. (7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid, such as, but not limited to, glacial acetic acid and concentrated sulfuric acid, in water and 1,4-dioxane with heat to provide (7-methoxy-2-methyl-3-quinolinyl)acetic acid. (7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with a reducing agent, such as, but not limited to, B2H6, borane-THF complex, or borane-pyridine complex, to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethanol. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated with methanesulfonyl chloride and a base, such as, but not limited to, triethylamine or diisopropylamine to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treated with an amine of formula (5) to provide amines of formula (47). Amines of formula (47) can be treated with BBr3 to provide hydroxy compounds of formula (48). Hydroxy compounds of formula (48) can be treated with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to provide triflates of formula (49). Triflates of formula (49) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (50).
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[S:31][C:32]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:9][CH:8]([CH3:10])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[S:31][C:32]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:40])=[O:5]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4cc(Cl)ccc4s3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4cc(Cl)ccc4s3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 386.1 %

Procedure:
To (S)-3-methyl-2-{4′-[(5-chloro-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester (30 mg) was added 3 mL of TFA/CH2Cl2 (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 105 mg of (S)-3-methyl-2-{4′-[(5-chloro-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.88 (m, 6 H) 1.85-2.07 (m, 1 H) 3.56 (dd, 1 H) 7.70 (dd, 1 H) 7.76-7.94 (m, 6 H) 8.03-8.12 (m, 3 H) 8.26 (d, 1 H) 8.35 (d, 1 H) 11.36-11.40 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)[CH3:2].[CH3:13][NH:14][CH3:15].[CH2:16]=O.[OH-].[Na+]>ClCCl.CO.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][N:14]([CH3:16])[CH3:15])[CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1ccc2[nH]ccc2c1
Reactant: CNC
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc2c(ccn2CN(C)C)c1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
A mixture of 5-ethoxy-indole (7.84 g, 48.7 mmol), 40% aqueous dimethylamine (9.25 ml, 73 mmol, 1.5 equiv), and 96% acetic acid (30 ml) is stirred at 0° C., then 36% aqueous formaldehyde solution (6.33 ml, 82.7 mmol, 1.7 equiv) is added drop wise. The mixture is allowed to come to room temperature, and after stirring overnight TLC (dichloromethane-methanol, 4:1) indicates the absence of starting material. 10% Aqueous NaOH (150 ml) is added and the mixture is stirred at room temperature for 2 h. It is then extracted with dichloromethane (4×200 ml), the organic layer is dried and concentrated. The residue is purified by column chromatography (dichloromethane-methanol, 4:1→methanol-aqueous ammonia 50:1) to give crude product (10.18 g, 96%), which is crystallized from acetone to provide pure (5-ethoxy-1H-indol-ylmethyl)-dimethyl-amine (10.2 g, 96%) as white crystals. M.p. 95-97° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35][C:29]=3[CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[C:2]([C:27]2[CH:44]=[CH:43][C:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:34][CH2:35][C:29]=3[CH:28]=2)[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1ccc(OCc2cnccn2)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)c1ccc(OCc2cnccn2)c(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Yield: 30 %

Procedure:
To a stirred solution of 1-{3-bromo-4-[(2-pyrazinylmethyl)oxy]phenyl}ethanone (0.2 g) and 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.34 g) in DME (4 ml) was added aqueous sodium carbonate (2M, 0.98 ml). This was degassed with nitrogen for 15 min before adding Tetrakis (37 mg). The reaction was heated under reflux overnight. TLC indicated the reaction had gone to completion and so it was cooled, diluted with water and extracted with ethyl acetate. The combined organics were dried over sodium sulphate and concentrated in vacuo to yield a crude product which was purified by column chromatography, eluting with 0-18% ethyl acetate in hexane. The appropriate fractions were concentrated in vacuo to yield the title compound, 0.093 g, 30% yield.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17].[CH2:19]([OH:23])[CH2:20]CC>>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH:17][CH2:20][CH:19]1[CH2:9][C:8]2[CH:7]=[CH:6][CH:5]=[CH:11][C:10]=2[O:23]1
Reactant: CN(C)CCCN
Reactant: CCCCO
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CN(C)CCCNCC1Cc2ccccc2O1

Procedure:
Finally, 23.5 g (0.075 mol) of the above tosylate and 38.6 g (0.378 mol) of 3-(dimethylamino)propylamine were suspended in 150 ml of butanol, and the mixture was brought to reflux until the tosylate had disappeared.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCCCCN1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCN1CCCCCC1=O
Yield: 85.4 %

Procedure:
Following example 10, from 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 33 g (0.2 M) of 1-bromohexane on 19 hr. reflux was obtained 29.8 g (85.3%) of colorless product; b.p 122-128°/0.4 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: COc1cccc(-c2ccc3ccc(N)nc3n2)c1
Solvent: O
Solvent: CC#N
Product: COc1cccc(-c2ccc3ccc(NC(=O)c4cccc(Br)c4)nc3n2)c1
Temperature: 4 °C
Yield: 13.2 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (4 g), N,N'-carbonyldiimidazole (3.2 g) and 2-amino-7-(3-methoxyphenyl)-1,8-naphthyridine (3.5 g). The product obtained by precipitation in water (4 g; m.p. approximately 90° C.) is dissolved in boiling acetonitrile (200 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×3 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-[7-(3-Methoxyphenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (0.8 g), m.p. 104° C., is obtained.
Reaction SMILES: [O-2].[Mg+2].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7][CH2:6][C:5]1=[O:22].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]([C:25](=[O:26])[CH2:24][Cl:23])[CH2:6][C:5]1=[O:22]
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Reactant: O=C(Cl)CCl
Agent: [Mg+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CN(C(=O)CCl)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 8.14 %

Procedure:
3 g. of magnesium oxide are added to a solution of 2.87 g. (0.01 mmoles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2 H-1,4-benzodiazepine-2-one in 30 ml. of chloroform, and a solution of 1.2 ml. (0.018 moles) of chloroacetyl chloride in 4 ml. of chloroform is added to the vigorously stirred mixture. After 3 hours of stirring at room temperature the magnesium salt is filtered off, washed with 20 ml. of chloroform, and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallized from acetone. 2.68 g. (8.14 %) of 1-methyl-4-chloroacetyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 197°-200° C.; Rf2 = 0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1.[Br:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=1>>[Br:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([S:27]([NH:18][C:15]2[S:16][CH:17]=[C:13]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=3[Cl:12])[N:14]=2)(=[O:28])=[O:29])=[C:22]([F:31])[CH:21]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: Nc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cs1)c1cc(F)c(Br)cc1F

Procedure:
The title compound was prepared 4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (85 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (38.2 mg) with purity >90%: MS (pos) m/z 567.2, 569.2, 571.2; MS (neg) m/z 565.5, 567.5, 569.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([CH3:35])=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([CH3:35])=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cnc(C(=O)CBr)cc1C
Product: COC(=O)Cc1c(C(=O)c2cc(C)c(C)cn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4,5-dimethylpyridine*.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH3:5][O:6][CH:7]([O:10][CH3:11])[CH2:8]Br>>[CH3:5][O:6][CH:7]([O:10][CH3:11])[CH2:8][O:4][CH2:1][CH:2]=[CH2:3]
Reactant: COC(CBr)OC
Reactant: C=CCO
Product: C=CCOCC(OC)OC

Procedure:
Perkin Elmer 8310 GC (8% carbowax+2% KOH on chromasorb 80-100 mesh, 80°-200° C. in 20 min. Product retention 5.775 minutes, allyl alcohol 3.61 min, bromo-acetaldehyde dimethyl acetal 5.44 min. FID detection.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][O:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18]>C(COC)OC.O>[CH2:18]([N:10]1[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:13]=[CH:12][O:11]1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)Nc1ccon1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=CCN1OC=CC1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
3-(t-Butoxycarbonylamino)isoxazole (12 g, 65.2 mM) was dissolved in dimethoxyethane (150 ml) and cooled to 0° C. under nitrogen. To the stirred solution was added sodium hydride (60% in oil, 2.87 g, 71.7 mM), and the mixture stirred 20 minutes. Allyl bromide (8.7 g, 71.7 mM) was added dropwise, and the mixture stirred at ambient temperature for 18 hours, then diluted with water (300 ml), and extracted into diethyl ether (3×100 ml). The extracts were washed with brine (100 ml), dried (magnesium sulfate), and chromatographed on silica (50 g) eluting with dichloromethane . Relevant fractions were combined to give the desired product as an oil (14.68 g). MS (ESP): 225 (MH+) for C11H16N2O3
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10](O)=O.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:7][CH2:8][C:9]([C:14]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:13])[CH3:10]
Reactant: CC(C)(CCl)C(=O)O
Reactant: CNC(=S)NN
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNc1nnc(C(C)(C)CCl)s1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
An 87.2 g. portion of 4-methylthiosemicarbazide and 113.2 g. of 3-chloro-2,2-dimethylpropionic acid were suspended in 300 ml. of dioxane. The mixture was heated to 90° C. and 139.5 g. of phosphorus oxychloride was added dropwise while holding the temperature constant. After the addition was complete, the reaction mixture was stirred at 90° C. for three hours. The mixture was then allowed to cool and stand overnight at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:18].[Na+].OO>C1COCC1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]2[OH:18])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(c2ccc(Cl)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(4-chlorophenyl)-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine (654 mg, 2.407 mmol) was dissolved in THF (4.81 mL). Borane-THF complex (2.407 mL, 2.407 mmol) was added dropwise via syringe and the reaction was stirred 72 h at rt. Then sodium hydroxide (1.5 mL, 4.50 mmol) and hydrogen peroxide (1.2 mL, 11.75 mmol, 30% solution) were added. The reaction was stirred 2 h at rt, then diluted with saturated Na2S2O3 and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 25 g column by eluting with 20% to 100% EtOAc:Hexane to provide the desired product. LC-MS: calculated for C12H16ClNO3S 289.05 observed m/e: 289.92 (M+H)+ (Rt 1.35/4 min).
Reaction SMILES: [C:1]([O:5][C:6]1([CH3:16])[CH:13]2[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:15][CH:7]1[CH2:8]3)[CH2:12]2)(=[O:4])[CH:2]=[CH2:3].[CH:17]1[CH2:21][CH:20]=[CH:19]C=1.[CH2:22]1COCC1>>[CH:3]12[CH2:22][CH:21]([CH:20]=[CH:19]1)[CH2:17][CH:2]2[C:1]([O:5][C:6]1([CH3:16])[CH:7]2[CH2:15][CH:11]3[CH2:10][CH:9]([CH2:14][CH:13]1[CH2:12]3)[CH2:8]2)=[O:4]
Reactant: C1=CCC=C1
Reactant: C1CCOC1
Reactant: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Product: CC1(OC(=O)C2CC3C=CC2C3)C2CC3CC(C2)CC1C3
Temperature: 50 °C
Reaction time: 20 h

Procedure:
20 2-methyl-2-adamantyl acrylate (44 g, 0.2 mol) was dissolved in 250 ml of THF, cyclopentadiene (20 g, 0.3 mol) was added slowly thereto at 0° C. and then the reaction temperature was raised to about 50° C. Then, the reaction was stirred for about 20 hours. After completion of the reaction, excess THF was removed using a rotary evaporator and then neutralized with dilute sulfuric acid. Then, the resultant product was extracted using diethyl ether and dried over magnesium sulfate. The obtained crude product was vacuum-distilled to yield the desired compound of viscous colorless liquid (yield: 90%) FIGS. 1 and 2 are NMR and FT-IR spectrums of the compound.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH:15]([C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH2:16]
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: O
Solvent: C1COCCO1
Product: C=Cc1[nH]c2ccccc2c1C(=O)OC
Yield: 156.9 %

Procedure:
Methyl 2-bromo-1H-indole-3-carboxylate (100 mg, 0.19 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (154 mg, 1 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) and cesiumcarbonate (326 mg, 1 mmol) in dioxane/water (20 mL, 5 mL) were stirred at room temperature for 15 hours. Filterated the solid and the solvent was concentrated in vacuum. The resulted residue was purified by silica gel column (ethyl acetate/petroleum ether=1/2) to give methyl 2-vinyl-1H-indole-3-carboxylate as a pale yellow solid (60 mg, 76%) LRMS (M+H+) m/z: calcd 201.1 found 201.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[S:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[S:38][C:39]1[CH:40]=[C:41]([NH:42][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:43]=[CH:44][CH:45]=1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 15 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 164B (0.114 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.033 g, 15%). 1H NMR (300 MHz, CDCl3) δ 9.4 (br, 1H), 8.75 (s, 1H), 7.79 (m, 1H), 7.62 (d, 1H), 7.27-7.46 (m, 5H), 6.36 (s, 1H), 4.34 (t, 2H), 4.04 (s, 3H), 3.90 (s and t, 5H), 3.49 (s, 3H); LC-MS (ESI) m/z 549 (M+H)+.