Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:18]([F:33])[CH:17]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[F:33][C:18]1[CH:17]=[C:16]([C:10]2[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([F:15])[CH:11]=2)[CH:21]=[CH:20][C:19]=1[S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:23])=[O:24]
Reactant: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3OCc3ccccc3)cc2F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3O)cc2F)cc1

Procedure:
The subtitle compound was prepared by the method of example 12 step (iii) using the product of step (ii) and 10% Pd/C in acetic acid.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH2:23]([NH2:25])[CH3:24]>>[CH2:23]([NH:25][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:24]
Reactant: CCN
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)O
Product: CCNC(=O)C=C(C)C=CC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and ethylamine were reacted in the same manner as in Preparation Example 9 to obtain the desired product as an oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]3[C:24]=2[N:23]([CH3:25])[C:22]([CH3:26])=[C:21]3[CH3:27])[C:7]1=[O:29].O.[OH-].[Li+]>C1COCC1.O>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:7]2=[O:29])=[C:24]2[C:20]=1[C:21]([CH3:27])=[C:22]([CH3:26])[N:23]2[CH3:25]
Reactant: COC(=O)CCn1c(=O)n(Cc2ccc(Cl)c3c(C)c(C)n(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)n(C)c2c(Cn3c(=O)n(CCC(=O)O)c4ccccc43)ccc(Cl)c12
Temperature: 25 °C
Yield: 13.5 %

Procedure:
To a stirred solution of 3-[3-(4-chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester (40 mg, 0.09 mmol) in THF (3 ml) and water (1 ml) was added lithium hydroxide monohydrate (10 mg, 0.24 mmol). The resulting mixture was stirred at ambient temperature until all of the starting material was consumed. After this time the reaction was concentrated to low volume and diluted with water (10 ml) and acetic acid (0.5 ml). The resulting heterogeneous mixture was stirred at ambient temperature for 18 h. The solid product was collected via filtration and suspended in acetonitrile. The product was collected once more via filtration and washed with minimal acetonitrile to give 5 mg (13%) of the desired product. LCMS (ESMS): m/z 412.88 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][N:15]([CH3:16])[C:33]([NH:32][C:27]2[CH:26]=[C:25]([Cl:24])[CH:30]=[C:29]([Cl:31])[CH:28]=2)=[O:34])([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: CN(CC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.7 %

Procedure:
4-(4-Iodo-phenyl)-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.35 mmol) was dissolved in CH2Cl2 (2 mL) and 3,5-dichlorophenylisocyanate (0.066 g, 0.35 mmol, 1 eq.) was added. The reaction was stirred at room temperature for 6 h, diluted with CH2Cl2 (25 mL) and washed with saturated brine (25 mL). The aqueous layer was washed with CH2Cl2 (2×20 mL). The combined organic extracts were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give 4-[3-(3,5-dichloro-phenyl)-1-methyl-ureidomethyl]-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.218 g, 100%). 1H NMR (CDCl3): δ 7.84 (d, 2H), 7.24 (m, 3H), 7.09 (m, 2H), 6.23 (br.s, 1H), 3.96 (d, 2H), 3.54 (s, 2H), 2.99 (dd, 2H), 2.70 (s, 3H), 2.28 (d, 2H), 1.90m (dd, 3H), 1.54 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:4](C(OC(C)(C)C)=O)[C:3]1=[O:24].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[NH:4][C:3]1=[O:24]
Reactant: CN1C[C@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C[C@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of (R)-1-tert-butyl 5-benzyl 3-methyl-2-oxoimidazolidine-1,5-dicarboxylate (25b) (0.650 g, 1.95 mmol) in DCM (20 mL), cooled to 0° C., TFA (3 mL, 2.9 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for further 1 h. After completion (by TLC), the reaction mixture was neutralized with saturated NaHCO3 solution and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to provide the crude residue which was purified by column chromatography to furnish 25c (0.320 g, 70%) as off white solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([O:25][CH2:26][C:27]([O:29]CC)=O)[C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:8]=[CH:9][CH:10]=1>>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([O:25][CH2:26][C:27]([NH:3][CH2:1][CH3:2])=[O:29])[C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCN
Reactant: CCOC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Product: CCNC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of EtNH2 in alcohol (30% by weight, 10 mL) was added (3R)-tert-butyl 3-((3-chlorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (100 mg, 0.243 mmol). The mixture was stirred at rt overnight. The mixture was concentrated under vacuum to give crude product, which was purified by preparative tlc (elution solvent: 5:1 petroleum ether/EtOAc) to give (3R)-tert-butyl 3-((3-chlorophenyl)(2-(ethylamino)-2-oxoethoxy)methyl)piperidine-1-carboxylate (57.9 mg. 58%) as a colorless oil. MS (E/Z): 411 (M+H+).
Reaction SMILES: [H-].[Na+].[N+](C1[CH:11]=[CH:10][C:9]([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:17][CH2:16]2)=[O:14])=[CH:8]C=1)([O-])=O.C1(O)CCC1.O>O1CCCC1>[CH:9]1([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]5[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=5)=[C:24]4[CH:23]=[N:22]3)[CH2:17][CH2:16]2)=[O:14])[CH2:10][CH2:11][CH2:8]1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC2CCC2)CC1
Reaction time: 0.08 h
Yield: 13.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 10 mg, 0.25 mmol) was added to a solution of 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 4-nitro-phenyl ester (Example 123; 60 mg, 0.13 mmol) in anhydrous tetrahydrofuran (1 mL) under argon. The mixture was stirred for 5 min and then cyclobutanol (11 μL, 0.14 mmol) was added and the mixture was stirred at room temperature for 7 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on a Silicycle 4 g column, eluting with 0-4% methanol/dichloromethane to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclobutyl ester (7 mg, 14%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:10]2(=[O:25])=[O:24])[CH2:3]1.C=O.[C:28]([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.O>[CH3:28][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:10]2(=[O:25])=[O:24])[CH2:3]1
Reactant: [BH3-]C#N
Reactant: O=S1(=O)N(CC2CNCCO2)c2ccccc2N1c1ccccc1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: CN1CCOC(CN2c3ccccc3N(c3ccccc3)S2(=O)=O)C1
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution of 1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride (Example 1, 76 mg, 0.20 mmol) in methanol (2 mL) was added a solution of formaldehyde (37% in water, 0.15 mL) and the mixture was stirred for 30 minutes. Sodium cyanoborohydride (38 mg, 0.60 mmol, 3 equiv.) was added portionwise and the mixture was stirred for an additional 3 hours. Saturated aqueous sodium bicarbonate (5 mL) was added slowly followed by the addition of water (5 mL). The reaction mixture was extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with brine, dried (anhydrous sodium sulfate), and concentrated. The crude liquid residue was purified by Isco flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to give 70 mg (98%) of 1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as viscous colorless liquid. This free base was dissolved in dichloromethane (3 mL) and was treated with an ethereal solution of hydrochloric acid (1 M, 0.3 mL, 0.3 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield 76 mg (96%) of 1-[(4-methylmorpholin-2-yl)methyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride. MS (ESI) m/z 360.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5]>Cl>[CH3:1][C:2]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2)cccc1[N+](=O)[O-]
Agent: Cl
Product: Cc1c(N)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 62 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A mixture of 3,750 ml of hydrochloric acid, 134 g of 2-methyl-3-nitro-4'-chloro-benzophenone and 536 g of stannous chloride was heated at 62° C for 6 hours and was then cooled to 5° C and held therefor 1 hour. The mixture was vacuum filtered and the precipitate was washed with hydrochloric acid and dried under reduced pressure. The residue was stirred for 2 hours at room temperature with 1,300 ml of water, 1,000 ml of 2N sodium hydroxide and 230 ml of ether and the mixture was then extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 68.7 g of 2-methyl-3-amino-4'-chloro-benzophenone melting at 65° C which was used as is for the next step.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:36][CH:35]([CH3:37])[C:34]([NH:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:11]1)=[O:38]
Reactant: CC(C)C(=O)Cl
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 80 μl of isobutyryl chloride (0.76 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 142 mg (65% of theory)
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5](#[N:8])[CH:6]=[CH2:7].Cl>CO>[CH2:1]([O:4][CH2:7][CH2:6][C:5]#[N:8])[CH2:2][O:3][CH2:7][CH2:6][C:5]#[N:8]
Reactant: C=CC#N
Reactant: OCCO
Agent: Cl
Solvent: CO
Product: N#CCCOCCOCCC#N
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.9 %

Procedure:
Small scale: Ethylene glycol (1 g, 16.1 mmol) was mixed with Triton B (40% in MeOH, 0.22 g, 0.53 mmol) and cooled in an ice-bath while acrylonitrile (1.71 g, 32.2 mmol) was added. The mixture was stirred at room temperature for 60 hours after which it was neutralized with 0.1 M HCl (0.6 cm3) and extracted with CH2Cl2 (80 cm3) The extracts were concentrated under reduced pressure and the residue was Kugelrohr-distilled to give 3,3′-(ethane-1,2-diylbis(oxy))dipropanenitrile (1.08 g, 39.9%) as a light colored oil, bp 150-170° C./20 Torr.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8](SC)=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.Cl.[F:28][C:29]1([F:36])[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([NH:35][CH:32]3[CH2:33][CH2:34][C:29]([F:36])([F:28])[CH2:30][CH2:31]3)=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1
Reactant: NC1CCC(F)(F)CC1
Reactant: CSc1ncc2c(N)cc(=O)n(C)c2n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(=O)cc(N)c2cnc(NC3CCC(F)(F)CC3)nc21
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of 5-amino-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (163 mg, 0.733 mmol) in DCM (200 mL) was added 3-chloroperoxybenzoic acid (77% max., 164 mg, 0.733 mmol) at RT and the resulting mixture was stirred for 1 h. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in anhydrous dimethyl sulfoxide (7.3 mL). To a portion of this solution (1.8 mL) was added TEA (0.13 mL, 0.90 mmol), followed by 4,4-difluorocyclohexylamine hydrochloride (62 mg, 0.36 mmol) at RT. The reaction mixture was stirred at 80° C. for 4.5 h and was then quenched with water. The resulting mixture was extracted twice with EtOAc (20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (from 0 to >10% of MeOH/DCM in 10 min.) to give 27 mg (49% yield) of 5-amino-2-(4,4-difluoro-cyclohexylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid. MS=310 [M+H]+.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:24]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: NCc1cccc(OCc2ccccc2)c1
Solvent: CO
Product: N#CNC(=NCc1cccc(OCc2ccccc2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.30 g, 1.6 mmol) was dissolved in methanol (10 ml), and 3-benzyloxybenzylamine (0.42 g, 2.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was then concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give the title compound (0.26 g, 0.8 mmol, yield: 48%) as colorless crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Si:21]([CH3:24])([CH3:23])[CH3:22])[CH3:12].[CH3:26][O:27][CH2:28]Cl>C1COCC1>[CH2:11]([N:13]([CH2:26][O:27][CH3:28])[C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Si:21]([CH3:24])([CH3:23])[CH3:22])[CH3:12]
Reactant: CCNC(=O)c1ccccc1[Si](C)(C)C
Reactant: COCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(COC)C(=O)c1ccccc1[Si](C)(C)C
Yield: 49.4 %

Procedure:
A 1M THF solution of sodium bis(trimethylsilyl)amide (52.5 mL, 52.5 mmol) was added dropwise over 5 min to a solution of the compound of Example 49 (11.07 g, 50 mmol) in THF (100 mL). The resulting mixture was cooled with a dry ice/acetone bath while neat chloromethyl methyl ether (4.83 g, 60 mmol) was added, maintaining the internal reaction temperature <-70° C. The cold bath was removed and the resulting reaction mixture was allowed to warm for 1 h, then was partitioned between sat aq NaHCO3 and ether. The ether phase was dried (MgSO4), concentrated, and purified by HPLC with 3:17 ethyl acetate/hexanes to afford 6.55 g of the title compound as a colorless oil, a 49% yield.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[CH2:36]([N:44]=[C:45]=[O:46])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>N1C=CC=CC=1>[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([NH:44][C:45](=[O:46])[NH:15][C:16]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCN=C=O
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCNC(=O)Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Reaction time: 3 h

Procedure:
Benzhydrol 2-(2-amino-4-trifluoromethylphenoxy)benzoate (700 mg, 0.0015 mol) was dissolved in pyridine and octylisocyanate (412 mg, 0.0027 mol) was added to the mixture at room temperature and stirred for three hours. The solvent was evaporated and the residue was flash chromatographed (silica gel, ethyl acetate/hexane) to give the title compound. 1H NMR (250 MHz, CDCl3) δ8.7 (s, 1H), 8.2 (s, 1H), 7.95 (d, 1H), 7.29 (m, 10H), 7.12 (s, 1H), 7.1 (d, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 4.8 (s, 1H), 3.1 (dd, 1H), 1.28 (s, 14H), 0.85 (t, 3H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[ClH:21].S(Cl)([Cl:24])=O>C(Cl)Cl>[ClH:24].[CH2:13]([O:12][C:10]([C:7]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][Cl:21])[CH2:5][CH2:6]1)=[O:11])[CH3:14]
Reactant: CCOC(=O)C1(c2ccccc2)CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccccc2)CCN(CCCl)CC1

Procedure:
A solution is prepared from 5.9 parts of the ester obtained in the preceding paragraph and 134 parts of methylene chloride. This solution is saturated with hydrogen chloride gas at below 10° and 5.1 parts of thionyl chloride is added. The mixture is refluxed for 1 hour and then cooled and volatile material is removed under reduced pressure. The residue is dissolved in 88 parts of benzene, and the solution evaporated under reduced pressure. The residue is then crystallized from a mixture of ethanol and ether to give 1-(2-chloroethyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride melting at about 216°-218°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:16]2[CH:17]=[C:18](B(O)O)[C:19]([F:22])=[N:20][CH:21]=2)[CH3:15])[C@H:10]([CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]1[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:29]=1.O1CCOCC1.C([O-])(=O)C.[K+].O.CC(N)CC1C=CC=CC=1.OP(O)(O)=O>>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:18]3[CH:17]=[C:16]([CH:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@H:10]4[CH3:26])[CH3:15])[CH:21]=[N:20][C:19]=3[F:22])[N:29]=2)=[CH:51][CH:50]=1
Reactant: CC(c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3F)n2)cc1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(1-((R)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (1.4 g, 3.81 mmol),4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.467 g, 3.81 mmol),1,4-dioxane (10 mL, 3.81 mmol), potassium acetate (1.122 g, 11.44 mmol), water (1 mL, 3.81 mmol), and amphos (0.270 g, 0.381 mmol). The reaction mixture was stirred and heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min (watts, Powermax feature, ramp time min). LC/MS showed desired product, starting triazine and debornated product. The reaction mixture was diluted with water (20 mL) and DCM (25 mL) and the aqueous layer was extracted with DCM (3×50 mL) dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide (3R)-tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (1.26 g, 1.876 mmol, 49.2% yield).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][NH:5][C:6](=[S:15])[S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.FB(F)F.CCOCC>>[CH3:1][O:2][CH:3]1[S:15][C:6]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:5][CH2:4]1
Reactant: COC(CNC(=S)SCc1ccccn1)OC
Agent: FB(F)F
Solvent: CCOCC
Product: COC1CN=C(SCc2ccccn2)S1
Yield: 96.9 %

Procedure:
68.1 g (0.025 mole) of dithiocarbamate (VI) obtained from Example 7 was reacted with 8.51 g (0.06 mole) of trifluoroborane ether according to the same procedure as that in Example 9-2 to obtain 5.82 g (yield 97%) of the desired thiazoline compound.