Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20](OCCN(CC)CC)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.[F:33]C1N=C(C=O)C=CC=1.C(CC(N[C@H](C1C=CC=CC=1)CCC)=O)#N>>[C:31](/[C:9](=[CH:8]\[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:33])[N:7]=1)/[C:10]([NH:12][C@H:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Reactant: O=Cc1cccc(F)n1
Agent: CCC[C@H](NC(=O)CC#N)c1ccccc1
Product: CCC[C@H](NC(=O)/C(C#N)=C/c1cccc(F)n1)c1ccccc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-fluoropicolinaldehyde was used instead of 6-bromopicolinaldehyde, and (S)-2-cyano-N-(1-phenylbutyl)acetamide was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29), This produced the crude product which was purified by flash silica gel column chromatography, eluting with 8:2 hexanes/ethyl acetate, to give 40 (115 mg, 96%) as a clear oil: MS (ES+) m/z 324.1 (M+H)+.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].Cl[C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][CH:19]=[C:13]2[N:12]=1.Br[C:21]1[CH:22]=NN2C=CC(Cl)=N[C:25]=12>>[C:1]1([C@H:4]2[CH2:8][O:7][C:6](=[O:9])[N:5]2[C:11]2[CH:16]=[CH:15][N:14]3[N:17]=[CH:18][CH:19]=[C:13]3[N:12]=2)[CH:3]=[CH:22][CH:21]=[CH:25][CH:2]=1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: Clc1ccn2nccc2n1
Reactant: Clc1ccn2ncc(Br)c2n1
Product: O=C1OC[C@H](c2ccccc2)N1c1ccn2nccc2n1
Yield: 77 %

Procedure:
(S)-4-Phenyl-3-(pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.423 g, 77%) was prepared by the procedure described in Example 1, Step 4, substituting (S)-4-phenyloxazolidin-2-one (0.638 g, 3.91 mmol) for (S)-4-isopropyloxazolidin-2-one and 5-chloropyrazolo[1,5-a]pyrimidine (0.300 g, 1.95 mmol) for 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:25][O:24][CH:23]([O:26][CH3:27])[C:21]1([CH3:20])[CH2:18][C:17](=[O:19])[C:12]2[CH:11]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:15]=[CH:14][C:13]=2[O:16]1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Reactant: COC(OC)C(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COC(OC)C1(C)CC(=O)c2cc(S(=O)(=O)c3ccccc3)ccc2O1

Procedure:
In 100 ml of toluene were dissolved 10 g of the compound obtained in step 4, 6.5 ml of pyruvic aldehyde dimethyl acetal and 1.5 ml of pyrrolidine. The resultant solution was heated to reflux for 16 hours and concentrated reduced pressure to obtain residue, which was purified by silica gel column chormatography using as an eluent a mixture of hexane and ethyl acetate (2:1) to obtain 11 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([NH2:21])=[CH:16][C:15]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([F:22])=[CH:16][C:17]([NH:21][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[CH:18][C:19]=2[F:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N)cc2F)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 0 °C
Yield: 89.4 %

Procedure:
To a solution of 4-(4-amino-2,6-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Intermediate III) (25 g, 0.08 mol), in 1:1 acetone:water (300 mL) was added sodium bicarbonate (15.1 g, 0.18 mol). The resulting solution was cooled to 0° C. and benzyl chloroformate (40 mL, 0.24 mol, 50% solution in toluene) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (500 mL). The organic layer was washed with water (2×50 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2:3 ethyl acetate:Pet. ether) to provide title compound (32 g, 90%) as off white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:20]([OH:23])(=[O:22])=[O:21]>C(Cl)(Cl)Cl>[N:14]1([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][C:5]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Oc2ccc(-n3ccnc3)cc2)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(Oc2ccc(-n3ccnc3)cc2)cc1
Reaction time: 8 h

Procedure:
137 mmol of 1-(4-phenoxyphenyl)imidazole are dissolved in 250 ml of chloroform. 190 mmol of chlorosulphonic acid are then added dropwise. The whole is left at 45° C. overnight. After cooling and removal of the solvent by evaporation, the resulting oil is taken up in diethyl ether. The resulting solid is filtered off and dried to yield the expected product.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:21]=1[CH2:22]Cl>CCO>[ClH:19].[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: ClCc1cc(Cl)ccc1Cl
Solvent: CCO
Product: Cl
Product: Clc1ccc(Cl)c(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,5-dichlorobenzyl chloride (327 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 175 mg of the product 238. 1H NMR (DMSO-d6) δ 11.50 (s, 2H), 8.00 (s, 1H), 7.70-7.50 (m, 2H), 7.20-7.00 (m, 6H), 6.95-6.80 (m, 4H), 5.81 (s, 2H), 4.90 (s, 2H); MS: m/z 413 (M++1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([CH2:22][CH2:23]O)[N:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:18][CH:19]=[C:20]([CH2:22][CH2:23][N:28]4[CH2:29][CH2:30][CH2:31][C@H:27]4[CH3:26])[N:21]=3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(-c3nc(CCO)co3)cc2)cc1
Reactant: C[C@@H]1CCCN1
Agent: Cl
Product: C[C@@H]1CCCN1CCc1coc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Example 53 from 2-[2-(4′-Methanesulfonyl-biphenyl-4-yl)-oxazol-4-yl]-ethanol (See Intermediate 71) and (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 411.2 (M+1)
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13](=O)[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=O)=[CH:11][CH:10]=1.C(O)(=O)C>O.CCOCC>[OH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]2[N:7]([CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[CH:14]=2)=[CH:11][CH:10]=1
Reactant: O=C(CC1CCCCC1=O)c1ccc(O)cc1
Reactant: CC(C)NCCN
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC(C)NCCn1c(-c2ccc(O)cc2)cc2c1CCCC2
Temperature: 25 °C

Procedure:
A solution of 7.25 g (0.071 mole) of isopropylaminoethylamine, 16.5 g (0.071 mole) of 2-(p-hydroxyphenacyl)cyclohexanone and acetic acid is refluxed under nitrogen for 6 hours, then cooled to ambient temperature, and diluted with water. The aqueous solution is washed with ether, then basified with 10% sodium carbonate and extracted with chloroform. The chloroform solution is washed with saturated sodium chloride solution, treated with charcoal, and dried over magnesium sulfate. The chloroform is removed to give a yellow solid which is recrystallized from acetonitrile to give a yellow-tan solid. The solid is dissolved in ether, the solution is filtered and concentrated to give 2-(p-hydroxyphenyl-1-(2-isopropylaminoethyl)-4,5,6,7-tetrahydroindole as a pale yellow solid, m.p. 149°-150° C.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH:7]=[O:8].[BH4-].[Na+].[OH-].[Na+]>C(O)C>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH2:7][OH:8]
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(OC(F)F)c(OC(F)F)c1

Procedure:
3,4-Bisdifluoromethoxybenzaldehyde (26.2 g, 110 mmol) in absolute ethanol (150 mL) was treated with sodium borohydride (8.32 g, 220 mmol) under an argon atmosphere at room temperature for 0.5 h. Ten percent aqueous sodium hydroxide (130 mL) was added, the ethanol was removed in vacuo, the mixture was partitioned between ether and water and was etracted twice with ether. The organic extract was dried (magnesium sulfate) and evaporated to a pale yellow oil (26.4 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19]Br)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C
Reactant: NCc1cccnc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1C
Temperature: 50 °C

Procedure:
4-(3-bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 5-a: 180 mg) and 3-picolylamine (500 μl) were dissolved in ethanol (2 ml) and heated at 50° C. for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 3-methyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester (150 mg) as a colorless oil. EI-MS: m/z 368 (M+); 1H-NMR (CDCl3): δ 1.44 (3H, t, J=7 Hz), 2.07 (2H, quintet, J=6.5 Hz), 2.67 (3H, s), 2.89 (2H, t, J=7 Hz), 3.84 (2H, s), 4.17 (2H, t, J=6 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, 8 Hz), 7.12 (1H, d, J=8 Hz), 7.21 (1H, dd, J1=8 Hz, J2=5 Hz), 7.30 (1H, t, J=8 Hz), 7.66 (1H, dd, J1=8 Hz, J2=2 Hz), 8.49 (1H, dd, J1=5 Hz, J2=2 Hz), 8.57 (1H, d, J=2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:42]=[CH:41][C:38](C=O)=[CH:37][CH:36]=1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[OH:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:27][N:24]2[CH2:23][CH2:22][CH:21]([N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:10](=[O:20])[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[CH:37][CH:36]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Hydroxybenzaldehyde (139 mg, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 459.2655, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.1, tr 2.84 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:12])[CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][N:24]3[C:27]([C:30]4[CH:31]=[C:32]([NH:36][C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:33]=[CH:34][CH:35]=4)=[CH:28][N:29]=[C:23]3[CH:22]=2)O1>>[CH3:12][C:8]1([C:4]2[CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][N:24]4[C:27]([C:30]5[CH:31]=[C:32]([NH:36][C:37]([NH:39][CH2:40][C:41]([F:42])([F:44])[F:43])=[O:38])[CH:33]=[CH:34][CH:35]=5)=[CH:28][N:29]=[C:23]4[CH:22]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:10][O:9]1
Reactant: CC1(c2cccc(Br)c2)CCO1
Reactant: CC1(C)OB(c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)OC1(C)C
Product: CC1(c2cccc(-c3ccn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)c2)CCO1

Procedure:
2-(3-Bromophenyl)-2-methyloxetane may be coupled with 1-{3-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea according to procedure E3.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[NH2:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13](O)=[O:14].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[NH2:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:14]
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(C)(N)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(N)CC(=O)N1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
2,3-Dihydro-1H-isoindole (543 mg) and 3-amino-3-methylbutanoic acid (700 mg) were dissolved in N,N-dimethylformamide (30 ml). N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (876 mg) and hydroxybenzotriazole (698 mg) were added thereto at 0° C., and then the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The organic phase was separated, and the aqueous phase was adjusted to pH 9 by adding a saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.60 g, Y.:60%) as a brown oily matter.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[C:11]1([S:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:7][CH:6]([CH3:8])[C:5]([C:14]1[CH:15]=[CH:16][C:11]([S:17][CH3:18])=[CH:12][CH:13]=1)=[O:9]
Reactant: CC(C)C(=O)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(=O)C(C)C)cc1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a suspension of aluminum chloride (136 g, 1.02 mol) in chloroform (1.0 L) cooled to -10° C., was added dropwise isobutyrylchloride (115 mL, 1.10 mol). Then thioanisole (100 mL, 0.85 mol) was added dropwise. Upon completion of addition the reaction was allowed to proceed at r.t. for 1.5 h. The reaction was cooled to 10° C. and quenched by addition of water (750 mL). The organic layer was separated, washed with water (2×500 mL), saturated NaHCO3 solution(2×500 mL), brine (1×500 mL), and then dried over Na2SO4. After concentration in vacuo., the resulting crude product crystallized upon standing under high vacuum for 30 min to give the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[N-:13]=[N+]=[N-].[Na+].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[NH:13][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)c(O)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1NCCc2cc(F)c(O)cc21
Reaction time: 3 h

Procedure:
To a solution of (90) (10.5 g, 63.3 mmol) in chloroform (600 ml) was added NaN3 (12.3 g, 190 mmol), followed by dropwise addition of methanasulfonic acid (33 ml, 506 mmol). Resulting mixture was stirred for 3 hr. The reaction mixture was poured into cold water and extracted with chloroform (3×). Organic extracts were combined and washed with H2O and sat. NaCl, then dried over Na2SO4. Concentration in vacuo gave a mixture of required product and reversed lactam. Purification of crude product on silica eluting with 30-60% EtOAc/Hex offered WAY-263746 as a off-white solid (5.3 g, 46%). 1H NMR/CD3OD, δ, 7.48 (d, 1H), 7.00 (d, 1H), 3.43-3.49 (t, 2H), 2.83-2.89 (t, 2H). MS (ES) m/z 180.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]=O.[OH-].[K+].[N+:20]([CH:23]([CH3:25])[CH3:24])([O-:22])=[O:21]>CO>[C:11]([C:7]1[CH:8]=[C:9]([CH2:24][C:23]([CH3:16])([N+:20]([O-:22])=[O:21])[CH3:25])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(CC(C)(C)[N+](=O)[O-])cc(C(C)(C)C)c1O

Procedure:
2,6-di-t-butylphenol, 20.6 g, in 100 ml of stirred methanol containing 16.2 g of 37% aqueous formaldehyde (excess) was treated with a freshly prepared solution of 5.6 g of potassium hydroxide and 8.9 g of 2-nitropropane and heated under nitrogen for 21/2 hours. Upon cooling, 19.8 g of product, mp 101°-4° C., was obtained in two crops. Recrystallization from methanol afforded product melting 103.5°-105.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[CH:21])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.I[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:19]([C:20]#[C:21][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Reactant: Oc1ccc(I)cc1
Product: C[S@@](=O)(=NC(=O)c1cnc(N)c(C#Cc2ccc(O)cc2)c1)c1ccccc1
Yield: 62 %

Procedure:
In a manner similar to that describe in Example 467, (S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodophenol are converted to the title compound (41 mg, 62%).
Reaction SMILES: C(OC(N1CCN([C:14](=[O:26])[NH:15][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:17][OH:18])CC1)=O)(C)(C)C.F[C:28](F)(F)[C:29](O)=O.[Cl:34][C:35]1[N:40]=[C:39](Cl)[C:38]([Cl:42])=[CH:37][N:36]=1>C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([CH:16]([NH:15][C:14]([CH:29]2[CH2:28][CH2:14][N:15]([C:39]3[C:38]([Cl:42])=[CH:37][N:36]=[C:35]([Cl:34])[N:40]=3)[CH2:16][CH2:17]2)=[O:26])[CH2:17][OH:18])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NC(CO)c2cccc(Cl)c2)CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: ClCCl
Product: O=C(NC(CO)c1cccc(Cl)c1)C1CCN(c2nc(Cl)ncc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[1 -(3-Chloro-phenyl)-2-hydroxy-ethylcarbamoyl]-piperazine- 1-carboxylic acid tert-butyl ester was deprotected with 10% trifluoroacetic acid in methylene chloride by stirring overnight at ambient temperature. The reaction was concentrated in vacuo and the resulting TFA salt was dissolved in DMF (1 mL) and DIEA (0.25 mL). This mixture was heated with 2,4,5-trichloropyrimidine (52 mg. 0.28 mmol) at 80° C. for 18 hours. Purification by prep HPLC (Gilson: Column=CombiHT SB-C189 5 μM 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2O gradient) afforded the title compound as a yellow oil (47 mg) Rt=5.97 minutes; MS FIA 429.9 (M+1).
Reaction SMILES: Cl[CH:2]([Cl:4])C.[F:5][C:6]([F:17])([F:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[O:18]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[F:5][C:6]([F:17])([F:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:18][CH2:2][Cl:4])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(Cl)Cl
Reactant: C1COOOC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 10 ml of dichloroethane were added 1 g of zirconium tetrachloride and 1 g of 4-trifluoromethylbenzoyl chloride, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 10° C., 0.16 g of trioxane was added, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour. The mixture was cooled to 0° C., water was added slowly, the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 0.92 g of chloromethyl 4-trifluoromethylbenzoate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12]CC3CC3)=[O:11])=[CH:8][C:7]=2[C:19]([F:22])([F:21])[F:20])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=2[C:19]([F:20])([F:21])[F:22])[CH2:3][CH2:2]1
Reactant: O=C(OCC1CC1)c1ccc(OCC2CC2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC2CC2)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a solution of cyclopropylmethyl 4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzoate (0.642 g, 2.043 mmol) in THF:MeOH (1:1, 10 mL) was added LiOH (1M, aq) (12.26 mmol). The reaction was stirred overnight, quenched with HCl (1M, aq) and extracted with EtOAc (twice). The combined extracts were dried over MgSO4 and concentrated to give the title compound as a white solid (0.502 g). LCMS m/z=261.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 0.39-0.46 (m, 2H), 0.62-0.71 (m, 2H), 1.23-1.38 (m, 1H), 4.03 (d, J=6.57 Hz, 2H), 7.02 (d, J=8.72 Hz, 1H), 8.23 (dd, J=8.72, 2.15 Hz, 1H), 8.34 (d, J=2.02 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:9]2=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].O>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:9]2=[O:10])=[CH:6][CH:7]=1)=[O:31]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: Nc1ccc(N2C(=O)CCc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3C(=O)CCc4ccccc43)cc2)c(OC)c1
Yield: 57.9 %

Procedure:
To a solution of 1-(4-aminophenyl)-3,4-dihydrocarbostyril (0.45 g) in dichloromethane (15 ml) is added triethylamine (0.29 g). Thereto is added 2,4-dimethoxybenzoyl chloride (0.42 g) with stirring under ice cooling. The mixture is refluxed with heating for 0.5 hour. After cooling, water is added thereto and the mixture is extracted with dichloromethane, washed with water and then dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography and recrystallized from ethanol/diethyl ether/n-hexane to give 1-[4-(2,4-dimethoxybenzoylamino)phenyl]-3,4-dihydrocarbostyril (0.44 g) as white powder, m.p.: 226°-227° C.