Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[N:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:16]1[CH:21]=[CH:20][C:19]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: Oc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccncc2)CC1

Procedure:
At 0° C., to a mixture of tert-butyl (cis-4-hydroxycyclohexyl)carbamate (100 mg, 0.5 mmol), 4-pyridinol (106 mg, 1.11 mmol), and triphenylphosphine (292 mg, 1.11 mmol) in tetrahydrofuran (2 mL) was added diethyl azodicarboxylate (176 μL, 1.11 mmol) with stirring. The mixture was stirred at r.t. overnight, then quenched with sat'd NH4Cl solution, and extracted with ethyl acetate. The extract was washed with water twice, brine once. Then, the extracdt was dried over Na2SO4. After filtration, the filtrate was concentrated to yield tert-butyl [trans-4-(pyridin-4-yloxy)cyclohexyl]carbamate.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([NH:8][C:9]([O:11]CC2C=CC=CC=2)=O)[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3]1.[N+:24]([C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2C([O:32][C:33](=O)[C:28]=12)=O)([O-:26])=[O:25]>C(O)(=O)C.[Pd]>[N+:24]([C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2[C:28]=1[C:33](=[O:32])[N:8]([CH:7]1[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:11])([O-:26])=[O:25]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC(=O)OC1CC(NC(=O)OCc2ccccc2)C(=O)NC1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)OC1CC(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O

Procedure:
A solution of 2,6-dioxo-3-benzyloxycarbonylamino-5-acetoxypiperidine (9 g, 28.2 mmol) and Pd/C (10%, 0.9 g) in acetic acid (90 mL) is shaken under hydrogen (50–60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with acetic acid. To the filtrate is added 3-nitrophthalic anhydride (5.4 g, 28.2 mmol), this mixture is heated at reflux for 18 hours, and the solvent is then removed in vacuo to give 3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which can be further purified by column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23]Br)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Yield: 121.9 %

Procedure:
1.9 g of 4-hydroxybenzaldehyde, 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide 8.3 g of potassium carbonate and 50 ml of butanone were reacted in an analogous manner to Example 1 to give 6.0 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde.
Reaction SMILES: [Cl:1]OC(C)(C)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=1>CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]([NH:17][Cl:1])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OCl
Reactant: NC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CO
Product: O=C(NCl)N(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
t-Butyl hypochlorite (7.5 g, 0.070 mole) was added to 1,1-di(p-fluorophenyl)urea (17.5 g, 0.071 mole) in 440 ml methanol at 0°-5° and the mixture stirred for 1 hour at that temperature to produce a solution containing step (a) title product.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([N:27]6[CH2:32][CH2:31][O:30][CH2:29][CH2:28]6)=[CH:41][CH:40]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, light yellow solid (97 mg, 75%), MS (ISP) m/z=518.4 [(M+H)+], mp 247° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-(morpholine-4-yl)-benzoic acid.
Reaction SMILES: [CH:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:13][CH2:14][C:15](=[O:19])[NH:16][C:17]=2[N:18]=1)=CC1C=CC=CC=1.[O:20]=[O+][O-].S(C)C>C(Cl)Cl>[O:19]=[C:15]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([CH:1]=[O:20])=[N:18][C:17]=2[NH:16]1
Reactant: O=[O+][O-]
Reactant: O=C1COc2ccc(C=Cc3ccccc3)nc2N1
Solvent: ClCCl
Solvent: CSC
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Reaction time: 24 h

Procedure:
To a solution of 6-styryl-4H-pyrido[3,2-b][1,4]oxazin-3-one (757 mg, 3.00 mmol) in CH2Cl2 (128 mL) was bubbled ozone at −78° C. with stirring until a pale blue color appeared. The excess ozone was removed by bubbling oxygen through the reaction mixture for 15 min. Me2S (1.0 mL, 14 mmol) was added, and the reaction was stirred at −78° C. for 3 h and then at RT for 24 h. The solvent was concentrated and the residue was triturated with Et2O (100 mL). The solid collected from filtration of the suspension was washed with additional Et2O and dried in vacuo to provide 340 mg (63% crude) of a solid, which was used without further purification. MS (ESI): exact mass calculated for C8H6N2O3, 178.04; m/z found, 179.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH:3]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[K+]>CN(C)C=O>[CH2:21]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CCCc1cccc(O)c1)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-hydroxy-3-(3-benzyloxycarbonylpropyl)benzene (2.0 g), benzylbromide (1.14 ml), potassium bicabonate (1.53 g) and dimethylformamide (20 ml) was stirred for 3 h at room temperature. The mixture was quenched by addition of water and extracted with a mixture of n-hexane:ethyl acetate (3:1). The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give the title compound (2.55 g) having the following physical data.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]O.Cl>ClCCl>[S:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][O:2][CH:1]1[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: OCc1ccccc1S
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: ClCCl
Product: N#Cc1ccc(C2OCc3ccccc3S2)cc1

Procedure:
Following the same procedure as outlined in Example 1 step b), 4-formylbenzonitrile (0.78 g, 5.95 mmol) and (2-mercaptophenyl)methanol (1 g, 7.14 mmol) in dichloromethane (30 ml) were treated with hydrogen chloride gas. After workup and chromatography, as in example 1 step b), the subtitle compound was obtained (1.12 g, 75%) as a white solid. 1H NMR (300 MHz, CDCl3, ppm) δ 5.10 (s, 2H); 6.15 (s, 1H); 7.04-7.21 (m, 4H); 7.59-7.68 (m, 4H); 13C NMR (75 MHz, CDCl3, ppm) δ 70.2; 81.7; 112.8; 118.6; 125.6; 126.1; 127.1; 127.6; 127.7; 129.9; 132.0; 132.6; 143.4; MS calculated for C15H11NOS+H 254 observed 254.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][C:52]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:60]=1
Reactant: COc1ccc(-c2cccc(N)c2)c(OC)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c(OC)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,4′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.019 g of product in 70% yield: LCMS (ESI) m/z 418 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.Cl.O[N:31]=[C:32]([NH2:35])[CH2:33][CH3:34]>>[CH2:33]([C:32]1[N:35]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:4]3[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]3)=[O:9])[CH2:11]2)[O:27][N:31]=1)[CH3:34]
Reactant: CCC(N)=NO
Reactant: O=C1CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCN1
Agent: Cl
Product: CCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCNC(=O)C3)C2)n1

Procedure:
250 mg (0.626 mmol) of 1-[(3-oxopiperazin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]-piperidine-3-carboxylic acid (Example 206A) and 85.8 mg (0.689 mmol) of N′-hydroxy-propanimidamide hydrochloride were reacted according to the General Method 1. Yield: 127 mg (44% of theory).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH3:28])([CH3:27])[C:23]([NH:25][CH3:26])=[O:24]>>[CH3:27][C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23](=[O:24])[NH:25][CH3:26])[CH3:28]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNC(=O)C(C)(C)N
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (EI): m/e=383.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:27])=[C:6]([CH3:26])[C:7]([CH3:25])=[N:8]2.[H-].[Na+].[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1.O>CN(C)C=O>[CH:32]1([C:35]([O:27][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:12]([O:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[C:3]=3[C:2]([F:28])([F:1])[F:29])[N:8]=[C:7]([CH3:25])[C:6]=2[CH3:26])=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
5-Trifluoromethyl-6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline (30 mg) prepared in Synthesis Example 3 was dissolved in 1 mL of dimethylformamide. Under ice cooling, 4.3 mg of 60% sodium hydride was added to the solution, and the mixture was stirred for one hr. Thereafter, 10.4 mg of cyclopropanecarbonyl chloride was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was added to 5 mL of water, and the mixture was extracted with 5 mL of ethyl acetate. The ethyl acetate layer was washed with a saturated sodium hydrogencarbonate solution and saturated brine, was dried over anhydrous sodium sulfate, and was then concentrated under the reduced pressure. The crude product thus obtained was purified by chromatography on silica gel (Mega Bond Elut SI (Varian) 10 mL, solvent: n-hexane/ethyl acetate) to give 4-Cyclopropanecarbonyloxy-2,3-dimethyl-6-(4-trifluoromethoxyphenoxy)-5-trifluoromethyl-quinoline (13.8 mg, yield 39.5%).
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[N+:5]([C:8]1[CH:9]=[C:10](/[CH:14]=[N:15]/[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]>C(#N)C.B(F)(F)F.CCOCC>[CH3:1][C:2]1([CH3:4])[C:17]2[C:16](=[CH:23][CH:22]=[C:19]([C:20]#[N:21])[CH:18]=2)[NH:15][CH:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C#N)cc21
Temperature: 30 °C
Reaction time: 10 h
Yield: 27.7 %

Procedure:
To a small reactor, isobutene (100 mL, 1.19 mol) was added to a mixture of boron trifluoride etherate (12 mL, 0.96 mmol) and 4-{[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amino}-benzonitrile (30 g, 0.12 mol) in dry acetonitrile (300 mL), sealed. The resultant mixture was allowed to stir at 30° C. for 10 h. The reaction mixture was washed by brine and dried over anhydrous sodium sulfate. It was filtered and concentrated to provide the crude product (30 g). The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford 4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile as yellow solid (10.2 g, yield: 27.8%).
Reaction SMILES: [CH2:1]([C@@H:8]([C@@H:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O>C(Cl)Cl>[CH2:1]([C@@H:8]([C@@H:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH3:12])[CH:9]=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CO[C@@H](C)[C@@H](CO)Cc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C)[C@@H](C=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of (2R,3S)-2-benzyl-3((4-methoxybenzyl)oxy)butan-1-ol (5.38 g, 17.91 mmol) in CH2Cl2 (90 mL) in a nitrogen flushed 250 mL round bottomed flask was added DMSO (17.9 mL, 25.24 mmol) and TEA (12.5 mL, 90 mmol) via syringe followed by sulfur trioxode-pyridine complex (8.55 g, 53.7 mmol) in three equal portions at 0° C. under N2. The reaction was removed from the cold bath and allowed to warm to room temperature, and stirred for 2 h. The reaction was diluted with ice cold 0.5 N HCl (100 mL) and EtOAc (150 mL). The phases were separated and the organic phase was washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL). The solution was dried over magnesium sulfate (MgSO4), filtered, and concentrated to afford the title compound (5.3 g, 96%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 9.78 (d, J=2.8 Hz, 1H), 7.29-7.09 (m, 7H), 6.89 (d, J=8.7 Hz, 2H), 4.56 (d, J=11.3 Hz, 1H), 4.34 (d, J=11.3 Hz, 1H), 3.82 (s, 3H), 3.03 (dd, J=14.0, 8.2 Hz, 1H), 2.87 (dd, J=14.0, 6.4 Hz, 2H), 2.78-2.55 (m, 1H), 1.29 (d, J=6.4 Hz, 3H); ESIMS m/z 321.3 ([M+Na]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([F:20])[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:16]2[CH:15]=[C:14]([F:13])[CH:19]=[C:18]([F:20])[CH:17]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1cc(F)cc(F)c1
Product: COC(=O)c1cc(Cl)ccc1Oc1cc(F)cc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3,5-difluorophenol: 1H-NMR (CDCl3) δ 8.00–7.90 (1H, m), 7.55–7.47 (1H, m), 7.08–7.00 (1H, m), 6.60–6.35 (3H, m), 3.81 (3H, s).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:39]=[CH:38][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)[N:10]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:25]1([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:5]=[C:4]([CH:42]=[CH:41][CH:40]=4)[C:1]([NH2:2])=[O:3])[C:14]([C:15]([F:17])([F:16])[F:18])=[CH:13][N:12]=3)=[CH:39][CH:38]=2)[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc(CCc2nc(Nc3ccc(CN4CCNCC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
tert-Butyl 4-(4-((4-(3-carbamoylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I146) (65 mg, 0.11 mmol) was dissolved in DCM (10 mL) then TFA (1 mL) was added and the resulting mixture stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure and the residue partitioned between 10% sodium hydroxide (25 mL) and ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL) then the combined ethyl acetate phases washed with brine, dried over sodium sulfate and evaporated. The residue was washed with toluene (2×2 mL) and DCM (2×0.5 mL) to give the title compound (37) (22 mg, 40% yield) as a white solid; 1H NMR (400 MHz, de-DMSO) δ 10.19 (s, 1H), 8.66 (s, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.74-7.64 (m, 3H), 7.40-7.35 (m, 2H), 7.35-7.29 (m, 1H), 7.23 (d, J=8.2 Hz, 2H), 3.38 (s, 2H), 3.17-3.02 (m, 4H), 2.75-2.61 (m, 4H), 2.29 (s, 4H). LCMS Method C: rt 4.52 min; m/z 485.1 [M+H]+; m/z 483.1 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)/[C:5](/[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:6]/[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)/[C:5](/[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:30])=[N:6]/[O:7][C:8]([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)O/N=C(/c1cccc(Br)c1)c1ncccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)O/N=C(/c1cccc(Br)c1)c1c(O)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of (Z)-2-(3-bromo-α-t-butoxyiminobenzyl)-3-hydroxypyridine (0.49 g), 70% m-chloroperbenzoic acid (0.70 g) and tetrahydrofuran (30 mL) was stirred overnight at room temperature. To the reaction mixture was added an aqueous solution of sodium sulfite. The reaction mixture was stirred for 30 minutes, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was crystallized from isopropyl ether, and recrystallized from ethanol-water to afford (Z)-2-(3-bromo-α-t-butoxyiminobenzyl)-3-hydroxypyridine 1-oxide (0.41 g) (compound 3). In substantially the same manner as above, compounds 4, 7, 8, 11, 12 and 15 were produced.
Reaction SMILES: CC1C=[C:5](C)[N:4]([C:8](=[O:22])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N=1.[CH2:23]([C:25]1[O:29]C(N)=[N:27][N:26]=1)[CH3:24]>>[CH2:23]([C:25]1[O:29][C:5]([NH:4][C:8](=[O:22])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:27][N:26]=1)[CH3:24]
Reactant: CCc1nnc(N)o1
Reactant: Cc1cc(C)n(C(=O)C(c2ccccc2)c2ccccc2)n1
Product: CCc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 123-125° C. and MS: m/e=308.2 (M+H+) was prepared in accordance with the general method of example 48a from 1-(3,5-dimethyl-pyrazol-1-yl)-2,2-diphenyl-ethanone and 5-ethyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1.Cl>C(O)C>[CH3:13][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=[C:2]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=2[CH3:30])[N:11]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1ccc2nc(Cl)nc(N(C)c3ccccc3)c2c1
Agent: Cl
Solvent: CCO
Product: COc1ccc2nc(Nc3ccc(F)cc3C)nc(N(C)c3ccccc3)c2c1
Yield: 54.3 %

Procedure:
2-Chloro-4-(N-methylphenylamino)-6-methoxyquinazoline (5.4 g, 0.02M) and 4-fluoro-2-methylaniline (4.96 g, 0.04M) were dissolved in ethanol (50 ml) and heated at 140° for 5 hours in a Berghof pressure reactor. The mixture was cooled and ethereal/HCl added. The precipitated solid was filtered off and recrystallised (isopropanol/ether followed by isopropanol) to yield the title compound (3.8 g) m.p. 248°-250°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[C:19]3[C:18]([C:20]([O:22]C)=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:25][NH2:26]>CO.Cl>[CH2:8]([C:9]1[C:11]2=[CH:12][NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]=32)[C:20](=[O:22])[NH:26][N:25]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]cc(C(=O)CCc3ccccc3)c12
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NN=C(CCc2ccccc2)c2c[nH]c3cccc1c23

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (3 mL) was treated with 3-phenylpropionyl chloride (361 mg, 2.14 mmol) at room temperature. The orange solution was cooled to 0° C. and treated with aluminum chloride (572 mg, 4.29 mmol). The reaction mixture was stirred at room temperature for 2 h, then poured into ice-cold 1M aqueous HCl. The aqueous solution was adjusted to pH=8 with 1M NaOH, and extracted with CH2Cl2 (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-(3-phenylpropionyl)-indole-4-carboxylate as a pale-yellow solid, 395 mg (90%). A solution of the 3-(3-phenylpropionyl)-4-carboxy indole (95.5 mg, 0.31 mmol) in MeOH (3 mL) and HCl (0.1 mL) was treated with hydrazine hydrate (47 mg, 0.93 mmol) and the solution was heated at reflux for 8 h. The solution was cooled in an ice/water bath and the precipitated solid was collected by filtration to give 1,5-dihydro-3-phenethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one, 60.2 mg (71%). The crude product was purified by radial chromatography (2 mm SiO2, 5:1 hexanes: EtOAc) to give a yellow solid. mp 182-183.5° C.; 1H NMR (300 MHz, d6-DMSO) δ2.80 (m, 2H), 2.84 (m, 2H), 7.22 (m, 2H), 7.31 (m, 4H), 7.54 (m, 2H), 7.81 (s, 1H), 10.19 (s, 1H), 11.92 (br s, 1H); Anal. (C10H7N3O.0.1 H2O) C, H N.