Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2.[H-].[Na+].C1(C)C=CC(S(O[CH2:27][CH2:28][O:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([O:36][CH2:37][C:38]3[N:39]=[C:40]([C:44]4[CH:45]=[C:46]([CH3:50])[CH:47]=[CH:48][CH:49]=4)[O:41][C:42]=3[CH3:43])[CH2:31]2)(=O)=O)=CC=1.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:27][CH2:28][O:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][C@H:32]([O:36][CH2:37][C:38]3[N:39]=[C:40]([C:44]4[CH:45]=[C:46]([CH3:50])[CH:47]=[CH:48][CH:49]=4)[O:41][C:42]=3[CH3:43])[CH2:31]1)[C:6]([C:12]([OH:14])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(F)cc(F)c2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCn4c(C(=O)O)cc5cc(F)cc(F)c54)C3)c(C)o2)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
79 mg of 5,7-difluoroindolecarboxylic acid are dissolved in 2 ml of dried DMF, and 34 mg of 60 percent strength sodium hydride suspension are added. After 30 min at room temperature, 100 mg of ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy)ethyl toluene-4-sulfonate, dissolved in 2 ml of DMF, are added. The mixture is stirred at 65° C. until the reaction has gone to completion (monitored by LC-MS). 50 μl of TFA are added, the mixture is filtered and the residue is purified by RP-HPLC. This gives 40 mg of (1R,3S)-5,7-difluoro-1-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}-1H-indole-2-carboxylic acid as a colorless oil. C29H30F2N2O5 (524.56), MS (ESI): 525 (M+H+).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:32]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)(=[O:34])=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (25.7 mg, 66.8%), MS (ISP) m/z=471.3 [(M+H)+], was prepared in accordance with the general method of example 69 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and benzenesulfonyl chloride.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:20](=[O:21])/[CH:19]=[CH:18]/[C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1cccnc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-pyridyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 258 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([SH:7])([CH3:6])[CH3:5].C([O:10][C:11](=[O:35])[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=2[CH2:26][N:27]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH3:29])[CH:18]=1)C>CN(C=O)C.O.N#N>[C:4]([S:7][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]([CH2:12][C:11]([OH:35])=[O:10])[CH:14]=[N:15][CH:16]=2)=[C:20]([CH2:26][N:27]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH3:29])[CH:21]=1)([CH3:6])([CH3:5])[CH3:3]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Reactant: CC(C)(C)S
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(SC(C)(C)C)ccc1-c1cncc(CC(=O)O)c1)C(=O)C1CC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in mineral oil; 0.042 g, 1.04 mmol) was suspended in DMF (5 mL). After stirring for 10 minutes, 2-methyl-2-propanethiol (0.13 mL, 1.15 mmol) was added, and the mixture was stirred for 30 minutes. (5-{2-[(N-Cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-fluoro-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.20 g, 0.52 mmol) was added, and the reaction was stirred at 90° C. overnight. The mixture was diluted with H2O, and N2 was bubbled through the solution into a bleach trap until all odor was removed. The aqueous layer was washed with EtOAc, and then acidified to pH 4 and extracted with EtOAc. The combined organic layers were concentrated, and the residue was purified by preparative HPLC to give Compound 22.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C(Cl)Cl>[CH3:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: COC(OC)OC
Reactant: Cc1ccc(N)c(C(=O)NC2CCC(=O)NC2=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2ncn(C3CCC(=O)NC3=O)c(=O)c2c1
Yield: 9 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-methyl-benzamide (0.45 g, 1.7 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (80 mg) was heated to 160° C. in a microwave oven for 8 minutes. To the suspension, was added methanol (20 mL), methylene chloride (20 mL), and Celite (5 mL). The solvent was removed in vacuo. The reside was placed in a SIM and was purified with column chromatography (Silca Gel, methanol/methylene chloride 0% gradient 10% in 15 min) to give as 3-(6-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a blue solid (50 mg, 9% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.78 min (96.1%); mp: 285-287° C.; 1H NMR (DMSO-d6) δ 2.11-2.18 (m, 1H, CHH), 2.46 (s, 3H, CH), 2.56-2.74 (m, 2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.48 (br, 1H, NCH), 7.61 (d, J=8 Hz, 1H, Ar), 7.70 (dd, J=2, 8 Hz 1H, Ar), 7.94 (br, 1H, Ar), 8.33 (s, 1H, CH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.72, 22.51, 30.91, 57.00 (br), 121.09, 125.38, 127.00, 135.89, 137.07, 145.46, 146.45, 159.60, 169.88, 172.44; LCMS: MH=272; Anal Calcd for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.78; H, 4.57; N, 15.34.
Reaction SMILES: Cl[C:2]1(Cl)[C:9](=[O:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([O:18][CH3:19])[CH2:16][CH3:17].ClC1(Cl)C(O)CC2C1CCC2CCCCC(OC)CC>C(O)(=O)C.[Zn]>[CH3:19][O:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][CH:9]([OH:10])[CH2:2]2
Reactant: CCC(CCCCC1CCC2C1CC(=O)C2(Cl)Cl)OC
Agent: CCC(CCCCC1CCC2C1CC(O)C2(Cl)Cl)OC
Agent: [Zn]
Solvent: CC(=O)O
Product: CCC(CCCCC1CCC2CC(O)CC12)OC

Procedure:
The reactions of this example can also be conducted using an equivalent amount of 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one {1,1-dichlorohexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} to first prepare 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-ol {1,1-dichlorooctahydro-4-(5-methoxyheptyl)-2-pentalenol} which is then treated by the zinc in glacial acetic acid to produce 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]-octan-7-ol {octahydro-4-(5-methoxyheptyl)-2-pentalenol}.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].O=[C:16]([CH2:22][CH3:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:22]([C:16]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)=[CH:2][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH3:23]
Reactant: O=C(CCl)c1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)OC
Reaction time: 2 h
Yield: 28.4 %

Procedure:
To a solution of 2-chloro-4′-(trifluoromethyl)acetophenone (50.9 g) and methyl 3-oxopentanoate (25 g) in toluene (500 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (28.7 mL) under ice-cooling over 30 min or longer. After the completion of the dropwise addition, and the mixture was stirred under ice-cooling for 30 min, and at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solution was concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (7.2 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 10% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (16.3 g, 29%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]([N:18]([C:20]2[C:21]([Cl:40])=[C:22]([C:36]([Cl:39])=[CH:37][CH:38]=2)[CH2:23][O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([CH3:35])[CH:31]=[CH:30]3)[CH3:19])=[O:17])=[O:13])=[CH:6][CH:5]=1)([OH:3])=O.[NH2:41][C:42]1[CH:47]=[N:46][CH:45]=[CH:44][N:43]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:40][C:21]1[C:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]2[CH:8]=[N:9][C:4]([C:1](=[O:3])[NH:41][C:42]3[CH:47]=[N:46][CH:45]=[CH:44][N:43]=3)=[CH:5][CH:6]=2)=[CH:38][CH:37]=[C:36]([Cl:39])[C:22]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[C:32]([CH3:35])[CH:31]=[CH:30]2
Reactant: Nc1cnccn1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)Nc5cnccn5)nc4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 18.5 %

Procedure:
To a mixture of 8-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)-acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), 2-aminopyrazine (19.7 mg) and N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (43 mg) and 1-hydroxybenzotriazole (35 mg), and the mixture was stirred for 36 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(2-pyrazinylcarbamoyl)-pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methylquinoline (21 mg) as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:27]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:27])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc(Cl)c1COc1cccnc1NC(=S)Nc1ccccc1
Reactant: N
Product: N=C(Nc1ccccc1)Nc1ncccc1OCc1c(F)cccc1Cl
Reaction time: 72 h

Procedure:
A mixture of N-[3-(2-fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (2 g, 0.0052 mol), yellow mercuric oxide (1.34g, 0.0062 mol) and methanolic ammonia solution (40 ml) was stirred for 72 hours. The solvent was removed in vacuo and the black residue was treated with chloroform and filtered through celite. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 1.07 g (56%), m.p. 147°-149 ° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([F:34])=[C:26]([CH2:35][C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)[CH:25]=1)(=O)C.[C:42]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)#[N:43]>>[C@@H:6]1([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([F:34])=[C:26]([CH2:35][C:36]3[S:37][C:38]([C:48]4[CH:47]=[CH:46][CH:45]=[C:44]([C:42]#[N:43])[CH:49]=4)=[CH:39][CH:40]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(Br)s3)c(F)c3ccccc23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: N#Cc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c4ccccc4c3F)s2)c1

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluoronaphthalene and 3-cyanophenylboronic acid were treated in a manner similar to Example 168 to give 1-(β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-fluoronaphthalene. APCI-Mass m/Z 523 (M+NH4).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:18])[CH:2]=1.[H-].[Na+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:3]1[CH:4]=[CH:5][C:6]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:1][CH:2]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccc(-c2ccccc2)cc1
Yield: 125 %

Procedure:
Using the procedure described in Example 1, Part E, 1-([1,1'-biphenyl]-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole (970 mg, 3.1 mmol) was treated with 124 mg (3.1 mmol) of 60% NaH/mineral oil and then 0.29 mL (3.1 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 747 mg (63% yield) of [[1-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 164°-167° C.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17]>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:2][NH2:3])=[O:17]
Reactant: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Temperature: 60 °C
Yield: 92 %

Procedure:
Hydrazine hydrate (2 ml) is added dropwise to a suspension of methyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate (227.1 mg, 0.73 mmol) in 10 ml of methanol. The reaction mixture is heated at 60° C. for seven hours under an atmosphere of nitrogen and then allowed to cool to room temperature overnight. The now clear colorless solution is concentrated in vacuo and chromatographed, eluting with ethyl acetate and hexane (gradient of 1:2 to 1:1), providing 208.6 mg (92%) of a white solid, mp 158°-160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=2[F:38])=[CH:26][CH:27]=1.O>CN(C)C=O>[F:38][C:29]1[CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=[CH:33][C:28]=1[C:25]1[N:24]=[C:23]([CH3:39])[C:22]([CH2:21][O:17][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[N:13]3)=[C:2]([CH3:1])[CH:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3F)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 8.0 ml N,N-dimethylformamide was treated at 0° C. with 26 mg (0.66 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 200 mg (0.66 mmol) 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine were added and stirred continued at r. t. over night. After addition of 16 ml water, the precipitate was isolated, washed thoroughly with water and diisopropylether. The residue was dried at 40° C. to give 250 mg (76%) of the title compound as light brown powder.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1cc2c(s1)CCCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCCCc3sccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.71 g of 5,6,7,8-tetra-hydro-4H-thieno[3,2-b]azepine and 19.4 ml of triethylamine in 150 ml of dichloromethane under argon is added in small portions 4-nitrobenzoyl chloride (exothermic). The mixture is stirred for 3 hours at 25° C. and then washed with water, sodium bicarbonate solution, brine and dried (Na2SO4). The solvent is removed, the residue dried under vacuum and recrystallized by dissolving in hot ethyl acetate and diluting with hexane. Chilling overnight and filtering gives 16 g of light brown crystals, m.p. 141°-142° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([NH2:11])=[S:10])=[CH:3][CH:2]=1.[C:12]([CH2:14][C:15](OCC)=[O:16])#[N:13]>C(O)(=O)C>[NH2:13][C:12]1[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:9](=[S:10])[NH:11][C:15](=[O:16])[CH:14]=1
Reactant: NC(=S)NCc1ccncc1
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Product: Nc1cc(=O)[nH]c(=S)n1Cc1ccncc1

Procedure:
The title compound was prepared in accordance with the general method described in Example 11(b), using N-(pyridin-4-ylmethyl)thiourea (1.0 g, 5.98 mmol) and ethyl cyanoacetate (0.64 mL, 5.98), with the exception that a 4 h reaction time was used, and the solution was neutralized with acetic acid. The crude title compound was obtained (1.07 g, 76%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28](/[C:42](/[NH:45]O)=[N:43]/[H])[CH:29]=[C:30]2[C:34]=1[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:43]=[C:42]([C:28]3[CH:29]=[C:30]4[C:34](=[C:26]([F:25])[CH:27]=3)[NH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31]4)[N:45]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (368 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (654 mg) and HOBT (522 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (500 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (1.78 g) was added. The reaction mixture was sealed and heated in Biotage Initiator using initial high to 120° C. for 0.5 h. After cooling the reaction, the solvent was removed. The residue was diluted with EtOAc (30 mL), and the organic phase was washed with water (25 mL×4), dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D166) (600 mg) as a yellow solid. MS (ES): C23H22ClFN4O4 requires 472; found 473.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](Cl)=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=C([C@@H](CC2CCCC2)[C:49]([NH:51][C:52]2C=CN(CC3C=C(C=CC=3)C(N)=O)N=2)=O)C=CC=1S(C)(=O)=O.CNC.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([N:51]([CH3:52])[CH3:49])=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)Cl)c3)n2)cc1Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(N)=O)c3)n2)cc1Cl
Agent: CNC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a 0.166 M solution of crude 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoyl chloride in methylene chloride (prepared in Example 63, 1.71 mL, 0.28 mmol) was added a 40% solution of dimethylamine in water (250 μL, 0.22 mmol) and the reaction stirred at 25° C. for 30 min. The solution was diluted with methylene chloride (40 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to an off white foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N,N-dimethyl-benzamide (72 mg, 46%) as a white powder: ESI-LRMS m/e calcd for C28H33ClN4O4S [M+] 556.19, found 557.27 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.19 (m, 2H, CH2), 1.36-1.78 (m, 8H, 4×CH2), 2.02-2.17 (m, 1H, CH), 2.84 (s, 3H, NCH3), 2.94 (s, 3H, NCH3), 3.32 (s, 3H, SO2CH3), 3.82-3.91 (m, 1H, CH), 5.21 (s, 2H, NCH2), 6.45 (d, J=2.3 Hz, 1H, Ar), 7.17-7.32 (m, 3H, Ar), 7.33-7.40 (m, 1H, Ar), 7.55 (dd, Jo=8.3, Jm=1.7 Hz, 1H, Ar), 7.65 (d, Jm=1.7 Hz, 1H, Ar), 7.73 (d, J=2.3 Hz, 1H, Ar), 7.97 (d, Jo=8.3 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:14])=[N+:5]([O-:13])[C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:2][C:3]1[C:4]([CH3:14])=[N+:5]([O-:13])[C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1
Reactant: Cc1c(CO)ccc(C(F)(F)F)[n+]1[O-]
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(CBr)ccc(C(F)(F)F)[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a stirring solution of 3-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide (207 mg, 1.0 mmol) and carbon tetrabromide (400 mg, 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added Ph3P (393 mg, 1.5 mmol) in small portions over 5 min. The reaction mixture was then stirred at 0° C. for 30 min. Analysis by HPLC/MS indicated the reaction was complete. The reaction mixture was directly loaded onto a silica gel cartridge (40 g) and eluted with a gradient of EtOAc (0-100%) in hexanes to afford 202 mg (75%) of the title compound as a white solid. HPLC/MS: retention time=2.10 min, [M+H]+=269.9.