Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 61.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (22 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (14 mg) was obtained.
Reaction SMILES: [C:1]([C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])#[CH:2].Br[C:12]1[CH:13]=[C:14]([S:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:16][CH:17]=1>>[F:26][C:23]([F:24])([F:25])[C:22]([NH:21][CH2:20][CH2:19][S:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:2]#[C:1][C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])[CH:13]=1)=[O:27]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCSc1cccc(Br)c1)C(F)(F)F
Product: CCCC(O)(C#Cc1cccc(SCCNC(=O)C(F)(F)F)c1)CCC

Procedure:
Sonogashira coupling of alkynol 20 with N-(2-(3-bromophenylthio)ethyl)-2,2,2-trifluoroacetamide (128) according to the method used in Example 1 followed by flash chromatography (5-50% ethyl acetate/hexanes gradient) gave 2,2,2-trifluoro-N-(2-(3-(3-hydroxy-3-propylhex-1-ynyl)phenylthio)ethyl)acetamide (129) as an orange. Yield (0.22 g, 52%): 1H NMR (400 MHz, DMSO) δ 9.52-9.60 (m, 1H), 7.26-7.36 (m, 3H), 7.16-7.20 (m, 1H), 5.11 (s, 1H), 3.60 (ddd, J=6.4 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 1.52-1.62 (m, 4H), 1.38-1.52 (m, 4H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([OH:9])[CH:3]=1.[Se](=O)=[O:11]>COCCOCCOC>[CH:1]([C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([OH:9])[CH:3]=1)=[O:11]
Reactant: O=[Se]=O
Reactant: Cc1cc(O)cc(=O)o1
Solvent: COCCOCCOC
Product: O=Cc1cc(O)cc(=O)o1

Procedure:
6-Methyl-4-hydroxypyran-2-one may be oxidised with selenium dioxide in boiling diglyme to give 6-formyl-4-hydroxypyran-2-one;
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O:12][C:13]([CH2:15][N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH:17]([CH2:22]O)[C:18]([O:20][CH3:21])=[O:19])=O)C>>[N+:33]([C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:16]2[CH2:15][C:13](=[O:12])[N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:22][CH:17]2[C:18]([O:20][CH3:21])=[O:19])(=[O:26])=[O:25])=[CH:28][CH:29]=1)([O-:35])=[O:34]
Reactant: CCCCCCCCN
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1=O
Yield: 88 %

Procedure:
A title compound was prepared by the same method as in Example 31, except that octylamine as the primary amine and the compound of Example 55 were used to obtain a white solid title compound (yield 88%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC1CCC(NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.1 %

Procedure:
1,4-Diaminocyclohexane (cis, trans mixture) (24.0 g, 210 mmol) and triethylamine (16.3 ml, 117 mmol) were dissolved in methylene chloride (400 ml). A solution of triphenylmethyl chloride (32.5 g, 117 mmol) dissolved in methylene chloride (100 ml) was dropwise added under ice-cooling and the mixture was stirred for 15 minutes and at room temperature for 45 minutes. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure. Water (100 ml) was added to the residue and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform/n-hexane=5/1-10/1) to give 18.4 g of 1-amino-4-(triphenylmethylamino)cyclohexane as a pale-yellow oil (25%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][OH:10].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:8][C:4]1[C:3]2[CH2:9][O:10][C:12](=[O:14])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)c1CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Br)c2CO1
Temperature: 25 °C
Yield: 268.6 %

Procedure:
A solution of (2-Amino-6-bromo-phenyl)-methanol (549 mg, 2.72 mmol) and triphosgen (282 mg, 0.95 mmol) in THF (20 ml) was heated at 50° C. for an hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed by water and brine. After drying over MgSO4, the solution was concentrated under vacuum to give 5-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one (582 mg, 94%) as a white solid. MS: 226.1 (M−H)−.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][NH2:11])[CH2:3][C@@H:4]([C:6](N)=[O:7])[NH2:5].FC(CCN)C[C@@H](C(N)=[O:18])N>Cl>[OH:1][CH:2]([CH2:9][CH2:10][NH2:11])[CH2:3][C@@H:4]([C:6]([OH:18])=[O:7])[NH2:5]
Reactant: NCCC(F)C[C@H](N)C(N)=O
Reactant: NCCC(O)C[C@H](N)C(N)=O
Agent: Cl
Product: NCCC(O)C[C@H](N)C(=O)O
Yield: 52 %

Procedure:
N,N'-Dicarbobenzyloxy-γ-hydroxy-L-lysine amide (2.0 g, 4.65 mmol) (described by Izumiya et al., Biochem, 4, 2501 (1965)) was placed in a Kel-F® reactor and anhydrous hydrogen fluoride (40 ml) was condensed at -78° C. Sulfur tetrafluoride (1.8 ml, 31 mmol) was condensed at -78° C. in a graduated tube attached to the reaction vessel. The cooling bath was removed and sulfur tetrafluoride was transferred into the reaction solution (cooled at -78° C.) by evaporation. The mixture was stirred at -78° C. for 5 hours and allowed to stand overnight. Hydrogen fluoride was removed by a stream of nitrogen and the residue dissolved in 30 ml of 2.5 N HCl. Insoluble material was filtered and the filtrate evaporated to dryness in vacuo to yield 1.01 g of crude 4-fluoro-L-lysine amide contaminated with unreacted 4-hydroxy-L-lysine amide. The crude amide (1.4 g) was hydrolyzed in 90 ml 2.5 N HCl by refluxing for 1.5 hours, the reaction solution was evaporated to dryness and separated by ion exchange chromatography (Dowex 50-X8 resin, 120 ml, H+ form, washed first with 500 ml water and eluted with 2.5 N HCl). The 4-hydroxy-L-lysine in strong acid formed the lactone which, being a strong base, was not eluted from the resin with 2.5 N HCl. 4-Fluoro-L-lysine.2HCl was obtained in 52% yield and >90% purity, [α]D25 +16.8° (3% in 2.5 N HCl. The monohydrochloride was obtained in 76% yield by dissolving the dihydrochloride in 15 volumes methanol and adding 50% molar excess pyridine. This material was recrystallized from isopropanol/water (2:1) to give a product with a rotation of [α]D25 +25° (2% in 2.5 N HCl) mp: 210° (discoloration), 215°-17° (d).
Reaction SMILES: [C:1]1(=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CC(C)=O>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 32.6 %

Procedure:
The O-alkylation procedure described for 190 was used. A round-bottom flask was charged with 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (0.882 g, 3 mmol), K2CO3 (0.518 g, 3.75 mmol) and acetone (100 mL). To the above mixture ethyl 4-bromobutanoate (0.644 mL, 4.5 mmol) was added at room RT and the mixture was refluxed for 24 h. Regular work-up and purification by column chromatography afforded 0.400 g (33%) of the title compound 217 as a white solid and 0.560 g (36%) of dialkylated product. 0.125 g unreacted of SM was also recovered. 1H NMR (300 MHz, CDCl3): δ 7.06 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 5.40 (s, 1H), 4.17 (q, J=14.1 Hz, 6.9 Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.34 (br s, 4H), 2.12 (quintet, J=13.2 Hz, J2=6.9 Hz, 2H), 1.59 (s, 8H), 1.28 (t, J=7.2 Hz, 3H). LCMS (ESI): m/z 407 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C#Cc1cccc(OC)c1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2cccc(OC)c2)n1C

Procedure:
The title compound, MS: m/e=299.3 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-ethynyl-3-methoxy-benzene.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: ClCc1ccc(Cl)cc1Cl
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(Cl)cc4Cl)CC3)cccc2n1
Yield: 60 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2,4-Dichlorobenzyl Chloride (72.3 mg; 0.37 mmol) to obtain 48.3 mg. (60% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.49 (s, 1H), 7.60 (m, 3H), 7.44 (m, 1H), 7.16 (m, 2H), 3.66 (s, 2H), 3.02 (br d, J=10.8 Hz, 3H), 2.90 (m, 4H), 2.41 (m, 2H). ESIMS+403.5 m/z
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CC#N>[CH3:20][S:21]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)(=[O:23])=[O:22]
Reactant: Oc1ccc(-c2cccs2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc(-c2cccs2)cc1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a mixture of 4-(2-thienyl)phenol (1.76 g) and triethylamine (1.50 g) in MeCN (10 ml) was added dropwise methanesulfonylchloride (1.26 g) with ice-cooling. The mixture was stirred for 1 hour, then for 1 hour at ambient temperature. The resulting mixture was concentrated and diluted with a mixture of AcOEt and H2O to separate solid. The separated solid was recovered and washed with H2O and AcOEt to give 1.62 g of 2-(4-methanesulfonyloxyphenyl)thiophene.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][C:27](=[O:33])[NH:28]2>>[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1/[C:26](=[CH:21]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=1[CH3:1])/[C:27](=[O:33])[NH:28]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 91.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 4-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 57 (68 mg, yield 91.2%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)C>C(O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:21](=[O:30])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)CCCC(=O)N1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NN=Cc1ccc(C2=NOC3(CCN(C(=O)CCCC(=O)O)CC3)C2)cc1

Procedure:
0.34 g (0.78 mmol) of the ethyl ester from Example 16 were dissolved in 5 ml ethanol, and after addition of 1 ml 2 N aqueous sodium hydroxide solution the mixture was stirred over night. It was brought to pH 5 with diluted acetic acid, stirred for 30 min, and the title acid was filtered with suction, washed with water and ethanol, successively, and dried in vacuo at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:32](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[Si:32]([O:23][CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][CH2:10][C:11]1=[O:26])[CH2:24][CH3:25])([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 2.03 g (5.2 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 121, Step H) and 877 mg (12.9 mmol) of imidazole in DMF (32 mL) was added 1.9 mL (7.3 mmol) of tert-butyldiphenylsilyl chloride. The resulting light yellow solution was stirred at room temperature for 4.5 h. The reaction was partitioned between water and EtOAc (2×), and then the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0 to 4% MeOH/DCM, gradient elution) provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:16])[NH:5][C:6]=1[CH2:7][O:8]CC1C=CC=CC=1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH3:16])[NH:5][C:6]=1[CH2:7][OH:8]
Reactant: Cc1nc(Cl)c(COCc2ccccc2)[nH]1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cl)c(CO)[nH]1
Temperature: 0 °C

Procedure:
A solution of 4-chloro-2-methyl-5-{[(phenylmethyl)oxy]methyl}-1H-imidazole (1.78 g, 7.5 mmol) and methanesulfonic acid (18.5 mL, 285 mmol) in chloroform (39 mL) was stirred at RT for 1 h. The reaction mixture was poured into ice (˜70 g) and the solution was neutralized by addition of 5N NaOH until the pH was 10. The solution was extracted with methyl tert-butyl ether (2×60 mL) and then with n-butanol (3×40 mL). The combined n-butanol extracts were washed with brine, concentrated, and dried in vacuo to provide crude (4-chloro-2-methyl-1H-imidazol-5-yl)methanol as a brown solid. A solution of this solid and manganese dioxide (2.0 g, 23.0 mmol) in CH2Cl2 (12 mL) and 1,4-dioxane (6 mL) was heated under reflux for 6 h. The reaction mixture was cooled to RT, filtered through Celite, which was washed thoroughly with CH2Cl2. The filtrate was concentrated and dried to provide crude 4-chloro-2-methyl-1H-imidazole-5-carbaldehyde as a yellow solid (0.308 g, 28%), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[CH:7].I[C:10]1[C:18]([N+]([O-])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[C:7][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CCNC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (71.3 mg, 0.63 mmol) (see below) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.3 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (11 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 25 mg, 23%).
Reaction SMILES: Cl.NO.C([N:6](CC)CC)C.[CH3:11][O:12][C:13]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:25]([N:27]2[CH2:32][CH2:31][C:30]3([CH2:41][C:40](=[O:42])[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:43]#[N:44])[CH:38]=4)[O:33]3)[CH2:29][CH2:28]2)=[O:26])[CH:14]=1>CCO>[CH3:11][O:12][C:13]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:25]([N:27]2[CH2:32][CH2:31][C:30]3([CH2:41][C:40](=[O:42])[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:43](=[NH:6])[NH2:44])[CH:38]=4)[O:33]3)[CH2:29][CH2:28]2)=[O:26])[CH:14]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C#N)ccc2O3)nc2c(OC)cccc12
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=N)N)ccc2O3)nc2c(OC)cccc12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
26.1 mg of hydroxylamine hydrochloride, 62.7 μl of triethylamine and 2.5 mL of EtOH were added to 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidine]-6-carbonitrile (115 mg) obtained in Example 16, and stirred at 60° C. for 24 hours. The reaction mixture was concentrated, and the residue was purified through silica gel column chromatography (2% MeOH/CHCl3) to obtain 83.4 mg of 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidine]-6-carboximidamide. 49.1 mg of the product was dissolved in 1.0 mL of DMF along with 9.7 μl of pyridine therein, and 21.6 μl of 2-ethylhexyl chloroformate was added thereto at 0° C. The mixture was stirred at 0° C. for 30 minutes, then diluted with ethyl acetate (15 mL), washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was dissolved in xylene, refluxed for 4 hours, and then concentrated, and the residue was purified through silica gel chromatography (developed with 20% MeOH/EtOAc) to obtain the intended compound. 1H-NMR (CDCl3) δ: 8.50 (1H, d, J=2.4 Hz), 8.11 (1H, dd, J=8.8, 2.4 Hz), 7.78 (1H, dd, J=8.3, 1.0 Hz), 7.47 (1H, dd, J=8.3, 7.8 Hz), 7.21 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.07 (1H, dd, J=1.0, 7.8 Hz), 4.61-4.53 (1H, m), 4.20-4.12 (1H, m), 4.10 (3H, s), 4.01 (3H, s), 3.71-3.62 (1H, m), 3.40-3.31 (1H, m), 2.95 (2H, s), 2.26-1.86 (4H, m). MS [M+H]+=517.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:23]1[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:9]([C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:23]2[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)[CH:5]=[C:6]([CH3:12])[CH:7]=1)([O-:11])=[O:10]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cc(C)cc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccc(C(=O)O)s2)cc(C)cc1[N+](=O)[O-]
Yield: 73.2 %

Procedure:
2-(2-Methoxy-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 24a (4.0 g, 14.5 mmol), 5-bromothiophene-2-carboxylic acid (1.0 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.276 g, 0.24 mmol) and sodium carbonate (1.01 g, 9.6 mmol) were dissolved in 30 mL of 1,4-dioxane and 10 mL of water. The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was filtered to remove tetrakis(triphenylphosphine)palladium and the filtrate was extracted with ethyl acetate. The aqueous layer was acidified to form precipitates. The precipitates were dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-nitro-2-methoxy-5-methyl-phenyl)thiophene-2-carboxylic acid 24b (1.03 g, 73.6%) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(Cl)cc3)CC2)cc1
Yield: 93.7 %

Procedure:
The title compound (D120) (45 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (34 mg) and 4-(Chloro)benzylbromide (35 mg). (Na2CO3: 4 eq; reaction time: 18 hrs; 68° C.)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([C:10]1[O:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=1[CH3:17])(=[O:9])[CH3:8]>>[CH2:15]([C:13]1[O:14][C:10]([C:7]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:9])[CH3:8])=[C:11]([CH3:17])[N:12]=1)[CH3:16]
Reactant: CCc1nc(C)c(C(C)=O)o1
Reactant: Brc1ccsc1
Product: CCc1nc(C)c(C(C)(O)c2ccsc2)o1

Procedure:
Starting with 3-bromothiophene and 5-acetyl-2-ethyl-4-methyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 77.5°-79° C.