Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].[C:10]([N:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C(OCC)C>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][N:17]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1cccc(Br)c1F
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Preparation according to Preparation 23: 1-bromo-2,3-difluorobenzene (3.12 g, 16.2 mmol), dry diethyl ether (30 mL), N-butyl lithium (2.5 M, 6.5 mL, 16.2 mmol), 1-N-boc-3-pyrrolidinone (2.0 g, 10.8 mmol). Stirred 2 h at −78° C. before addition, and 1 h at ambient temperature after addition of 1-N-boc-3-pyrrolidinone. Yield: 1.72 g. MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 243 (46), 226 (38), 198 (68), 57 (bp).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2
Reactant: C#CCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 1 supra) using DPPFPdCl2 (12.8 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=O.CO[C:19]1C2C(=CC=CC=2)C(OC)=C[C:20]=1/[CH:31]=[C:32](\C)/[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CCOCC>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1/[CH:15]=[C:32](\[CH2:31][CH2:20][CH3:19])/[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Reactant: COc1cc(C=O)c(OC)c2ccccc12
Solvent: CCOCC
Product: CCC/C(=C\c1cc(OC)c2ccccc2c1OC)C(=O)OCC

Procedure:
Compound 28b was prepared from 27 (0.495 g, 2.29 mmol) as described above for 28a to give 0.443 g (1.35 mmol, 59%) of the product as a white solid following flash chromatography (1:19 Et2O:hexanes) and recrystallization from Et2O/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:25][CH2:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1O2
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C2=Nc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 88.8 %

Procedure:
A mixture of 3.14 g of 2-chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine and 1.20 g of ethyl acrylate in 16 ml of ethanol was refluxed for 2 hrs. The reaction mixture was concentrated and the residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (2:1 and 1:1) as eluents to give 3.68 g of yellow crystals, which were recrystallized from a mixture of isopropyl ether and n-pentane to give yellow prisms, mp 73°-75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[NH:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[F:31][C:32]1[CH:66]=[CH:65][C:35]([C:36](/[N:38]=[C:39]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:37])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:36](/[N:38]=[C:39]2\[NH:1][C:2]3[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][CH2:11][N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[CH:4][C:3]=3[N:18]\2[C@H:19]2[CH2:24][CH2:23][C@@H:22]([C:25](=[O:26])[NH:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:20]2)=[O:37])=[CH:65][CH:66]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCOCC3)c(F)cc2N)CC1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cc(F)c(OCCN4CCOCC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(2-amino-4-fluoro-5-(2-morpholinoethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used to prepare (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. The product was isolated as an off-white solid (161 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=8 Hz, 6H) 1.53-1.66 (m, 2H) 1.70-1.80 (m, 2H) 2.00-2.08 (m, 2H) 2.52-2.60 (m, 1H) 2.70-2.91 (m, 8H) 3.49-3.70 (m, 4H) 3.89-4.08 (m, 1H) 4.27 (t, J=6.06 Hz, 2H) 4.93 (br. s., 1H) 7.24 (dd, J=8.85, 8.85 Hz, 2H) 7.38 (d, J=10.76 Hz, 1H) 7.77 (d, J=7.73 Hz, 2H) 8.29 (dd, J=8.61, 5.97 Hz, 2H) 12.73 (s, 1H). M/Z calc'd for C30H37F2N5O4: 569.64. found 570 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1>C(CN)O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:13][CH2:14][CH2:15][OH:21])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: NCCO
Product: Cc1ccccc1N1CCc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Yield: 180.2 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in ethanolamine(5.0 ml), and reacted at the same condition of Step 6 in the Example 30 to obtain 489 mg of desired compound as solid in 92% of yield.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)=O
Product: CC(C)=NNC(=O)c1ccccc1
Temperature: 5 °C

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 136 g (1.0 mol) of benzohydrazide and 600 ml of acetone and then heated under reflux for 12 hours. The reaction liquid was cooled down to 5° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[C:4]([N+:20]([O-])=O)[CH:3]=1.[O:23]1CCC[CH2:24]1>[Pt].C(O)C>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:24](=[O:23])[NH:20][C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)N1CCC(Nc2ccc(C)cc2[N+](=O)[O-])CC1
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(C)ccc32)CC1
Reaction time: 7 h

Procedure:
A mixture of 8.23 g of ethyl 4-(4-methyl-2-nitroanilino)-1-piperidinecarboxylate, 200 mL of tetrahydrofuran, 225 mL of ethanol and 2 g of 5% platinum on carbon was stirred under an atmosphere of hydrogen for 7 h. The catalyst was filtered off and the filtrate concentrated to to a thick oil. To an ice cold, vigorously stirred solution of the resulting crude ethyl 4-(4-methyl-2-aminoanilino)-1-piperidinecarboxylate in 500 mL of ethyl acetate was added 500 mL of saturated sodium carbonate followed by 20 mL of 1.9 M phosgene in toluene dropwise over 30 min. After stirring overnight at room temperature, the layers were separated and the organic layer dried over MgSO4 and concentrated to dryness. Trituration of the residue with ether-hexane gave 8 g of ethyl 4-(5-methyl-2-oxo-1-benzimidazolinyl)piperidine-1-carboxylate as a white crystalline solid.
Reaction SMILES: [CH2:1]1[CH:4]([C:5]([OH:7])=O)[CH2:3][CH2:2]1.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:5]([CH:4]4[CH2:1][CH2:2][CH2:3]4)=[O:7])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)C1CCC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3CCC3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 4-cyclobutanecarboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (45.6% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.97, 6.97, 3.82-3.64, 3.57-3.49, 3.26, 2.43-2.27, 2.22-2.05 2.02-1.81, 1.50, 0.75, 0.46, 0.08. MS (ES+) m/z 358 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c(OC)cc21
Yield: 44.5 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (37 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (50 mgs) gave the title compound (35 mgs) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): 9.54 (s, 1H), 8.55 (d, J=8.4 Hz, 1H); 8.21 (s, 1H), 8.15 (s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.67-7.60 (m, 2H), 7.32-7.28 (m, 1H); 6.73 (s, 1H); 4.10-3.90 (broad abs., 2H), 3.93 (s, 3H); 3.29-3.25 (m, 1H), 2.70-2.40 (broad abs, 2H), 2.28-2.25 (m, 2H), 2.20-2.00 (broad abs, 2H); 1.33 (d, J=6.8 Hz, 6H), 1.16 (t, 7.1 Hz, 3H); LC/MS: (M+H)+ found 544.14; MP:195-197° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][C:15]1([CH3:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([CH3:25])([CH3:14])[CH2:16][CH2:17]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Reactant: CC1(C)CCNc2ccccc21
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To 5-bromo-4-chloro-2-fluorobenzenesulfonyl chloride (3.15 g, 10.8 mmol) in dry DCM (40 mL), was added 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (1.50 g, 9.3 mmol) and triethylamine (2.15 mL, 15.5 mmol). The mixture was stirred at ambient temperature for 16 hrs. Additional sulfonyl chloride (0.93 g, 3.2 mmole) was added and the mixture was stirred an additional 72 hrs. The mixture was washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution and brine. The organic layer was dried over MgSO4 and the filtrate evaporated. The residue was purified by silica gel chromatography [eluent: 5% ethyl acetate in hexane] to give 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline as a yellow solid (3.6 g). tR=2.82 min (method 1).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:23][C@@H:22]([CH2:24][C:25]([O:27]CC)=[O:26])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[CH2:19][C:18]=2[CH:34]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:23][C@@H:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[CH2:19][C:18]=2[CH:34]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCc3ccc4c(n3)NCCC4)cc2Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@@H]1Cc2ccc(OCCc3ccc4c(n3)NCCC4)cc2Cc2ccccc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
To a solution of ethyl (S)-10,11-dihydro-3-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (131 mg, 0.29 mmole) in THF/H2O (2 mL) was added 1.0 N LiOH (0.43 mL, 0.43 mmole), and the mixture was heated to 50° C. After 18 hr, the mixture was cooled to RT and washed with Et2O (2×2 mL). The aqueous layer was acidified to pH 6 using 10% HCl. The resulting milky solution was passed through a C-18 bond-elute column (gradient elution: H2O, then 20% CH3CN/H2O, then CHCl3 as eluent). Fractions containing the product were concentrated under reduced pressure to give the title compound (30 mg, 24%) as a white powder: MS (ES) m/e 429 (M+H)+. Anal. Calcd for C27H28N2O3.0.95 HCl: C, 70.02; H, 6.30; N, 6.05. Found: C, 70.01; H, 6.33; N, 5.71.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:30]=[CH:29][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].C(O)C.Cl.[NH2:35][OH:36].C(N(CC)CC)C>O>[OH:36][NH:35][C:25](=[NH:26])[C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[CH:29]=[CH:30][C:10]([C:5]3[N:6]=[C:7]([CH3:9])[S:8][C:4]=3[CH:1]([CH3:2])[CH3:3])=[CH:11][CH:12]=2)=[CH:28][CH:27]=1
Reactant: Cc1nc(-c2ccc(OCCCCCOc3ccc(C#N)cc3)cc2)c(C(C)C)s1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(OCCCCCOc3ccc(C(=N)NO)cc3)cc2)c(C(C)C)s1
Reaction time: 15 h
Yield: 91.1 %

Procedure:
While 45 g of 4-5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzonitrile (10) prepared in Example 6 were added to 300 ml of ethanol and stirred, 15 g of hydroxylamine hydrochloride and 30 ml of triethylamine were added. The temperature was gradually increased and stirring under reflux was continued for 15 hr. After the reaction was completed, the temperature was decreased to 40° C., and the resultant reaction solution was slowly added with water, thereby being crystallized. The precipitated solid was filtered and washed with water, thus obtaining 44.2 g (yield: 95%) of a title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=2[C:17](Cl)=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27].NN>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=2[C:17]([NH:26][NH2:27])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)Cl)cc1
Reactant: NN
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Temperature: -10 °C
Yield: 85 %

Procedure:
The crude 2-(4-tert-butyl-benzenesulfonylamino)-5-chlorobenzoyl chloride was dissolved in dichloromethane (300 mL) and transferred to an addition funnel. Hydrazine hydrate (212 mL, 4.35 mol), dissolved in 1.2 L dichloromethane in a 4 L Erlenmeyer flask, was cooled to −10° C. in a dry ice-acetone bath and the acyl chloride solution was added in a slow stream to the stirring hydrazine solution over a 15 minute period. The cold bath was subsequently removed following the addition and LCMS analysis at 15 minutes indicated the reaction was complete. The resultant reaction mixture was quenched with water (500 mL), resulting in a voluminous white precipitate that was collected by vacuum filtration. The precipitate was slurried in 800 mL ethyl acetate and acetic acid was added while stirring until a homogeneous solution was formed. The solution was transferred to a separatory funnel and extracted with 3×100 mL of water. The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to produce 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)benzenesulfonamide (71 g) in an 85% yield: HPLC retention time=2.49 minutes; MS (ES) M+H expected 382.0, found 382.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>>[F:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=3)[CH:17]=2)(=[O:25])=[O:24])[CH:31]=1
Reactant: CC(C)CN
Reactant: COc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Product: COc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(NCC(C)C)n2)c1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-5-fluoro-2-(methyloxy)benzenesulfonamide (89 mg, 0.171 mmol) and isobutylamine (0.172 mL, 1.715 mmol) the title compound was obtained as a yellow foam (58 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.27 (s, 1H), 7.92 (d, J=5.1 Hz, 1H), 7.36-7.52 (m, 2H), 7.29 (t, J=5.9 Hz, 1H), 7.09-7.26 (m, 4H), 7.06 (d, J=7.5 Hz, 1H), 5.92 (dd, J=6.6, 0.9 Hz, 1H), 3.79 (s, 3H), 3.15-3.27 (m, 1H), 2.99 (d, J=0.9 Hz, 2H), 1.71-1.87 (m, 1H), 1.31 (d, J=6.9 Hz, 6H), 0.82 (d, J=6.7 Hz, 6H). MS (ESI): 556.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:37][NH:38][O:39][CH3:40]>C1COCC1>[CH3:40][O:39][N:38]([CH3:37])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To a stirred, ice-cold solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (233 g, 1.2 mol) in THF (1.2 L) was added carbonyldiimidazole (230 g, 1.42 mol) under stirring. The mixture was stirred for 1 h in the ice-water bath. A suspension of triethylamine (207 mL, 1.41 mol) and N,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900 mL) was added. The reaction mixture was allowed to warm to rt and stirred overnight. Tlc showed the reaction was complete. Solvent was evaporated, and the residue was dissolved in CH2Cl2 (1.2 L), washed successively with 0.5 N aq HCl, satd aq Na2CO3 and brine, dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 g, 90.6%), which was used in the next step directly without further purification. Chiral HPLC indicated that the product had an enantiomeric excess of 96%˜98%. 1H NMR (400 MHz, CDCl3): 4.05-4.19 (m, 2H), 3.71 (s, 3H), 3.16 (s, 3H), 2.75-2.85 (m, 2H), 2.65 (t, 1H), 1.90 (d, 1H), 1.60-1.78 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: O=C(C1CCC2(OCCO2)CC1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:19]1[C:23]2([CH2:28][CH2:27][CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]2)[O:22][CH2:21][CH2:20]1.O1C2(CCC(C(O)=O)CC2)OCC1>>[O:31]=[C:29]([CH:25]1[CH2:26][CH2:27][CH2:28][C:23]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:24]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Reactant: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Agent: O=C(O)C1CCC2(CC1)OCCO2
Product: CCOC(=O)CC(=O)C1CCCC2(C1)OCCO2

Procedure:
Ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-7-yl)propanoate was synthesized in a manner similar to the synthesis of ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate, but with 1,4-dioxaspiro[4.5]decane-7-carboxylic acid substituted for 1,4-dioxaspiro[4.5]decane-8-carboxylic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11]=O.[CH:13](C1C=NC=NC=1)=C>>[CH:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[CH2:13]
Reactant: O=Cc1cnc2ccccc2n1
Reactant: C=Cc1cncnc1
Product: C=Cc1cnc2ccccc2n1

Procedure:
Prepared in a similar manner to that described for Intermediate 2, replacing 2-vinylpyrazine with 2-vinylquinoxaline.* The product was purified by SPE using cyclohexane:ethylacetate (2:1 v/v) as eluent to provide the title compound as an oil. *{2-Vinylquinoxaline was synthesized from quinoxaline-2-carboxaldehyde using the procedure described in Intermediate 10 for 5-vinylpyrimidine}.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=O)[CH2:2][CH3:3].[NH:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[NH2:12]>CO.C(O)(=O)C>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:11][N:12]=[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: NNc1nc2ccccc2o1
Reactant: CCC(=O)c1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: CCC(=NNc1nc2ccccc2o1)c1ccccn1

Procedure:
A mixture of 2-propionyl pyridine (0.60 g, 4.42 mmol) and 2-hydrazinobenzoxazole (0.60 g 4.02 mmol) in 25 ml of methanol is refluxed for 24 hours after the addition of 6 drops of glacial acetic acid. The reaction mixture is stored over night in the refrigerator at approximately 5° C. The precipitate is filtered and recrystallized from diisopropyl ether. Yield: 0.68 g (64% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:18][C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])([CH2:15]3)[CH2:9]1)[CH2:11]2)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(O)(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)C2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
5.6 g (21 mmole) of tert-butyl(3-hydroxy-1-adamantyl)carbamate are dissolved in 80 ml of dichloromethane, 4.4 ml (31.5 mmole) of triethylamine are added to it. The mixture is cooled to 0° C. and 1.82 ml (23.5 mmole) of methanesulphonyl chloride is added to it dropwise. The reaction mixture is stirred at that temperature for 45 minutes, then washed consecutively with water and saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate, evaporated, the residue is purified by column chromatography (n-hexane—ethyl acetate—chloroform 2:1:1) and crystallised from n-hexane, to obtain 2.9 g (40%) of product: Mp.: 100-102° C. 1H-NMR (DMSO-d6): 1.37 (s, 9H), 1.48 (s, 2H), 1.77 (q, 4H), 2.05 (t, 4H), 2.17 (d, 2H), 3.10 (s, 3H), 6.66 (s, 1H).