Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-piperidine 1-carboxylic acid tert-butyl ester (0.44 g, 2.2 mmol) and 4-chlorophenyl acetic acid (0.34 g, 2 mmol) in dichloromethane (10 mL) were added EDCI (0.55 g, 2.8 mmol), HOBT (0.42 g, 2.8 mmol) and N-methylmorpholine (0.6 g, 6 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate solution. The aqueous layer was back extracted twice with dichloromethane. The combined organics were dried over sodium sulfate and concentrated in vacuo. Crude product was purified using a short plug of silica gel using ethyl acetate to give the desired product 1H-NMR (CDCL3) δ: 1.15-1.25 (2H, m), 1.40 (9H, s), 1.80-1.90 (2H, m), 2.85 (2H, dd), 3.5 (2H, s), 4.00 (1H, br s), 5.20 (1H, d), 7.15-7.35 (4H, m). ESI-MS m/z: 353 (M+1), UV retention time: 2.47 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: NCCCn1ccnc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCn2ccnc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.750 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 113 mg (0.900 mmol) of 1-(3-aminopropyl)imidazole were dissolved in 10 ml of DMF. 216 mg (1.13 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)Cl>[Cl:23][C:12]1[S:11][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:14][CH:13]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(-c2nccs2)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2ncc(Cl)s2)c1

Procedure:
To a stirred solution of 2-(3-nitro-phenyl)-thiazole (18.5 g, 89.7 mmol) in a mixture of chloroform (150 ml) and anhydrous DMF (40 ml) was slowly added sulfuryl chloride (28.2 ml, 359 mmol). After the addition, the resultant mixture was stirred at reflux for 3 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between aqueous calcium chloride (3M) and ethyl acetate. The organic layer was washed with aqueous sodium carbonate, dried over magnesium sulphate and evaporated to dryness to leave the desired product. 20.6 g (80%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[OH:25])=[C:11]([C:40]3[CH2:41][CH2:42][O:37][CH2:38][CH:39]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(F)(F)F)nc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(F)(F)F)nc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][C:35]1([CH3:42])[NH:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:34][C:35]1([CH3:42])[N:40]([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[CH2:39][CH2:38][NH:37][C:36]1=[O:41]
Reactant: CC1(C)NCCNC1=O
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1

Procedure:
Following the procedure reported for Example 179, the reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (102 mg, 0.193 mmol, Intermediate B), 3,3-dimethylpiperazin-2-one (26.0 mg, 0.203 mmol, ChemBridge, San Diego, Calif.), and potassium carbonate (80 mg, 0.579 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (1.286 mL). Purification by silica gel chromatography (1.5 to 7% MeOH in CH2Cl2 gradient) delivered the title compound as a mixture of two isomers.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH3:31])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[CH3:28]
Reactant: CCNCC
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CCN(CC)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and diethylamine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 450.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])=[C:8]([N+:19]([O-])=O)[CH:7]=1)=[O:4].[H][H]>[Pt]=O.CO>[NH2:19][C:8]1[CH:7]=[C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:11]=[CH:10][C:9]=1[NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: COC(=O)Nc1ccc(NC(=O)CN(C)C)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)Nc1ccc(NC(=O)CN(C)C)c(N)c1
Yield: 69 %

Procedure:
N-(4-methoxycarbonylamino-2-nitrophenyl)-2-dimethylaminoacetamide (25.3 g), platinum oxide (0.4 g) and methanol (250 ml) were shaken together in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature until the uptake of hydrogen was complete. Six litres of hydrogen were absorbed. The mixture was filtered and the ethanol evaporated. The residual solid was recrystallised from isopropanol to give N-(2-amino-4-methoxycarbonylaminophenyl)-2-dimethylaminoacetamide (15.7 g), m.p. 140°-142° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[O:11][C:12]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[N:13][N:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([NH:9][C:10]1[O:11][C:12]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2[S:21]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)(=[O:22])=[O:23])=[N:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nnc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)o1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1nnc(NCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzaldehyde (101 μl) was added to a solution of 2-amino-5-[(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidyl]-1,3,4-oxadiazole (163 mg) [see Example 32] in tetrahydrofuran (2 ml), followed by acetic acid (172 μl) and sodium triacetoxyborohydride (297 mg). The reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 40:60 (in 10% increments), by volume, ethyl acetate:hexane, to afford 2-benzylamino-5-[(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidyl]-1,3,4-oxadiazole (6 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]([O:30][CH2:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)=[CH:5][CH:4]=1.[CH2:34]([O:36][C:37](Cl)=[O:38])[CH3:35].C(N(CC)CC)C>CN(C=O)C>[CH2:34]([O:36][C:37](=[O:38])[N:29]=[C:27]([NH2:28])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:17](=[O:18])[CH:16]([C:12]2[C:13]([F:15])=[CH:14][C:9]([C:6]3[CH:7]=[N:8][C:3]([NH2:2])=[CH:4][CH:5]=3)=[CH:10][C:11]=2[F:33])[O:30][CH2:31][CH3:32])=[CH:22][CH:23]=1)[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)cc(-c2ccc(N)nc2)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N=C(N)c1ccc(CNC(=O)C(OCC)c2c(F)cc(-c3ccc(N)nc3)cc2F)cc1

Procedure:
Analogous to example 15.4, (RS)-(2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-N-(4-carbamimidoyl-benzyl)-2-ethoxy-acetamide hydrochloride (example 271) was reacted with ethylchloroformate and triethylamine in DMF to give (RS)-[amino-[4-({2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-2-ethoxy-acetylamino]-methyl)-phenyl]-methylene}-carbamic acid ethyl ester. Off-white solid. MS 512.1 ([M+H]+)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.I[CH:33]([CH3:35])[CH3:34]>CN(C=O)C.CCOC(C)=O>[CH:33]([N:29]1[CH2:30][CH2:31][CH:26]([N:24]2[CH:25]=[C:21]([C:19]3[CH:20]=[C:15]([C:5]4[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=5)[CH:6]=4)[CH:16]=[N:17][CH:18]=3)[CH:22]=[N:23]2)[CH2:27][CH2:28]1)([CH3:35])[CH3:34]
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Reactant: CC(C)I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1cc(-c2cncc(-c3cnn(C4CCN(C(C)C)CC4)c3)c2)cc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) (1 eq, 0.122 mmol, 50 mg) in DMF (3 ml) cooled at 0° C. is added 2-iodopropane (7 eq, 0.854 mmol, 0.084 ml) and the reaction is stirred at room temperature for 5 hours. The reaction mixture is dissolved in EtOAc and washed with water. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 454.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:20][CH:19]=[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[NH:22][C:21]1[C:16]([NH2:8])=[N:17][C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of di-tert-butyl(3-{[(benzyloxy)carbonyl]amino}-6-phenylpyridin-2-yl)imidodicarbonate (359 mg, 0.691 mmol) and methylene chloride (2.76 mL) was treated with TFA (0.691 mL) in one portion. The reaction was stirred for 3 h, then concentrated via rotovap slowly to afford a residue purified via MPLC, silica cartridge, 0-5% MeOH in methylene chloride to afford the product as a light orange solid. 1H NMR (DMSO-d6, 600 MHz, rotamers present) δ 9.04 (br s, 1H), 7.86 (d, J=7.3 Hz, 1H), 7.47-7.30 (m, 5H), 7.15 (d, J=8.2 Hz, 1H), 6.40 (br s, 2H), 5.16 (s, 2H); MS cal'd 320 (M+H)+, exp 320 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].[CH2:34]([O:36][C:37](=[O:40])[CH2:38]Br)[CH3:35]>>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([N:13]([C:6]3[C:7]([O:11][CH3:12])=[N:8][C:9]([CH3:10])=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=3)[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:40])=[O:15])[CH2:17][CH2:18]2)[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)=O)c(C)nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C(C)=O)c(C)nc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
1-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxylphenyl)piperazine(200 mg, 0.5 mmol) was dissolved in dimethylfornamide(15 ml) and thereto sodium hydride(18.5 mg, 0.5 mmol) was added, then followed by stirring at room temperature for 15 min, and ethylbromoacetate(83.5 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for 3 hrs, concentrated under the reduced pressure to remove the used solvent, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>CO>[N:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Nc1ccc(S)cc1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(SCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
4-aminothiophenol (8.9 g) was dissolved in methanol (178 ml), aqueous solution of sodium hydroxide (6.8 g, 53.4 ml) was added to the mixture, 4-(chloromethyl)pyridine hydrochloride (14.0 g) was added to the mixture at 0° C., and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 4-[(4-pyridinylmethyl)sulfanyl]aniline (13.7 g).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]([F:25])([F:24])[C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[O:10][C:11]1[C:16]([C:17](OC)=[O:18])=[N:15][CH:14]=[CH:13][N:12]=1>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:17]([C:16]2[C:11]([O:10][C:9]3[CH:21]=[CH:22][CH:23]=[C:7]([C:6]([F:24])([F:5])[F:25])[CH:8]=3)=[N:12][CH:13]=[CH:14][N:15]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COC(=O)c1nccnc1Oc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)c1nccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
0.11 g (2.0 mmol) of cyclopropylamine is added to a suspension of 3.0 g (10 mmol) of methyl 2-(3-trifluoromethylphenoxy)-3-pyrazinecarboxylate, 20 g of 3 Å molecular sieve and 20 g of 5 Å molecular sieve in 240 ml of dry toluene at room temperature. The reaction mixture is refluxed for 6 hours. After the mixture has cooled to room temperature, solid components are filtered off. The filtrate is extracted with 10% strength, aqueous hydrochloric acid, washed with distilled water, dried over magnesium sulfate, filtered and freed from the solvent under reduced pressure. 2.8 g (81%) of a colorless, crystalline solid of melting point 74-77° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[CH:18]1(/[CH:22]=[CH:23]/[C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[CH:18]1([CH:22]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1
Reactant: N#C/C=C/C1CCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.63 g, 0.0496 mol) in acetonitrile (124 mL, 2.37 mol) was added (E)-3-cyclobutylacrylonitrile (5.30 g, 0.0495 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.70 mL, 0.0248 mol). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as a racemic mixture (11.2 g, 75.2%). LCMS (M+H) 302.4.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[C:40]([NH2:44])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([NH:44][CH2:1][CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:22][CH2:23][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:29]=3[CH2:30]2)=[CH:7][CH:6]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)N
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCNC(C)(C)C)cc2)c1
Yield: 16.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and tert-butylamine (6.8 mg) according to an analogous synthetic method to Example 806, the title compound (4.6 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:26](Br)[C:27]#[CH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:28]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:27]#[CH:26]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)OC
Reaction time: 16 h

Procedure:
Methyl 2-hydroxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoate (0.5 gm, 1.42 mmol) from Step 1 of Example 25 was dissolved in DMF (5 mL) and propargyl bromide (186 mg, 1.56 mmol) was added followed by cesium carbonate (925 mg, 2 eq.) and the mixture was stirred 16 hrs. The solids were removed by filtration and the filtrate solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:1 ethyl acetate:hexanes as eluant. Methyl 2-propargyloxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoate was obtained as a gum.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:12]([CH:21]=1)[C:13]([CH2:15][CH2:16][C:17](OC)=[O:18])=O)(=[O:6])[CH3:5]>C(O)(=O)C>[C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:12]([C:13]2[CH2:15][CH2:16][C:17](=[O:18])[NH:2][N:3]=2)[CH:21]=1)(=[O:6])[CH3:5]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1
Yield: 85 %

Procedure:
Hydrazine hydrate (0.0785 ml, 0.00157 mole) was added to a stirred solution of methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g, 0.0005 mole) in glacial acetic acid (2 ml) and the solution was heated under reflux for 90 minutes. The residue after evaporation was treated with an excess of sodium bicarbonate solution and the solution evaporated to dryness under reduced pressure. The residue was extracted with dichloromethane and the dried extract evaporated to dryness. An aqueous solution of the residue was washed with two small portions of dichloromethane and then evaporated to an oily residue, which with ethyl acetate gave 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (0.16 g, 80%, m.p. 165°-168°).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([Si](C)(C)C)[CH:7]=2.ClN1C(=O)CCC1=O.[Br-:22].[Li+]>CO>[Br:22][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[CH:2]([CH3:1])[CH2:9]2
Reactant: [Br-]
Reactant: CC1Cc2cc([Si](C)(C)C)ccc21
Agent: O=C1CCC(=O)N1Cl
Agent: [Li+]
Solvent: CO
Product: CC1Cc2cc(Br)ccc21
Reaction time: 2 h

Procedure:
To a solution of 7-methyl-3-trimethylsilylbicyclo[4.2.0]octa-1,3,5-triene (48.1 g, 0.25 mol) in MeOH (1000 ml) at 25° C., was added N-chlorosuccinimide (37.1 g, 0.28 mol), followed by lithium bromide (24.1 g, 0.28 mol) and the reaction mixture was allowed to stir at this temperature for 2 hrs. It was then quenched with H2O (200 ml), and concentrated under reduced pressure. The residue was extracted with hexane (200 ml×4), the combined organic extracts were washed with H2O (3×200 ml), dried over MgSO4 and concentrated under reduce pressure to give a pale yellow oil. The oil was purified by column chromatography (silica, hexane) to give the desired product 3-bromo-7-methyl-bicyclo[4.2.0]octa-1,3,5-triene as a colourless oil (42.6 g, GC-MS: M+=196, M−=198, isolated as a mixture of isomers).