Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH2:11]2)[CH:3]=1.[CH3:26][C:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=2)[NH:29][N:28]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:16][C@H:15]1[N:10]([C:4]2[CH:3]=[C:2]([C:32]3[CH:31]=[C:30]4[C:35]([C:27]([CH3:26])=[N:28][NH:29]4)=[CH:34][CH:33]=3)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)[CH2:11][C@@H:12]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH2:13][CH2:14]1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)Nc3ccccc3)CC[C@H]2C)n1
Reactant: Cc1n[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc3c(C)n[nH]c3c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 39 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-phenyl-3-piperidinecarboxamide (420 mg, 1.17 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (452 mg, 1.75 mmol, 1.5 equiv), tricyclohexylphosphine (49 mg, 0.175 mmol, 0.15 equiv), Pd2(dba)3 (80 mg, 0.088 mmol, 0.075 equiv) and K3PO4 (412 mg, 1.98 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (6 mL) and water (2 mL). The mixture was bubbled with argon for 10 minutes, followed by heating at 100° C. for 20 hours. After cooling to room temperature, the mixture was filtered through celite and rinsed with EtOAc (30 mL). The filtrate was concentrated in vacuo, and the resulting residue was partitioned between EtOAc (30 mL) and brine (10 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 70% A in CHCl3 (A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3). Trituration of the purified material in a mixture of CHCl3 (1 mL), MTBE (2 mL) and hexane (6 mL), and drying under vacuum at 65° C. for 20 hours afforded the title compound (208 mg) as a tan solid. LC-MS (ES) m/z=456 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.33 (d, J=6.8 Hz, 3H), 1.78-1.96 (m, 3H), 2.05-2.16 (m, 1H), 2.58-2.16 (m, 1H), 2.59 (s, 3H), 2.99 (s, 3H), 3.18-3.27 (m, 1H), 6.53 (s, 1H), 7.12 (t, J=7.3 Hz, 1H), 7.34 (t, J=8.0 Hz, 2H), 7.60 (d, J=7.3 Hz, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 8.04 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[O:13][C:14]3[CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=[CH:17][C:15]=3[CH:16]=2)=[O:9])=[CH:6][CH:5]=[C:4]([CH2:29][O:30][CH3:31])[N:3]=1.C([Sn](CCCC)(CCCC)[CH2:37][O:38][CH3:39])CCC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[C:4]([CH2:29][O:30][CH3:31])[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:37][O:38][CH3:39])[CH:18]=[CH:17][C:15]=2[CH:16]=1)=[O:9]
Reactant: COCc1ccc(C(=O)NCc2cc3ccc(OS(=O)(=O)C(F)(F)F)cc3o2)c(N)n1
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: COCc1ccc2cc(CNC(=O)c3ccc(COC)nc3N)oc2c1
Temperature: 135 °C
Reaction time: 4 h
Yield: 6 %

Procedure:
To a 1-methyl-2-pyrrolidinone (500 μL) solution of trifluoromethanesulfonic acid 2-(((2-amino-6-methoxymethyl-pyridin-3-carbonyl)-amino)-methyl)-benzofuran-6-yl ester (15 mg, 33 μmol) described in Production Example 47-1 were added tributyl-methoxymethyl-stannane (14 mg, 43 μmol), tetrakis(triphenylphosphine)palladium (0) (3.78 mg, 3.3 μmol) and tetrabutyl ammonium chloride (1.82 mg, 6.5 μmol) at room temperature, which was stirred at 135° C. for 4 hours under nitrogen atmosphere. After allowing the reaction solution to cool to room temperature, the reaction solution was filtered and purified by reverse phase high-performance liquid chromatography (using an acetonitrile-aqueous mobile phase (containing 0.1% trifluoroacetic acid)) followed by further purifying by silica gel column chromatography (ethyl acetate) to obtain the title compound (0.7 mg, 6%) as a white solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]([NH:51][C:52]2[C:53]([S:61][CH3:62])=[N:54][C:55]([CH3:60])=[CH:56][C:57]=2[S:58][CH3:59])=[O:50])[CH2:44][CH2:43]1)(=O)=O>CN(C=O)C.O>[NH:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:2]1[S:1][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]([NH:51][C:52]2[C:53]([S:61][CH3:62])=[N:54][C:55]([CH3:60])=[CH:56][C:57]=2[S:58][CH3:59])=[O:50])[CH2:44][CH2:43]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCOS(C)(=O)=O)CC1
Reactant: Sc1nc2ncccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ncccc3[nH]2)CC1
Yield: 40 %

Procedure:
To a solution of 2-mercaptoimidazolo[4,5-b]pyridine (38.1 mg, 0.252 mmol) in DMF (0.5 ml) were added 18-crown-6 (6.6 mg, 0.025 mmol) and potassium carbonate (63 mg, 0.454 mmol) and the mixture was stirred. Then to the mixture was dropped a solution of crude 2-[4-(2-methanesulfonyloxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide in DMF (1 ml) and stirred at 80° C. for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:methanol=10:1) to provide 51 mg (yield 40%) of the desired compound as colorless powdery crystals. IR (KBr) cm−1: 3140, 1688, 1600, 1564, 1485. 1H-NMR (CDCl3) δ: 2.38 (3H, s), 2.46 (3H, s), 2.49 (3H, s), 2.72-3.00 (10H, m), 3.29 (2H, s), 3.37 (2H, t, J=5.8 Hz), 6.63 (1H, s), 7.12 (1H, dd. J=7.8, 4.9 Hz), 7.82 (1H, d. J=7.8 Hz), 8.25 (1H, d. J=4.9 Hz), 8.49 (1H, br s).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C(OC([NH:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH2:43])=[O:42])=[CH:36][CH:35]=1)[C:31](O)=[O:32])=O)(C)(C)C>>[CH3:10][CH:9]([S:11][C:12]1[NH:13][N:14]=[N:15][N:16]=1)[C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:31](=[O:32])[CH:30]([C:34]3[CH:35]=[CH:36][C:37]([NH:40][C:41]([NH2:43])=[O:42])=[CH:38][CH:39]=3)[NH2:29])[C:20](=[O:21])[N:4]2[C:5]=1[C:17]([OH:19])=[O:18]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(NC(N)=O)cc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(NC(N)=O)cc3)[C@H]2SC1

Procedure:
When 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.28 g, 0.01 mol) was acylated with the product of Example 1 (3.1 g, 0.01 mol) according to the procedure of Example 2, the title compound was obtained: mp >300°.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33].O>ClCCl>[CH3:35][O:34][C:32](=[O:33])[NH:2][CH:3]1[CH2:4][C:5](=[O:23])[N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:7]1
Reactant: NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A solution of 250 mg (0.74 mmol) of (RS)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 1f)] in 12 ml of dichloromethane is cooled to 0° C. and successively treated with 226 μl (1.6 mmol) of triethylamine and 64 μl (0.8 mmol) of methyl chloroformate. The mixture is left to warm to RT and stirred for 1 hour. For the working-up, dichloromethane and water are added to the reaction mixture. The organic layer is separated, dried over sodium sulfate, and evaporated. There are obtained 203 mg (76% of theory) of (RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-carbamic acid methyl ester as a white solid. MS: m/e=359 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([OH:22])([C:16]([F:24])([F:23])[F:15])[C:6]1[C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[NH:3][C:2]=1[CH3:1]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: Cc1ccc(-n2[nH]c(C)cc2=O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 3-methyl-1-(4-methylphenyl)-5-pyrazolone (94 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (172 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[OH:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:37][C:36]6[CH:39]=[CH:40][C:33]([OH:32])=[CH:34][CH:35]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: O=Cc1ccc(O)cc1
Product: Oc1ccc(CN2CCc3[nH]c(-c4n[nH]c5cc(-c6cc(F)c(O)cc6CC(F)(F)F)ccc45)nc3C2)cc1

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 4-hydroxybenzaldehyde (56.6 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 24.4% yield, 28 mg.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][Cl:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][Cl:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Product: Nc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 80.3 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.0 g.) was treated with conc. hydrochloric acid (0.7 g.) in a similar manner to that of Example 24-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.53 g.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[F:8][C:4]1[N:3]=[C:2]([C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: Fc1cccc(Br)n1
Product: Fc1cccc(-c2cccs2)n1

Procedure:
2-Bromo-6-fluoropyridine and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(6-fluoro-2-pyridyl)thiophene as yellow oil. APCI-Mass m/Z 180 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:23])[CH3:22])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[C:25]([Cl:31])(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:22])[CH3:23])[N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[C:25]([Cl:31])(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Agent: CCCCC(=O)Cl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C

Procedure:
According to US 2006/0149079 A1 N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methylester is acylated with valerylchloride in the presence of inorganic base to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methylester with valerylchloride, followed by the conversion of cyano to tetrazole and hydrolyzing the tetrazole derivative to obtain valsartan.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1cccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)c1

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-methoxy-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C20H24O6 [M+H]+: 361.4.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=C(C3C=CC(OC)=CC=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[CH:21]([C:24]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=O)([CH3:23])[CH3:22]>>[Br:1][C:2]1[C:7]2[N:8]=[C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:24]=3[CH:21]([CH3:23])[CH3:22])[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1ccc(-c2nc3c(Br)cc(OC)cc3s2)cc1
Reactant: COc1cccc(C(=O)Cl)c1C(C)C
Product: COc1cc(Br)c2nc(-c3cccc(OC)c3C(C)C)sc2c1

Procedure:
The procedure was the same with 4-bromo-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole except using 2-isopropyl-3-methoxy-benzoyl chloride instead of p-anisoyl chloride. Mass spec: MH+=392.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: COc1ccccc1CC(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Solvent: CC#N
Product: COc1ccccc1CC(=O)N1CC[C@@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-methoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=[C:4]2[C:3]=1[O:20][CH2:21]OCC[Si](C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].IC.CCOC(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:10]=[C:4]2[C:3]=1[O:20][CH3:21]
Reactant: C[Si](C)(C)CCOCOc1c(Br)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(Br)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 192 h
Yield: 51 %

Procedure:
To a stirred suspension of the mixture of 7-bromo-8-methoxy-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one and 7-bromo-8-hydroxy-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (from step 4) in DCM (120 mL) at 0° C. was added DIPEA (35 mL, 0.2 mol). After 5 min, (2-chloromethoxy-ethyl)-trimethylsilane (11.9 mL, 67.2 mmol) was added. The mixture was stirred at 0° C. for 1 hour and at RT for a further 2 hours. The resulting mixture was diluted with DCM (200 mL) and washed successively with 0.5 M HCl (aq) (400 mL) and water, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 30% ethyl acetate in cyclohexane) to afford the title compound (1.30 g, 20%) as a yellow solid. Fractions containing 7-bromo-8-(2-trimethylsilanyl-ethoxymethoxy)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one were evaporated and the resultant residue was dissolved in MeOH (120 mL). The solution was stirred for 8 days at RT before evaporating to dryness. The resultant residue was dissolved in DMF (25 mL), cooled to 0° C., and cesium carbonate (13 g, 40 mmol) and iodomethane (3.11 mL, 50 mmol) were added. The reaction mixture was stirred at RT for 16 hours. EtOAc and water were added, the aqueous phase was isolated and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 30% EtOAc in cyclohexane) to afford a further quantity of the title compound (3.26 g, 51%) as a yellow solid. LCMS (Method A): RT=4.70 min, [M+H]+=396/398.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1>O.C(O)C.C(N(CC)CC)C>[CH3:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:10][CH:9]=1
Reactant: O=C(O)CCS
Reactant: Cc1ccc(CBr)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(CSCCC(=O)O)cc1

Procedure:
A solution of betamercaptopropionic acid (5.3 g, 50 mMol) in water (95 ml) was diluted with absolute ethanol (80 ml) and triethylamine (15 ml). While this solution was mechanically stirred and cooled with an ice bath, a solution of 4-methylbenzyl bromide (9.4 g) in ethanol (80 ml) was added over a period of 15 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. The mixture was then concentrated in vacuo and the residue was suspended in water (100 ml). As the pH of the suspension was adjusted to 10, the residue dissolved. The resulting solution was extracted three times with di-ethyl ether and the aqueous phase was acidified to pH 1 with concentrated HCl. An oily residue separated. The mixture was then exhaustively extracted with di-ethyl ether, the ether extracted was dried over MgSO4 and concentrated to an oil. The latter solidified on standing and the solid residue was recrystallized from ethyl acetate-liquid petroleum. The yield was 7.9 g (75%), m.p. 75.8° C., NMR (CDCl3) 11.5 (s, 1H), 7.09 (q, 4H), 3.67 (s, 2H), 2.60 (m, 4H), 2.30 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(COc2ccc(-c3cc4ccccc4[nH]3)cc2)cc1
Reaction time: 4 h
Yield: 73.5 %

Procedure:
While stirring and under nitrogen, a mixture of 3.14 g (0.15 mol) of 2-(4'-hydroxy-phenyl)-indole, prepared as in Example 2, 2.1 g of anhydrous potassium carbonate and 100 ml of anhydrous acetone was refluxed and a solution of 50 ml of anhydrous acetone containing 1.8 ml (0.015 mol) of benzyl bromide was then added, drop-by-drop. The solution was heated for 4 hours and 0.4 ml (0.003 mole) of benzyl bromide was added with 0.5 g of potassium carbonate. Heating was continued for 4 hours and the hot solution was filtered. The filter was washed with 50 ml of acetone, the filtrate was concentrated under vacuum and was taken up in 100 ml of boiling methylethylketone. The hot reaction medium was filtered and the filtrate was cooled in an ice-bath for 30 minutes. The precipitate which was obtained was centrifuged and recrystallized from methylethylketone to give 3.3 g of 2-(4'-benzyloxy-phenyl)-indole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:21][C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(F)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-cyanophenyl)amino]pyrimidine and 4-fluorobenzyl bromide
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[C:23]1([C:20]2[N:19]=[N:18][C:17]([CH2:16][NH2:8])=[CH:22][CH:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2ccccc2)nn1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCc1ccc(-c2ccccc2)nn1
Temperature: 30 °C
Reaction time: 1 h
Yield: 119.1 %

Procedure:
To a solution of 3-[bis(tert-butoxycarbony)aminomethyl]-6-phenylpyridazine (178 mg, 0.462 mmol) obtained in Reference Example 2-(b) in methylene chloride (2.33 ml) was added a 4N hydrogen chloride/1,4-dioxane solution (2.33 ml, 9.32 mmol), followed by stirring at 30° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to afford the title compound (122 mg) substantially quantitatively as a slightly brown solid.