Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1.Cl>CS(C)=O.O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:42][C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: ClCc1nnn[nH]1
Reactant: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3nnn[nH]3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (1R,3S,5R)-2-[2-(3-Acetyl-6-hydroxy-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]-hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 584 (80.0 mg, 0.165 mmol) in DMSO (2 mL) was treated with cesium carbonate (162 mg, 0.496 mmol). After stirring at RT for 5 min, 5-(chloromethyl)-1H-tetrazole (21.0 mg, 0.174 mmol) was added and stirring was continued at RT for 36 h. The mixture was neutralised by addition of 1N HCl, diluted with water extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine. The resulting suspension was filtered over phase separator and concentrated. The filtered solid was triturated with methanol, decanted and dried in vacuo to give the title compound. The filtrate was purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40×250 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford after lyophilization of the purified fractions a second batch of the title compound as a white solid. MS (LC/MS): 566 [M+H]+; tR (HPLC conditions k): 3.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:32](=[N:34][OH:35])[NH2:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:36](N1C=CN=C1)(N1C=CN=C1)=[O:37].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]3[NH:33][C:36](=[O:37])[O:35][N:34]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (408 mg, 0.82 mmol) and 1,1′-carbonyldiimidazole (146 mg, 0.90 mmol) dissolved in acetonitrile (8.2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.488 mL, 3.26 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C26H29ClFNγO2 [M+H]+ 526. found 526. 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 7.83 (s, 1H), 4.67-4.42 (m, 3H), 3.91-3.81 (m, 1H), 3.79-3.64 (m, 2H), 3.53-3.45 (m, 1H), 2.20-2.12 (broad, 1H), 2.06-1.98 (broad, 1H), 1.94-1.78 (m, 2H), 1.40-1.31 (broad, 2H), 1.17-1.07 (broad, 1H), 1.06-0.96 (broad, 1H), 0.89 (d, J=12.5, 1H), 0.67 (d, J=6.4, 3H), 0.63-0.36 (m, 5H).
Reaction SMILES: [F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:23])[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cnc3c(F)c(F)ccc3c2c1=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cnc3c(F)c(F)ccc3c2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A suspension of 35 g of ethyl 7,8-difluoro-1-oxo-1,4-dihydrobenzo[f][1,7]-naphthyridine-2-carboxylate and 31.8 g of potassium carbonate in 350 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature of 90° C. for 3 hours. After cooling to 50° C., 65 g of methyl iodide were added; the mixture was heated at 90° C. for 3 hours. After cooling to 20° C., the insoluble material was dewatered, washed 4 times with 100 cm3 of water, 3 times with 100 cm3 of ethanol, and twice with 100 cm3 of diethyl ether. 25.5 g of ethyl 7,8-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of white crystals, which melted at 320° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1C(=O)C(F)(F)F.[OH-].[Na+]>CO>[NH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[CH2:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: O=C(N1CCCCC1Cc1nc2ccccc2s1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2sc(CC3CCCCN3)nc2c1

Procedure:
1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-2,2,2-trifluoroethanone, D29 (1.2 g) was dissolved in methanol (40 ml) and 2N sodium hydroxide solution (20 ml) and heated to 50° C. for 0.75 h. After cooling, the reaction solution was partitioned between dichloromethane and water. The organic solution was dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0-10% [9:1 MeOH/conc. ammonia solution] in dichloromethane) to afford the title compound (0.68 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[N-]1C=CN=C1.[NH2:19][C:20]1[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([NH:19][C:20]2[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([CH:29]=2)[C:25]([O:27][CH3:28])=[O:26])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: CNc1ncc(C(=O)OC)cc1N
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CNc1ncc(C(=O)OC)cc1NC(=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.6 g (15 mmol) of 3-(4-cyanophenyl)propionic acid in 25 mL of absolute tetrahydrofuran was mixed with 2.4 g (15 mmol) of N,N′-carbonyldiimidazole and stirred for 20 minutes at room temperature. Then the imidazolide was mixed with a solution of 2.3 g (13 mmol) of methyl 5-amino-6-methylaminonicotinate in 25 mL of dimethyfformamide and heated for 3 hours to 100° C. After the removal of the solvent in vacuo, the crude product obtained was taken up in ethyl acetate, the organic phase was washed with water and after drying over sodium sulfate it was again freed from solvent. The residue obtained was purified by flash chromatography (silica gel; gradient: dichloromethane to dichloromethane/ethanol=19:1). Yield: 2.1 g (50% of theory) of beige solid; Rf value: 0.54 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1).
Reaction SMILES: C(S[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[N:5][CH3:6])C.[C:14]([NH:22][NH2:23])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)CCC>[CH3:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:5]([CH3:6])[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:22][N:23]=1
Reactant: CCSC(=NC)c1ccccc1C
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCO
Product: Cc1ccccc1-c1nnc(-c2ccccc2)n1C
Temperature: 120 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
Into a 100-mL three-neck flask were put the total amount of N-[(ethylsulfanyl)(2-methylphenyl)methylidene]methylamine obtained in Step 3, 7.0 g (51.4 mmol) of benzoylhydrazine, and 30 mL of 1-butanol (1-BuOH), and the mixture was heated and stirred at 120° C. for 15 hours. After reaction for the predetermined time, the solvent was distilled off to give a yellow liquid. This liquid was purified by silica gel chromatography. Ethyl acetate was used as a developing solvent. The obtained fraction was concentrated to give a white solid. This solid was recrystallized with ethyl acetate, so that 7.0 g of a white solid of Hmpptz-Me (abbreviation), an objective 4H-triazole derivative, was obtained in a yield of 58%. A synthesis scheme of Step 4 is shown in (f-4).
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]#[CH:6])[CH3:2].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9]>>[CH2:11]([O:10][C:8](=[O:9])[C:6]#[C:5][CH2:4][S:3][CH2:1][CH3:2])[CH3:12]
Reactant: C#CCSCC
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C#CCSCC

Procedure:
The title compound was prepared from 3-ethylsulfanyl-propyne and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2([CH2:35][C:36]([NH2:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C:29]2([CH2:35][C:36]([NH2:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[N:14]([CH3:16])[CH3:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(NC3(CC(N)=O)CCCCC3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide in an analogous manner to Example 61e. Product isolated as a pale yellow foam (0.064 g, 51%). MP: 90-107° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 7.92 (s, 1H), 7.87 (s, 1H), 7.17 (s, 1H), 6.65 (s, 1H), 5.43 (br s, 1H), 5.25 (s, 1H), 5.07 (br s, 1H), 3.85 (s, 3H), 3.29 (s, 2H), 3.14 (s, 3H), 2.98 (s, 3H), 2.92-2.86 (m, 6H), 2.72-2.67 (m, 4H), 2.38 (m, 2H), 1.70-1.58 (m, 5H), 1.50-1.40 (m, 3H). MS: 544.27 (MH)+.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:29]([O-:34])([N+]([O-])=O)=[O:30]>C(Cl)(Cl)Cl>[OH:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:4]2[O:3][C:2]([N+:29]([O-:34])=[O:30])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: OCCc1ccc2oc(Br)c(-c3ccccc3)c2c1
Agent: O=C(O)C1CC=CCC1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1oc2ccc(CCO)cc2c1-c1ccccc1
Reaction time: 0.5 h

Procedure:
The product from step B is mixed with 8.83 g. (0.07 mole) of cyclohexene-4-carboxylic acid in 175 ml. of chloroform, and 6.5 g. (0.07 mole) of dinitrogen tetraoxide in 15 ml. of chloroform is added dropwise. After 30 minutes an additional 1.0 g. of dinitrogen tetraoxide in 5 ml. of chloroform is added, and the mixture is stirred for about 18 hours. The mixture is washed twice with water, twice with saturated sodium bicarbonate solution and twice again with water, then dried. Evaporation to dryness provides a residue which is recrystallized from aqueous ethanol, then benzene, to provide 5-(2-hydroxyethyl)-2-nitro-3-phenylbenzofuran as a yellow solid, m.p. 169°-173° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[O:9][C:10]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:12]=1.Cl>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([O:6][CH:4]([CH3:5])[CH3:3])[O:9][C:10]=2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:14][CH:15]=1
Reactant: CC(C)O
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.60 g) was added to 2-propanol (20 ml), and stirred at room temperature for 10 minutes. To the reaction mixture was added 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), and stirred under reflux for 30 minutes. Next, water was added to the resulting reaction mixture, which was then acidified with 2 N hydrochloric acid, and the crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-isopropoxy-5-oxazolepropionic acid (1.35 g, 87%). This was recrystallized from isopropyl ether to give colorless prisms. mp 116-117° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([N:8]2[C:20]3[C:19]4[CH:18]=[C:17]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][OH:28])=[CH:25][CH:26]=5)[CH:16]=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]([CH3:29])[C:9]2=[O:30])[C:5]([CH3:31])=[N:4]1)[CH3:2].[H-].[Na+].I[CH3:35]>CN(C=O)C>[CH2:1]([N:3]1[CH:7]=[C:6]([N:8]2[C:20]3[C:19]4[CH:18]=[C:17]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][O:28][CH3:35])=[CH:25][CH:26]=5)[CH:16]=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]([CH3:29])[C:9]2=[O:30])[C:5]([CH3:31])=[N:4]1)[CH3:2]
Reactant: CI
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5ccc(CO)nc5)cc4c32)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5ccc(COC)nc5)cc4c32)c(C)n1
Reaction time: 0.33 h

Procedure:
To a mixture of 1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 16.1, 28 mg, 0.068 mmol) in DMF (1 ml) was added NaH 55% (4 mg, 0.092 mmol) and the mixture was stirred for 20 min. Then iodomethane (0.006 ml, 0.096 mmol) was added and the RM was stirred again at rt for 30 min. After that, the RM was quenched with saturated aqueous NaHCO3 (20 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in DMA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.30 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 8.15-8.10 (m, 1H), 7.98-7.93 (m, 1H), 7.92-7.87 (m, 1H), 7.58-7.53 (m, 1H), 7.49-7.44 (m, 1H), 4.54-4.50 (m, 2H), 4.23-4.15 (m, 2H), 3.58 (s, 3H), 3.37 (s, 3H), 1.95 (s, 3H), 1.32 (t, 3H))
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:8][C:7]=1[CH2:19]Br)=[O:5])[CH3:2].[CH2:21]([O:23][C:24](=[O:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:8][C:7]=1[CH2:19][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2cccc(OC)c2)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2cccc(OC)c2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
A mixture of 4-bromomethyl-2-(3-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (2.03 g, 5.71 mmole), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (1.45 g, 5.71 mmole) and potassium carbonate (1.18 g, 8.56 mmole) in anhydrous dimethylformamide (18 ml) was stirred at room temperature for 16 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (2.31 g). MS: (+) m/z 551.13 (M+Na+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH2:23]([Sn](CCC)(CCC)CCC)[CH2:24][CH3:25]>CN(C)C=O.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:23][CH2:24][CH3:25])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: CCC[Sn](CCC)(CCC)CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (152 mg, 0.40 mmol), tetra-n-propyltin (211 μL, 0.80 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (28 mg, 0.04 mmol) in dimethylformamide (2.5 mL) was stirred at 130° C. for 1 h before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (79 mg): MS: (+) m/z 343.00 (M+1), MS: (−) m/z 341.00 (M−1).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:41])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([C:37]#[N:38])[CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH:12]=1.S(OC)(O[CH3:46])(=O)=O>C1COCC1.CN(C=O)C>[CH3:46][N:17]([C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[C:18](=[O:41])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([C:37]#[N:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[CH:24][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)Nc4cccnc4)cc3)c2cc1C#N
Reactant: COS(=O)(=O)OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(CC(=O)N(C)c4cccnc4)cc3)c2cc1C#N
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, a 1M solution of lithium hexamethyldisilazane in THF (0.27 ml) was added dropwise to a stirred solution of N-(3-pyridyl)-2-[4-(6-cyano-7-methoxyquinolin-4-yloxy)phenyl]acetamide (0.1 g) in DMF (2 ml) that had been cooled to −5° C. After 5 minutes, a solution of dimethyl sulphate (0.026 ml) in DMF (0.5 ml) was added dropwise and the resultant mixture was stirred at 0° C. for 30 minutes. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.04 g); 1H NMR: (CDCl3) 3.34 (s, 3H), 3.52 (s, 2H), 4.08 (s, 3H), 6.51 (d, 1H), 7.07 (d, 2H), 7.18 (d, 2H), 7.42 (m, 1H), 7.53 (br s, 2H), 8.5 (br s, 1H), 8.65 (br s, 1), 8.67 (d, 1H), 8.69 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:22][C@@H:23]([CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(OCC)(=O)C>CN(C=O)C>[CH3:22][C@@H:23]([CH2:32][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26]
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)CC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COc1ccc(N2CCN(c3ccncc3)CC2)cc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (15.5 g) in dry DMF (120 ml) and the mixture was stirred for 45 minutes at room temperature. tert-Butyl (3R)-3-methyl-4-(p-toluene-sulphonyloxy)butyrate (20 g) was added and the mixture was stirred at. room temperature for 20 hours. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, filtered through phase separating paper (Whatman IPS) and evaporated. The residue was triturated under diethyl ether. The solid so obtained was recrystalltsed from ethyl acetate to give tert-butyl (3R)-3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (10.6 g), m.p. 112°-113° C.; [alpha]D =-5.5° (conc.=1 g/100 ml of methanol; 20° C.); NMR (CDCl3) δ 8.3(2H,d), 6.89(4H,m), 6.7(2H,m), 3.79(2H,d), 3.46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08-2.21(1H,m), 1.44(9H,s), 1.07(3H,d).
Reaction SMILES: [C:1]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH:17]=[CH2:18])[OH:16])([CH3:3])=[CH2:2].C(OCC)C>O1CCCC1>[CH3:3][C:1]1[CH2:2][CH2:18][CH2:17][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:4]=1
Reactant: C=CC1(O)CCCCCCCCCCC1C(=C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=CCCCCCCCCCCC(=O)CCC1

Procedure:
A mixture of 2-isopropenyl-1-vinylcyclododecan-1-ol (0.100 g; 0.4.10-3 mol) and dichloro-bis-(benzonitrile)-palladium(II) (0.007 g; 0.018.10-3 mol) in tetrahydrofuran (5 cc) is kept at a temperature of the order of 20° C. under an inert atmosphere. After a reaction time of 6 hours, diethyl ether (75 cc) is added and the mixture is then washed with water (5×15 cc). After drying over magnesium sulphate, filtration and evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), 5-methylcyclohexadec-5-en-1-one (0.065 g) is obtained, which has the following characteristics:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[NH2:27].Cl.[N:29]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:6]=1[NH:27][N:29]=[C:13]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=N[O-]
Reactant: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c(N)c(OCCCl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OCCCl)c2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-methoxy-6-(naphthalene-1-sulfonylmethyl)-phenylamine (1.0 g, 2.46 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.17 g, 2.6 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.0 g, 2.39 mmoles).