Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:11])[CH2:4][CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[S:18][C:17]=2[CH:25]=1.C(N(CC)CC)C>O.C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([S:21]([N:9]3[CH2:8][CH2:7][NH:6][CH:5]([CH2:4][CH:3]([CH3:11])[CH3:2])[CH2:10]3)(=[O:23])=[O:22])[S:18][C:17]=2[CH:25]=1
Reactant: CC(C)CC1CNCCN1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)CC1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a methylene chloride solution (30 ml) of 2-(2-methylpropyl)piperazine hydrochloride (353 mg) were added 6-chlorobenzo[b]thiophene-2-sulfonyl chloride (438 mg) and triethylamine (498 mg). The resulting mixture was stirred at room temperature for 3 hours. Distilled water and methylene chloride were added. The water layer thus obtained was extracted three times with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol methylene chloride=1:100), whereby the title compound (363 mg) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([C:17]2[C:18](Cl)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([C:17]2[C:18]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([S:27][CH3:26])[CH:29]=3)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Reactant: CSc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
{cis-4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (5.44 g, 14.6 mmol), 3-methylsulfanylphenol (2.05 g, 14.6 mmol) and caesium carbonate (7.15 g, 21.9 mmol) were suspended in dimethylformamide (100 ml) and the reaction was heated to 65° C. and stirred at this temperature under nitrogen for 18 h, then at room temperature for 48 h. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was diluted with water (75 ml). It was then extracted with ethyl acetate (3×100 ml) and the combined organic extracts were washed with water (2×30 ml), brine (30 ml), dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with pentane:ether (50:50 changing to 45:55 then 40:60, by volume) to give (cis-4-{[-5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester (3.69 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])=[O:7].[CH3:23][NH:24][CH3:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:24]([CH3:25])[CH3:23])=[O:13])=[O:7]
Reactant: CNC
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(C)C(=O)c1cccc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (100 mg, 0.29 mmol), dimethylamine (0.031 ml, 0.59 mmol) in DMF 3.0 mL was added EDC (83.4 mg, 0.44 mmol), HOBt (58.9 mg, 0.44 mmol) and DIPEA (0.076 ml, 0.44 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give 3-[2-(2,4-dichloro-phenoxy)acetylamino]-N,N-dimethyl-benzamide as a white solid (59.3 mg, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:16]#[N:17])[N+:13]([O-])=[CH:14][C:8]=3[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:16]#[N:17])[N:13]=[CH:14][C:8]=3[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(C#N)cc2c2c(Cl)ccnc21
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxide (1.3 g, 3.52 mmol) in dichloromethane (11 mL) was treated with phosphorus trichloride (2N solution in dichloromethane, 1.9 mL, 3.9 mmol) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 40 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as a white solid (1.2 g, 93%). 1H NMR (400 MHz, CDCl3) δ 9.20 (d, J=0.9, 1H), 8.74 (d, J=0.9, 1H), 8.60 (d, J=5.3, 1H), 7.39 (d, J=5.3, 1H), 6.02 (s, 2H), 3.60 (t, J=8.0, 2H), 0.94 (t, J=8.0, 2H), −0.08 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:11][C:5]2[CH2:6][O:7][CH:8]([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:19]([NH:27][C:28](=[S:29])[NH:1][C:2]1[S:11][C:5]2[CH2:6][O:7][CH:8]([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC1Cc2c(sc(N)c2C(=O)OC(C)(C)C)CO1
Solvent: CCO
Product: CC1Cc2c(sc(NC(=S)NC(=O)c3ccccc3)c2C(=O)OC(C)(C)C)CO1
Yield: 34.2 %

Procedure:
To a solution of tert-butyl 2-amino-5-methyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.104 g, 0.386 mmol, 1 eq) in dry ethanol (1 mL) under argon was added benzoyl isothiocyanate (0.15 mL, 1.08 mmol, 2.8 eq). The mixture was heated at reflux for 16 hours. The solvent was evaporated in vacuo. Purification by reverse-phase chromatography (10-100% CH3CN: Water ramp over 20 min) afforded the desired product tert-butyl 2-(3-benzoylthioureido)-5-methyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate as a pale yellow oil (0.057 g, 0.132 mmol, 34% yield). 1H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.89 (s, 1H), 8.06-7.95 (m, 2H), 7.69 (t, J=7.4, 1H), 7.57 (t, J=7.7, 2H), 4.78 (d, J=14.8, 1H), 4.66 (d, J=15.0, 1H), 3.80-3.63 (m, 1H), 2.93 (d, J=16.7, 1H), 2.50-2.44 (m, 1H), 1.59 (s, 9H), 1.30 (d, J=6.1, 3H).
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N1C=CC=CC=1.P(Br)(Br)[Br:28].O>CCOCC>[Br:28][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCC#CCO
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCC#CCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 18.8 g of 2-nonadecyn-1-ol, 110 ml of ether, 1.14 ml of pyridine and 5.7 ml of phosphorous tribromide in 25 ml of ether is heated at reflux for 2 hours, then stirred at room temperature for 2 hours, poured into water and washed with hydrochloric acid. The solution is evaported and filtered through silicon dioxide with hexane, to give 16.9 g of the desired product as a white solid, mp. 34°-35° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]=[C:9]([C:13]2([CH3:18])OCC[O:14]2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]=[C:9]([C:13](=[O:14])[CH3:18])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC=C(C2(C)OCCO2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOC(=O)N1CCC=C(C(C)=O)C1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of 2-(1-allyloxycarbonyl-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1,3-dioxolane (6.95 g) in acetone (140 ml) was added p-toluenesulfonic acid dihydrate (523 mg) at room temperature and the mixture was stirred at the same temperature for 1 hour. Then, saturated aqueous sodium hydrogen carbonate solution was added for neutralization of the acid and the reaction mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate and water, followed by stirring, and the aqueous layer was separated and extracted with 2 portions of ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by column chromatography to give 1-allyloxycarbonyl-3-acetyl-1,2,5,6-tetrahydropyridine (4.43 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH:11]([N:15]([CH:17]3[CH2:19][CH2:18]3)[CH3:16])[CH2:10][CH2:9][C:8]([CH3:21])([CH3:20])[C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH:17]1([N:15]([CH3:16])[CH:11]2[CH2:10][CH2:9][C:8]([CH3:20])([CH3:21])[C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]2=3)[CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CCC2N(C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (Intermediate 55, 0.236 g, 0.83 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was treated with a 2M solution of sodium hydroxide (4 mL, 8 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a solid (0.22 g, 100%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3].[C:26](N1C=CN=C1)([N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:27]>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]([C:26]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[O:27])[N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)n1ccnc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (0.492 g, 1.37 mmol) in THF (8 mL) was added 1,1′-carbonyl diimidazole (0.266 g, 1.64 mmol). After stirring at 75° C. for 2 hours, the reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane (20 mL). The solution was washed with HCl (0.5 M), dried over Na2SO4 and concentrated to provide the crude product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[I-].[K+].[Cl:16][C:17]1[N:22]=[C:21]([S:23][CH3:24])[N:20]2[CH:25]=[C:26]([CH2:28]Cl)[N:27]=[C:19]2[CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([S:23][CH3:24])[N:20]2[CH:25]=[C:26]([CH2:28][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:27]=[C:19]2[CH:18]=1
Reactant: CSc1nc(Cl)cc2nc(CCl)cn12
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)cc2nc(CN3CCOCC3)cn12
Reaction time: 16 h

Procedure:
158 mg (1.81 mmol) of morpholine are introduced into 10 ml of DMF at 0° C., and 367 mg (3.63 mmol) of triethylamine and a catalytic amount of potassium iodide are added. A solution of 300 mg of 7-chloro-2-(chloromethyl)-5-(methylthio)imidazo[1,2-c]pyrimidine (Example 26A) in DMF is then slowly added dropwise. The mixture is allowed to reach RT and is stirred at this temperature for a further 16 h. Purification of the crude product by preparative HPLC and drying under high vacuum result in 221.8 mg (41% of theory) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9].C(N(CC)CC)C.Cl[O-].[Na+].[OH:20][N:21]=[CH:22][C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:46])[CH2:35][N:36]3[C:40]([CH3:41])=[CH:39][C:38]([C:42]([F:45])([F:44])[F:43])=[N:37]3)[CH2:30][CH2:29]2)[S:26][CH:27]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:20][N:21]=[C:22]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([C:34](=[O:46])[CH2:35][N:36]4[C:40]([CH3:41])=[CH:39][C:38]([C:42]([F:45])([F:43])[F:44])=[N:37]4)[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH2:9]1
Reactant: C=Cc1ccccc1Cl
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4Cl)C3)cs2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-2-ethenylbenzene (0.035 g, 0.25 mmol), triethylamine (2.5 mg, 0.025 mmol) and Clorox® aqueous sodium hypochlorite solution (1 mL, 16.1 mmol) in dichloromethane (5 mL) was added 4-[4-[(hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step C) (0.10 g, 0.25 mmol) in dichloromethane (5 mL) dropwise over 1 h at 0° C. The reaction mixture was allowed to stir for 1 h, then filtered through Celite® diatomaceous filter aid, and concentrated under reduced pressure to give an oil, which was purified by column chromatography on silica gel using 50% ethyl acetate in hexane as eluant to give 73 mg of the title compound as a white foam, melting at 115-122° C. (crystallized from methyl acetate/petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:10][S:11]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N)cn1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C#N)nc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
5-Amino-2-cyanopyridine (5 g) was dissolved in pyridine (30 ml). The solution was cooled to 0° C. and to the solution was added dropwise methanesulfonyl chloride (3.6 ml), followed by stirring at room temperature for 17 hours. The resulting mixture was concentrated under reduced pressure, extracted with water and dichloromethane, and then dried. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=2/1) to yield an orange colored solid (6.4 g, 77%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Cl[C:17]1[CH:22]=[C:21]([CH2:23][CH3:24])[N:20]=[CH:19][N:18]=1>CN1CCCC1=O.C(OCC)(=O)C>[CH2:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:11]3)[CH:22]=1)[CH3:24]
Reactant: CCc1cc(Cl)ncn1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCc1cc(NCc2ccc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 100 °C
Yield: 34.7 %

Procedure:
A stirred mixture of {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 34, 171 mg, 0.8 mmol), 4-chloro-6-ethylpyrimidine (Intermediate 12, 171 mg, 1.200 mmol) and DI PEA (0.279 mL, 1.600 mmol) in N-methyl-2-pyrrolidone (1 mL) was heated at 100° C. for 2 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate. The solution was washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 50-100% ethyl acetate in isohexane to give the crude product which was triturated with ether/isohexane and the resulting colourless solid was collected, washed with cold ether and dried to give the title compound (89 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[N:15]=[N:16][C:11]3=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32].[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[N:15]=[N:16][C:11]3=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: COC(=O)CCNc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCNc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.7 %

Procedure:
To a solution of example 57 (0.080 g, 0.165 mmol) in methanol (0.8 ml), lithium hydroxide (0.064 g, 1.54 mmol) in water (0.8 ml) was added and stirred at RT. After 12 h, pH was adjusted to ca. 7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale green solid (0.075 g, 68%). M.P.: 132-135° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=[O:9])=[C:5]([CH3:7])[N:6]=1.[OH-].[Na+].O1CCCC1>O>[NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N)sc1C(=O)O
Yield: 94 %

Procedure:
A solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (6.58 g, 35.00 mmol) and sodium hydroxide (5.40 g, 135.00 mmol) in the mixture of tetrahydrofuran (60 mL) and water (30 mL) was heated at reflux for 18 hours. The tetrahydrofuran was removed in vacuo, and the aqueous solution was neutralized with 5% HCl solution to pH 5-6. The precipitated solid was collected by filtration, washed with water and dried to afford 2-amino-4-methylthiazole-5-carboxylic acid as a white solid in 94% yield (5.20 g): 1H NMR (300 MHz, DMSO-d6) δ 7.63 (s, 2H), 2.30 (s, 3H); MS (ES+) m/z 159.1 (M+1).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Cl:22])[CH:16]=1)C>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)=[CH:16][C:17]=1[Cl:22]
Reactant: CCOC(=O)CNc1ccc(Br)c(Cl)c1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Clc1cc(NCC2=NCCN2)ccc1Br
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (1.90 ml, 3.79 mmol, 2 M solution). A solution of ethylenediamine (0.25 ml, 3.79 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 100 min at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of (4-bromo-3-chloro-phenylamino)-acetic acid ethyl ester (0.56 g, 1.90 mmol) in toluene (3 ml). The reaction mixture was then heated at 95° C. for 45 min and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: dichloromethane/methanol=gradient 100:0-98:2) to yield a yellow gum; MS (ISP): 292.1, 290.0, 288.1 ([M+H]+.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH:43]1[CH2:50][CH:49]2[N:51]([CH3:52])[CH:45]([CH2:46][CH2:47][CH2:48]2)[CH2:44]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)C>[CH3:52][N:51]1[CH:45]2[CH2:46][CH2:47][CH2:48][CH:49]1[CH2:50][CH:43]([NH:42][C:17]([C:15]1[CH:16]=[C:2]([Br:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:44]2
Reactant: O=C(O)c1cc(Br)cc2oc(-c3ccccc3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cc(Br)cc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
A mixture of 6-bromo-2-phenylbenzoxazole-4-carboxylic acid (82 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99 mg, 0.52 mmol), 1-hydroxybenzotriazole (70 mg, 0.52 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (48 mg, 0.31 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.10 mL, 1.03 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether (50 mL) and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. During the concentration, a white solid was crashed out. The solid was isolated, washed with ether and dried under high vacuum to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide (40 mg, 34%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.89 (d, J=7.3 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.25-8.20 (m, 2H), 7.86 (d, J=1.8 Hz, 1H), 7.65-7.55 (m, 3H), 4.60-4.52 (m, 1H), 3.12 (d, J=10.8 Hz, 2H), 2.70-2.60 (m, 2H), 2.54 (s, 3H), 2.20-1.95 (m, 2H), 1.62-1.52 (m, 2H), 1.50-1.45 (m, 2H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 454 (M+H); HPLC>99% (AUC), tR=13.52 min.
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][C:14]([CH3:16])=[O:15]>>[C:14]([CH2:16][S:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)(=[O:15])[CH3:13]
Reactant: CC(C)=O
Reactant: Sc1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)CSc1nnn[nH]1
Reaction time: 2 h

Procedure:
5-Mercapto-1,2,3,4-tetrazole (1 g), potassium carbonate (2 g) and β-chloroacetone (1.4 g) are added to acetone (50 ml) and the solution is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (Kieselgel 60, eluant: benzene-ether (10:1) to obtain 5-acetylmethylthio-1,2,3,4-tetrazole (0.4 g) as colorless liquid.