Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](SC)=[N:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3].[CH2:23]([NH2:25])[CH3:24]>>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:25][CH2:23][CH2:24][S:11][CH2:10][C:8]2[O:9][CH:5]=[CH:6][CH:7]=2)=[N:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CSC(=NS(C)(=O)=O)NCCSCc1ccc(CN(C)C)o1
Reactant: CCN
Product: CN(C)Cc1ccc(CSCCNC(=NS(C)(=O)=O)NCCSCc2ccco2)o1
Yield: 184.5 %

Procedure:
A mixture of N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'-methylsulphonylcarbamimidothioic acid, methyl ester (1.82 g) and 2-(2-furanylmethyl)thio]ethanamine (0.785 g) was heated at 120° for 5 hours. The reaction mixture was chromatographed (silica/ethyl acetate-methanol 3:1) and the appropriate eluate evaporated to dryness to give the title compound (2.18 g), as a yellow oil.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[CH:12]3[CH2:13][NH:14][CH2:15][C:16](=[CH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]3=[N:10][N:9]2[CH2:24][C:25]([F:28])([F:27])[F:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]#[C:30][NH2:31]>C(O)C>[ClH:1].[C:2]1([CH:8]2[CH:12]3[CH2:13][N:14]([C:30](=[NH:29])[NH2:31])[CH2:15][C:16](=[CH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]3=[N:10][N:9]2[CH2:24][C:25]([F:27])([F:26])[F:28])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: FC(F)(F)CN1N=C2C(=Cc3ccccc3)CNCC2C1c1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(N)N1CC(=Cc2ccccc2)C2=NN(CC(F)(F)F)C(c3ccccc3)C2C1
Yield: 48 %

Procedure:
Ten grams of 3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2-(2,2,2-trifluoroethyl)-2H-pyrazolo[4,3-c]-pyridine, monohydrochloride (see Example 2) is reacted with 8.2 g of cyanamide in 350 ml of ethanol at reflux temperature for 24 hours. The bulk of ethanol is removed on a rotary evaporator and the residue (which does not crystallize) is converted to 10.8 g of the free base (using sodium hydroxide and chloroform extractions); melting point 155°-157° C (foaming), sintering at 120° C. The base is dissolved in 400 ml of dichloromethane, treated with 5 ml of 6.1 N alcoholic hydrogen chloride, and the solvents removed on a rotary evaporator. The foamy residue (11.7 g) is stirred with 50 ml of water and 150 ml of ether. The material becomes gummy, then slowly crystallizes on cooling in ice-water, continued stirring, and rubbing. After standing in the cold for about 16 hours, the product is filtered, washed with ether, and air-dried, yielding 5.3 g of material; melting point 222°-225° C, sintering at 210° C. Crystallization from acetonitrile (dissolved in 200 ml of boiling solvent, then concentrated to approximately 100 ml; crystallization proceeeds very slowly while standing in the cold for several days) yields 3.0 g of product; melting point 230°-232° C, sintering at 223° C.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:19]2)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:19]2
Reactant: COC(=O)CCc1cc2cc(OCCCNC(=O)OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1cc2cc(OCCCN)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-{5-[3-(benzyloxycarbonylamino)propoxy]indolyl}propanoate (300 mg, 0.73 mmol), as prepared in the preceding step, 10% palladium(0) on carbon (50 mg) in ethanol (20 mL) was stirred at ambient temperature under hydrogen (balloon) for 3 h. The catalyst was removed by filtration through Celite. The filtrate was concentrated to give the title compound as an off white solid (150 mg, 74%). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 7.25 (d, J=8.9 Hz, 1H), 7.13 (d, J=2.6 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.9, 2.5 Hz, 1H), 6.38 (d, J=2.9 Hz, 1H), 4.43 (t, J=6.8 Hz, 2H), 4.10 (t, J=5.8 Hz, 2H), 3.66 (s, 3H), 3.01 (q, J=7.0 Hz, 2H), 2.83 (t, J=6.8 Hz, 2H), 2.04 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>C(#N)C>[C:19]([NH:18][C:17](=[N:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[O:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)#[N:20]
Reactant: COc1cccc(N)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: COc1cccc(N=C(NC#N)Oc2ccccc2)c1

Procedure:
m-Anisidine (4.56 mL, 4.06 mmol, 1 eq.), and diphenylcyanocarbonimidate (967 mg, 4.06 mmol, 1 eq.) were mixed and refluxed in acetonitrile under N2 for 1 hour. Solids precipitated. The reaction was worked up by filtering off the solids. Obtained 580 mg as product. M.P.=170.0-171.0° C. NMR (300 MHz, DMSO-d6) δ 8.70-8.50 (m, 1H); 7.43 (t, 2H, J=7 Hz); 7.40-7.20 (m, 2H); 7.14 (d, 2H, J=7 Hz); 7.00-6.80 (m, 2H); 6.80-6.70 (m, 1H); 3.80 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH2:2]1.Cl[CH2:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:21]>CN(C)C=O>[N:22]1([C:20](=[O:21])[CH2:19][N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:10])[CH2:2]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: O=C(CCl)N1CCc2ccccc21
Reactant: O=C(NCC1CNCCO1)Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCC1CN(CC(=O)N2CCc3ccccc32)CCO1)Nc1ccccc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a stirred solution of Intermediate 7 (0.01 g) in N,N-dimethylformamide (0.5 ml) was added 1-(2-chloroacetyl)indoline (0.0092 g). The mixture was stirred at 22° C. for 17 h before tris-(2-aminoethyl)amine polystyrene (Argonaut Technologies, 0.01 g @ 4.46 mmol/g) and polystyrene methyl isocyanate (Argonaut Technologies, 0.033 g @ 1.39 mmol/g) was added. Stirring was continued for a further 30 min before the mixture was purified by solid phase extraction (1 g Isolute SCX sulphonic acid column), eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was evaporated in vacuo to give the title compound as a white solid (0.012 g). LC/MS (System A) Rt 2.69 min, Mass Spectrum m/z 394 [MH+].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25](OC)[O:26]C)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A mixture of a solution of dimethyl 2-methyl-4-(2-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (10.68 g) in acetone (110 ml) and 6N hydrochloric acid (10 ml) was stirred at 25° C. for 3 hours, which was neutralized with an aqueous sodium bicarbonate solution and acetone was distilled off under reduced pressure. The resultant reddish yellow oily precipitates were solidified, which were cracked finely, collected by filtration, washed with water and air dried over-night to give crude crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (9.33 g).
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].CI.[C:17](OCC)(=O)C>O1CCCC1>[CH3:17][CH:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCOC(C)=O
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
9.91 Gram (95%, 56.9 mmol) of tert-butyl methyl malonate was dissolved in 120 mL of tetrahydrofuran (THF), and the resulting solution was added dropwise to a suspension containing 2.28 g (60 wt %, 56.9 mmol) of sodium hydride (NaH) and 120 mL of THF at 0° C. over 0.5 hours, followed by stirring for 0.5 hours. Thereafter, a solution containing 8.08 g (56.9 mmol) of methyl iodide (MeI) and 20 mL of TI-IF was added dropwise over 0.5 hours, and the resulting mixture was stirred at 0° C. for 0.5 hours and further stirred at 25° C. for 5 hours. After adding 200 of ethyl acetate, the organic layer was washed, in order, twice with saturated brine and twice with water, and dried over sodium sulfate, and the solvent was concentrated to obtain 13.0 g of 1-tert-butyl 3-methyl 2-methylmalonate as a colorless transparent oil. Subsequently, 45.9 g of an aqueous formalin solution was added to 13.0 g of the oil, and resulting mixture was cooled to 0° C. Furthermore, 7.81 g of potassium carbonate was added, and the mixture was stirred at 0° C. for 1 hour and further stirred at 25° C. for 3 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in order, three times with an aqueous saturated sodium hydrogensulfite solution and twice with water, and dried over sodium sulfate. The solvent was concentrated, and the residue was dissolved in 50 mL of pyridine. The resulting solution was cooled to 0° C., and 21.7 g of p-toluenesulfonyl chloride was added thereto. The obtained mixture was stirred at 0° C. for 2 hours and then stirred at 60° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in order, three times with an aqueous saturated ammonium chloride solution and twice with water, and dried over sodium sulfate. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate=4/1) to obtain 15.8 g of the objective Compound (I-31) as a colorless transparent oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([Cl:18])[CH:11]([CH3:13])[CH3:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)C(=O)Nc1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)C(Cl)=Nc1ccccc1C(F)(F)F
Yield: 99.3 %

Procedure:
A solution of 11.56 g of the product of Step A in 200 ml of toluene was added over 15 minutes to a suspension of 11.45 g of phosphorus pentachloride in 25 ml of toluene and after gas evolution ceased, the mixture was refluxed for 11/2 hours and was evaporated to dryness to obtain 12.4 g of N-(2-trifluoromethylphenyl)-2-methyl-propanimidoyl chloride as a yellow oil which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH2:15])=[N:5][C:6]1([CH2:14][NH:13][CH2:12]1)[NH:7]2.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29]>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH2:15])=[N:5][C:6]1([CH2:12][N:13]([C:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[O:29])[CH2:14]1)[NH:7]2
Reactant: O=C(Cl)c1cccs1
Reactant: NC1=NC2(CNC2)Nc2cccc(F)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC1=NC2(CN(C(=O)c3cccs3)C2)Nc2cccc(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
5'-Fluorospiro[azetidine-3,2'(1'H)quinazoline]-4'-amine (Example 250, 206 mg, 1 mmol) and triethylamine (0.28 ml., 2 mmol) in dry dichloromethane (15 ml) was stirred at 20° C. and thiophene-2-carbonyl chloride (0.12 ml, 1.1 mmol) added. The mixture was stirred at ambient temperature for 3 h then concentrated to dryness and separated by flash chromatography on silica using dichloromethane/methanol mixtures as eluant. The more polar fraction eluted afforded the title compound (50 mg) as a solid, m.p. 214°-215° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14](Cl)=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1.[CH2:22]([N:24]1[C:28]([OH:29])=[CH:27][CH:26]=[N:25]1)[CH3:23].C(N(CC)CC)C>ClCCCl>[CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14]([C:27]3[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[C:28]=3[OH:29])=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCn1nccc1O
Reactant: O=C(Cl)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCn1ncc(C(=O)c2ccc(Cl)c(Cn3nnn(C4CC4)c3=O)c2Cl)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
A 1,2-dichloroethane solution of 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl chloride (0.70 g) was added drop by drop to the solution of 1-ethyl-5-hydroxypyrazole (0.24 g) and triethylamine (0.24 g) in 1,2-dichloroethane (4 ml) at 5° C. and the mixture was stirred at room temperature for 6 hours. After reaction it was extracted with dichloromethane (100 ml), washed with diluted hydrochloric acid and aqueous solution of sodium hydrogen carbonate and then dried with anhydrous magnesium sulfate. The residue, obtained by distilling off the solvent, was dissolved in 1,4-dioxane (8 ml), added with potassium carbonate (0.38 g) and refluxed by heating for 3 hours. After the solvent was distilled off, the residue was teated with an aqueous solution of potassium carbonate and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate (150 ml). The organic layer was washed with saturated salt water and dried with anhydrous magnesium sulfate. By distilling off the ethyl acetate, the objective 4-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl}-5-hydroxy-1-ethylpyrazole (0.73 g, 88% yield from 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoic acid) was obtained. nD20: 1.5510.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][C:34]#[N:35])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:50]=[N+:51]=[N-:52])(C)C>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][C:34]5[NH:52][N:51]=[N:50][N:35]=5)[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(c1ccn2c1CSC2c1cccnc1)c1cn(Cc2nnn[nH]2)c2cc(-c3ccc(F)cc3)ccc12
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A mixture of 3(pyridin-3-yl)-7-[1-cyanomethyl-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (77 mg, 0.161 mmol), prepared as in Example 94, dibutyltin oxide (40 mg, 0.161 mmol), and trimethylsilylazide (47.3 μL, 0.322 mmol) in toluene (15 mL) was heated at reflux for three hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude product was azeotroped with CH2Cl2 and purified by flash chromatography on silica gel (9:1 CHCl3, methanol) to give 3-(Pyridin-3-yl)-7-[1-(1H-tetrazol-5-ylmethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (53 mg), m.p. 110°-118° C. 1H NMR (D3COD, 300 MHz) δ45 (d; 1H, J=15 Hz), 4.63 (dd, 1H, 15, 3 Hz), 5.75 (s, 2H), 6.57 (d, 1H, J=3 Hz), 6.67 (bs, 1H), 6.98 (d, 1H, J=3 Hz, 7.15 (t, 2H, J=9 Hz), 7.45-7.51 (m, 2H), 7.67-7.77 (m, 3H), 7.79 (s, 1H), 8.25 (s, 1H), 8.31 (d, 1H, 9 Hz), 8.55 (bs, 2H). MS (FAB) m/e 522 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:17])=[N:7][CH:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:18]Br>CC(O)=O>[Br:18][CH2:17][C:6]1[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[CH:8][N:7]=1
Reactant: CCCCc1c(C)ncnc1-c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCCc1c(CBr)ncnc1-c1ccccc1

Procedure:
A solution of 5-butyl-4-methyl-6-phenyl-pyrimidine (320 mg, 1.14 mmol) and Br2 (0.08 ml, 1.48 mmol) in AcOH (2 mL) is stirred at 80° C. for 2 hours. After cooling, the solution is concentrated. The residue is then partitioned between Et2O and half saturated aqueous NaHCO3. The layers are separated, and the aqueous layer is reextracted once with Et2O. The combined extracts are dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel. Elution with 3:1 hexanes-EtOAc affords 4-bromomethyl-5-butyl-6-phenyl-pyrimidine and a small amount of an unidentified impurity. 1H NMR (CDCl3, 300 MHz) δ 9.08 (s, 1H), 7.47 (s, 5H), 4.57 (s, 2H), 2.79–2.74 (m, 2H), 1.52–1.42 (m, 2H), 1.38–1.20 (m, 2H), 0.80 (t, J=7.4 Hz, 3H) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:19]([C:3]1[CH:4]=[C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:6]=[CH:7][C:2]=1[O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(-c2ccc(F)c([N+](=O)[O-])c2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)c([N+](=O)[O-])c2)nc1C
Temperature: 100 °C
Yield: 98.8 %

Procedure:
A reaction mixture solution prepared by suspending 931 mg of ethyl 2-(4-fluoro-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate, 339 mg of phenol and 622 mg of potassium carbonate in 15 mL of dimethylformamide was heated at 100° C. for 14 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, water was added and extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 1.14 g of ethyl 2-(3-nitro-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: F[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16].[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C>[CH2:19]([S:26][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1F
Reactant: SCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1SCc1ccccc1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 3.00 g (10.5 mmol) of 5-fluoro-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole and 1.48 ml (12.6 mmol) of benzylmercaptan is initially introduced into 24 ml of acetonitrile at 0° C. 4.78 ml (34.3 mmol) of triethylamine are then added dropwise and the reaction mixture is stirred for two hours at between 0° C. and 10° C. Following concentration by evaporation in vacuo, the resulting oil is purified by chromatography on silica gel, giving 3.19 g of 5-(benzylsulphanyl)-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole (78%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:7]2[CH2:6]1>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]2[CH2:6]1
Reactant: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: COCCN1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of 304a (286 mg, 1.26 mmol) in methanol (10 mL) was added Pd/C (28.6 mg). The system was evacuated and then refilled with H2. After stirring at room temperature for 2 h, the mixture was filtered off. The filtrate was concentrated under reduced pressure to afford 304b as a yellow solid (240 mg, 97%), which was used in the next step without further purification. MS-ESI: [M+H]+ 197.0
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>C1COCC1>[O:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(COc2ccccc2)cc(COc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(COc2ccccc2)cc(COc2ccccc2)c1
Yield: 99.2 %

Procedure:
Methyl 3,5-diphenoxymethylbenzoate (525 mg 1.51 mM) 2.0M sodium hydroxide (2.3 n 4.6 mm) methanol (5 ml) water (3 ml) and THF (10 ml) were stirred together at room temperature for 3 hours. After concentrating to ½ volume the mixture was acidified with 2.0M hydrochloric acid and partitioned between ethyl acetate and water. The organic extracts were washed with water, dried (magnesium sulphate) filtered and evaporated to give 3,5-diphenoxymethylbenzoic acid as a colourless solid (500 mg, 99%); H1 NMR δ (d6-DMSO) 5.19 (4 H s) 6.9–7.18 (6 H m) 7.28 (4 H t) 7.78 (1 H s) 7.95 (2 H s); MS [MH]− 333.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]([NH:67][CH3:68])=[O:66])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH:58]5[CH2:59][CH2:60][N:61]([CH2:64][C:65]([NH:67][CH3:68])=[O:66])[CH2:62][CH2:63]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNC(=O)CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)-N-methylacetamide. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.86 (m, 11 H) 1.95 (d, J=4.29 Hz, 2 H) 2.15 (t, J=10.61 Hz, 2 H) 2.62 (s, 3 H) 2.81 (d, J=11.37 Hz, 2 H) 2.90 (s, 2 H) 3.33 (s, 3 H) 3.94 (s, 3 H) 4.05 (t, J=14.02 Hz, 2 H) 4.77 (t, J=8.46 Hz, 1 H) 7.43-7.53 (m, 2 H) 7.57-7.69 (m, 1 H) 7.97 (s, 1 H) 8.14 (d, J=7.58 Hz, 1 H) 8.20-8.35 (m, 2 H) [M+H] calc'd for C29H38F2N8O4, 601; found 601.
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>CN(C=O)C.C(#N)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][S:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[NH2:2])=[CH:14][CH:13]=1
Reactant: Nc1cccc(S)c1
Reactant: COc1ccc(CCl)cc1
Agent: [Na]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(CSc2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium ydride (99%, 8.22 g) was added in portions of a stirred solution of 3-aminothiophenol (44.23 g) in dry DMF (132 ml) at 0° . After 30 minutes a solution of 4-methoxybenzyl chloride (53.61 g) in acetonitrile (132 ml) was added dropwise and the mixture was stirred 30 minutes at 0° and 1 hour more at ambient temperature. The mixture was poured into ice-water (200 ml) and the resulting solid was collected by filtration and dried in air to provide the title compound, m.p. 85°-86°.