Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[N:16]=[C:17]([N:20]=[C:21]([NH2:23])[NH2:22])[S:18][CH:19]=2)[N:14]=1.[CH3:24][N:25]=[C:26]=[O:27]>CO>[NH2:22][C:21](=[N:20][C:17]1[S:18][CH:19]=[C:15]([C:13]2[N:14]=[C:10]([CH2:9][NH:8][C:26]([NH:25][CH3:24])=[O:27])[S:11][CH:12]=2)[N:16]=1)[NH2:23]
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: CN=C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.6 %

Procedure:
Triethylamine (0.7 g) was added to a suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (1.0 g) in methanol (20 ml). To the mixture was added methylisocyanate (0.21 g). The mixture was stirred at room temperature for 1.5 hours. The solvent was removed under the reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from a mixture of water and methanol afforded 2-(diaminomethyleneamino)-4-[2-(3-methylureido)methylthiazol-4-yl]thiazole (0.5 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](SC)=[N:13][CH2:14][Si](C)(C)C)=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:26]=[C:25]([Cl:35])[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.COC(C)(C)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:30][C:29]([C:27]3[CH:26]=[C:25]([Cl:35])[CH:24]=[C:23]([Cl:22])[CH:28]=3)([C:31]([F:32])([F:34])[F:33])[CH2:14][N:13]=2)=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(COC(C)=O)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Yield: 93.2 %

Procedure:
Under argon atmosphere, a mixed solution of 2-bromo-4-[(methylsulfanyl){[(trimethysilyl)methyl]imino}methyl]benzyl acetate (0.90 g) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.56 g) in THF was cooled to −5° C. to be stirred, and a solution of tetrabutylammonium fluoride (0.56 ml, of 1.0 M in THF) was added thereto gradually. The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with t-butyl methyl ether and washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzyl acetate (1.1 g).
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20](O)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.NC1C=C(C(C)C)C(OS(=O)(=O)NC(=O)CC2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)=C(C(C)C)C=1.[NH2:59][CH:60]=[C:61]1[CH:66]=[C:65]([CH:67]([CH3:69])[CH3:68])[C:64]([O:70][S:71](=[O:92])(=[O:91])[NH:72][C:73](=[O:90])[CH2:74][C:75]2[C:80]([CH:81]([CH3:83])[CH3:82])=[CH:79][C:78]([CH:84]([CH3:86])[CH3:85])=[CH:77][C:76]=2[CH:87]([CH3:89])[CH3:88])=[C:63]([CH:93]([CH3:95])[CH3:94])[CH2:62]1>N1CCCCC1.CN(C)C=O>[NH2:18][CH2:19][C:20]([NH:59][CH2:60][C:61]1[CH:62]=[C:63]([CH:93]([CH3:95])[CH3:94])[C:64]([O:70][S:71](=[O:91])(=[O:92])[NH:72][C:73](=[O:90])[CH2:74][C:75]2[C:76]([CH:87]([CH3:89])[CH3:88])=[CH:77][C:78]([CH:84]([CH3:85])[CH3:86])=[CH:79][C:80]=2[CH:81]([CH3:82])[CH3:83])=[C:65]([CH:67]([CH3:68])[CH3:69])[CH:66]=1)=[O:21]
Reactant: CC(C)C1=CC(=CN)CC(C(C)C)=C1OS(=O)(=O)NC(=O)Cc1c(C(C)C)cc(C(C)C)cc1C(C)C
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(N)cc2C(C)C)c(C(C)C)c1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(CNC(=O)CN)cc2C(C)C)c(C(C)C)c1

Procedure:
When in the procedure of Example 1, bis-N,N'-(t-butoxycarbonyl)-(S)-lysine is replaced with N-(9-fluorenylmethyoxycarbonyl)-glycine, [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-amino-2,6-diisopropyl-phenyl ester is replaced by [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-(aminomethylene)-2,6-diisopropyl-phenyl ester, and the crude product is stirred in 20% piperidine/N,N-dimethylformamide for 0.5 hours followed by trituration with hexanes, the title compound is obtained; mp 193-195° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][N:10]=2)[NH:5][C:4](=[O:13])[N:3]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([NH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][N:10]=2)[NH:5][C:4](=[O:13])[N:3]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cnc2c(N)nc(=O)[nH]c2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cnc2c(NC(=O)c3ccccc3)nc(=O)[nH]c2n1
Temperature: 80 °C

Procedure:
In 20 mL of pyridine is dissolved 1.63 g (0.01 mole) of 4-amino-7-methyl-pteridine-2-one (20). Then 3.12 g (0.02 mole) of benzoyl chloride is added dropwise while stirring the mixture. The mixture is heated to 80° C. for 30 minutes and then poured on ice. The resulting precipitate is collected, washed with ethanol and ether and then recrystallized from DMF to give 21.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5]([Cl:25])=[CH:4][N:3]=1.[NH2:26][CH2:27][CH2:28][OH:29]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:7][C:2]([NH:26][CH2:27][CH2:28][OH:29])=[N:3][CH:4]=1
Reactant: Fc1ccc(SC(c2cc(F)ccc2F)c2cc(Cl)ncc2Cl)cc1
Reactant: NCCO
Solvent: C1COCCO1
Product: OCCNc1cc(C(Sc2ccc(F)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 56 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of 2,5-dichloro-4-[(2,5-difluorophenyl)-(4-fluorophenylthio)methyl]pyridine (200 mg, 0.50 mmol) and 2-aminoethanol (300 μl) was stirred at 120° C. for 2 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (120 mg, 56%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4I)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1.CC1C=C(C)N=C(N2CC3C[N:41]([C:43]([C:45]4[CH:50]=[CH:49][CH:48]=C(F)C=4I)=O)CC3C2)N=1>[Cu]I.COCCOC>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[C:48]4[CH:49]=[CH:50][CH:45]=[CH:43][N:41]=4)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccc(F)cc4I)CC3C2)n1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4I)CC3C2)n1
Agent: [Cu]I
Solvent: COCCOC
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccc(F)cc4-c4ccccn4)CC3C2)n1
Temperature: 130 °C

Procedure:
The title compound was prepared in a manner analogous to Example 367 substituting (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-iodophenyl)methanone for (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-iodophenyl)methanone, with the addition of catalytic CuI, substituting dioxane for DME, heating 130° C. in microwave for 60 min. The reaction was filtered through celite, rinsed with EtOAc and then concentrated and purified on RP agilent HPLC and fractions lyophilized. MS (ESI) mass calcd. for C24H24FN5O, 417.20; m/z found, 418.2 [M+H]+.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([N:9]2C(=O)C(C)(C)[N:11]([CH2:17][CH2:18][CH2:19][C:20](O)=O)[C:10]2=O)=[CH:5][C:4]=1C(F)(F)F)#N.[C:28](O)(C)(C)[CH3:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CC(C)=O>[CH:17]1([N:11]=[C:10]=[N:9][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]2)[CH2:18][CH2:19][CH2:20][CH2:29][CH2:28]1
Reactant: CC(C)(C)O
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
By carrying out the esterification of the product of Example 62, with terbutanol in the presence of dicyclohexylcarbodiimide and 4-dimethylamino-pyridine as in Example 60, the expected product melting at 96°-97° C. with a Rf=0.32 (eluant: methylene chloride-acetone (98-2)) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[Si:12]([O:29][CH2:30][CH2:31][CH2:32][CH:33]=CC1C=CC=CC=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C.S(=O)(O)[O-].[Na+]>ClCCl>[Si:12]([O:29][CH2:30][CH2:31][CH2:32][CH:33]1[O:10][CH:8]1[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](OCCCC=Cc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCCC1OC1c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 100.5 %

Procedure:
3-Chloroperbenzoic acid (2.14 g) was added to a solution of 5-(t-butyldiphenylsilyloxy)-1-phenyl-1-pentene (3.30 g) in dichloromethane (65 ml) at ambient temperature and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into a mixture of diethyl ether and 5% aqueous sodium bisulfite (100 ml). The organic layer was separated, washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, and evaporated in vacuo to give (2R*, 3R*)-3-[3-(t-butyldiphenylsilyloxy)propyl]-2-phenyloxirane (3.45 g) as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.[Br:23][C:24]1[S:25][C:26](Br)=[N:27][N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:23][C:24]1[S:25][C:26]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[N:27][N:28]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1nnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nnc(Br)s2)CC1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
To a 5 mL microwave vial was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (247 mg, 0.8 mmol), 2,5-dibromo-1,3,4-thiadiazole (98 mg, 0.4 mmol), K3PO4 (212 mg, 1.0 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture was purged with N2 for 10 min, then heated to 100° C. in the microwave for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 64 mg (46%) of tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate: MS (M+2)=348.1; 1H NMR (400 MHz, CHLOROFORM-d) δ 6.46 (td, J=3.0, 1.9 Hz, 1H), 4.15 (d, J=3.0 Hz, 2H), 3.64 (t, J=5.6 Hz, 2H), 2.73 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:6][C:5]=1[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:3].[H][H]>CO.[Pd]>[NH2:1][C:2]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:3]
Reactant: [H][H]
Reactant: NC(=O)c1ccc(C(=O)OCc2ccccc2)cc1NC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(C(=O)O)cc1NC1CCCCC1
Yield: 74.2 %

Procedure:
To a solution of benzyl 4-(aminocarbonyl)-3-(cyclohexylamino)benzoate (45 mg, 0.128 mmol) in methanol (2 mL) was added palladium on carbon (10W %, Degussa type, 45 mg). The mixture was vigorously stirred under 1 atm of hydrogen for 50 minutes. The catalyst was removed by filtration through celite, and the filtrate was concentrated to provide 4-(aminocarbonyl)-3-(cyclohexylamino)benzoic acid (25 mg, 0.095 mmol, 74% yield) as a yellow powder. 1H NMR (400 MHz, CD3OD): 7.59 (d, 1H), 7.35 (s, 1H), 7.14 (dd, 1H), 3.47-3.39 (m, 1H), 2.05-1.98 (m, 2H), 1.81-1.73 (m, 2H), 1.68-1.60 (m, 1H), 1.52-1.41 (m, 2H), 1.38-1.25 (m, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][CH2:4]1)(=[O:18])=[O:17]
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)CC1
Yield: 89 %

Procedure:
To a solution of 4-hydroxypiperidine (5.10 g, 50 mmoles) and triethylamine (20.9 ml, 150 mmoles) in methylene chloride (150 ml) was added methanesulfonyl chloride (8.54 ml, 110 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was solidified with ethyl acetate-n-hexane to obtain 11.45 g of the desired product (88.3%, pale yellow solid).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]=[C:7]([N:10]3[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]3)[N:8]=[CH:9][C:4]=2[CH2:3]1.[ClH:25]>CO.O1CCOCC1>[ClH:25].[ClH:25].[ClH:25].[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]=[C:7]([N:10]3[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11]3)[N:8]=[CH:9][C:4]=2[CH2:3]1
Reactant: CN1CCc2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ncc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCc2nc(N3CC[C@@H](N)C3)ncc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
tert-Butyl [(3R)-1-(6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)pyrrolidin-3-yl]carbamate (10.0 g, 30.0 mmol) was dissolved in methanol (40 mL) and cooled to 0° C. To this was added a solution of 4 N hydrochloric acid in dioxane (80 mL). The mixture was allowed to warm to room temperature and then stirred at room temperature for 1 hour and then evaporated to dryness. The residue was boiled with ethanol (100 mL) then cooled to 0° C. and the resulting precipitate was filtered off. This gave the title compound (6.99 g, yield 69%) as a pale pink hygroscopic solid. LCMS (ES+) M+H 234. 1H NMR (DMSO-d6) 2.12 (m, 1H) 2.30 (m, 1H) 2.86-2.94 (s+m, 4H) 3.14-3.24 (m, 1H) 3.37-3.46 (m, 1H) 3.56-3.77 (br m, 6H) 3.78 (br m, 1H) 4.13 (dd, J=14.6, 8.3 Hz, 1H) 4.35 (d, J=14.0 Hz, 1H) 8.28 (s, 1H) 8.52 (br s, 3H) 11.71 (br s, 1H). LRMS M+H 234.
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1.N([O-])=O.[Na+].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: Nc1ncc(N2CCOCC2)nc1N1CCOCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1ncc(N2CCOCC2)nc1N1CCOCC1

Procedure:
This product is obtained by treating the 2-amino-3,5-dimorpholinopyrazine with sodium nitrite by the method described in the preceding procedure, Step C, and then with phosphorus oxychloride by the method described in Preparation 13, Step B.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(O)(=O)CC[C:13]([OH:15])=[O:14]>>[C:13]([OH:15])(=[O:14])[CH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCCC(=O)O
Reactant: O=C(O)CCC(=O)O
Product: O=C(O)CCCCC(=O)O

Procedure:
The mother liquor with the urea-succinic acid adduct removed was treated with AMBERLYST 15 to remove urea and cooled to and allowed to stand at 15° C. after 200 g. of methanol had been distilled off, to deposit crude adipic acid. By subjecting the solution to filtration, 11.0 g. of crude adipic acid was obtained. The obtained crude adipic acid contained 1.8% by weight of glutaric acid and 1.6% by weight of succinic acid. This crude adipic acid may be recycled to a purification step in the production of adipic acid to obtain pure adipic acid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>>[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([S:2]([N:1]=[C:23]=[O:24])(=[O:3])=[O:4])[CH:14]=1)[CH3:17]
Reactant: CCCCN=C=O
Reactant: CCOc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Agent: O=C(Cl)Cl
Product: CCOc1ccc(C(=O)OC)c(S(=O)(=O)N=C=O)c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of methyl 2-(aminosulfonyl)-4-ethoxybenzoate (7.56 g, 29.2 mmol), n-butyl isocyanate (3.29 mL, 29.2 mmol), and 1,4-diaza[2.2.2]bicyclooctane (0.13 g, 1.2 mmol) in mixed xylenes was heated at reflux for 10 minutes. Phosgene was then added at such a rate that the internal temperature stayed at 133° C. or above. When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporation gave methyl 4-ethoxy-2-(isocyanatosulfonyl)benzoate as a cloudy yellow oil (8.2 g). This was used immediately without further purification or characterization.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.O>[CH3:19][S:20]([N:16]1[CH:17]=[CH:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[N:15]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)n1ccc(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 3-(4-phenoxyphenyl)-1H-pyrazole (125 mg, 0.529 mmol) in pyridine (10 mL) at room temperature was added neat methanesulfonyl chloride (50 μL, 0.64 mmol). After stirring overnight at room temperature, the reaction was diluted with water. Column chromatography afforded 152 mg (91%) of the title compound as white solid, mp 136° C. 1H NMR (CDCl3): δ 8.06 (d, J=3.0 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.37 (t, J=8.7 Hz, 2H), 7.14 (t, J=7.5 Hz, 1H)), 7.06 (d, J=8.7 Hz, 2H), 7.06-7.04 (m, 2H), 6.72 (d, J=3.0 Hz, 1H), 3.38 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)CO.O.NN.[OH-].[K+]>O>[CH2:7]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:25]([F:28])([F:26])[F:27])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(Cc3ccccc3)cnc12
Temperature: 120 °C
Yield: 54.2 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (Example 1, 0.244 g, 0.65 mmol) was taken into ethylene glycol (5 mL) along with hydrazine hydrate (0.3 mL) and heated at 120° C. for 2 hours. Next, a few pellets of KOH were added and reaction was heated at 180° C. for 4 hours. The reaction was allowed to cool to room temperature, where water was added and the mixture was extracted with ether and concentrated. The resulting material was purified via column chromatography using 5% ethyl acetate in hexane as the eluent to produce 0.128 g of desired product. MS (ESI) m/z 364 ([M+H]+); 1H NMR (CDCl3) δ 9.01 (s, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.51 (m, 3H), 7.44 (m, 1H), 7.20 (m, 5H), 6.97 (m, 2H), 3.98 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33](O)[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:32]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1cc(O)nc(OC)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(OC)nc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 2-hydroxy-6-methoxy-isonicotinic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. Light yellow oil (77%). MS (Turbo Spray): m/z=556.2 [M+H].
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](I)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([N:25]([CH2:33][C:34]#[CH:35])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24].C(N(CC)CC)C>[Cu]I.C(#N)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:35]#[C:34][CH2:33][N:25]([CH2:23][CH3:24])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ncc1Cl
Reactant: C#CCN(CC)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)C(=O)OC(C)(C)C
Yield: 66.5 %

Procedure:
The sub-titled compound was prepared from N-(1 adamantylmethyl)-5-chloro-2-iodoisonicotinamide (Example 2(i)) (0.40 g), tert-butyl ethyl(prop-2-ynyl)carbamate (Example 7(i)) (0.34 g), copper (I) iodide (0.004 g), bis-triphenyphosphine palladium dichloride (0.014 g), triethylamine (5 ml) and anhydrous acetonitrile (5 ml) by the method of Example 2(iii). The crude product was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (9:1 to 7:3) to afford the sub-titled compound (0.30 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([I:10])[N:7]=[CH:6]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CS(C)=O.O>[I:10][C:8]1[N:7]=[CH:6][N:5]([CH2:4][CH2:3][CH2:2][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1
Reactant: ClCCCn1cnc(I)c1
Reactant: C1CCNC1
Solvent: O
Solvent: CS(C)=O
Product: Ic1cn(CCCN2CCCC2)cn1
Yield: 78.2 %

Procedure:
A solution of the chloride 292 (1.2 g, 4.44 mmol) and pyrrolidine (1.1 mL, 13.3 mmol) in dry DMSO (2 mL) was heated at 60° C. under nitrogen for 3 h. The reaction mixture was cooled, diluted with water and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane, 5:95 to 20:80) to afford 293 (1.06 g, 3.47 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, J=1.2 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 2.45-2.33 (m, 4H), 2.29 (t, J=7.2 Hz, 2H), 1.84 (q, J=7.2 Hz, 2H), 1.72-1.62 (m, 4H). MS (m/z): 305.9 (M+H).