Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[CH:15]([OH:20])([OH:19])[CH2:16][CH2:17][CH3:18]>>[C:1]([OH:13])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:15]([OH:20])([OH:19])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: *CCCC*
Agent: *CC*
Agent: CCCC(O)O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 180 °C

Procedure:
A polyethylene glycol terephtalate/polybutylene terephthalate copolymer may be synthesized from a mixture of dimethyl terephthalate, butanediol (in excess), polyethylene glycol, an antioxidant and a catalyst. The mixture is placed in a reaction vessel and heated to about 180° C., and methanol is distilled as transesterification proceeds. During the transesterification, the ester bond with methyl is replaced with an ester bond with butylene and/or the polyethylene glycol. After transesterification, the temperature is raised slowly to about 245° C., and a vacuum (finally less than 0.1 mbar) is achieved. The excess butanediol is distilled off and a prepolymer of butanediol terephthalate condenses with the polyethylene glycol to form a polyethylene/polybutylene terephthalate copolymer. A terephthalate moiety connects the polyethylene glycol units to the polybutylene terephthalate units of the copolymer and thus such a copolymer also is sometimes referred to as a polyethylene glycol terephthalate/polybutylene terephthalate copolymer (PEGT/PBT copolymer).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[CH2:17][CH2:16]1
Reactant: ClCc1nc2cccnc2s1
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 4-(1-piperazinyl)phenol (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.73 (m, 4H) 3.02 (m, 4H) 4.03 (s, 2H) 6.72 (m, 4H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H): (ESI) m/z 327 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].O.NN>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.5 g of (+/−)-cis-1,2-dimethoxy-4-(2-nitrocyclohexyl)benzene are dissolved in 400 ml of methanol and treated with 7 ml of hydrazine hydrate and 2.5 g of Raney nickel in portions at RT in the course of 8 h. After stirring overnight at RT, the reaction mixture is filtered, the filtrate is concentrated and the residue is chromatog raphed on silica gel using a mixture of toluene/ethyl acetate/triethylamine=4/2/0.5. The title compound is obtained as an oil.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]([NH2:27])[NH2:26])=[CH:20][CH:19]=1.C(O)(O)=O>CN1C(=O)CCC1.O>[C:21]1([NH:24][C:25]2[N:27]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:26]=2)[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Reactant: NC(N)=Nc1ccccc1
Agent: O=C(O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of (2E)-3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (0.49 g, 2 mmol) and phenylguanidine carbonate salt (0.30 g, 2.2 mmol) in NMP (4 ml), is stirred at 120° C. for 2 days. It is then cooled to room temperature and diluted with water (40 ml). The resulting suspension is filtered, and the precipitate is washed with 50% ammonium chloride solution, water, and hexanes, and then dried in vacuo to give 0.56 g of an off-white solid; mp 162-163° C.; HRMS: calcd for C17H12F3N3, 315.0983; found (ESI_FTMS, [M+H]1+), 316.1048.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a stirred solution of 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbothioamide (0.69 g), ethyl 2-butynoate (0.43 mL), tetrahydrofuran (15 mL) and toluene (25 mL) was added tributylphosphine (0.54 mL) at room temperature under argon atmosphere. After the mixture was stirred at 40° C. for 4 h, ethyl 2-butynoate (0.22 mL) and tributylphosphine (0.27 mL) were added thereto. After stirring at 40° C. for 2 h, the reaction mixture was concentrated to give a light brown oil, which was purified by silica gel chromatography (ethyl acetate:hexane=30:70 to 75:25, volume ratio) to give the title compound (684 mg, 72%) as a light yellow oil. MS 489 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]([NH2:13])([CH2:11][CH3:12])[CH3:10].C(#N)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:13][CH:9]([CH2:11][CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCC(C)N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(C)Nc1ncc(Br)cn1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In a sealed tube 2.00 g (10.3 mmol) 5-bromo-2-chloropyrimidine and 3.13 mL (31.0 mmol) sec-butylamin are added to 12 mL ACN. The reaction mixture is stirred at 120° C. for 2 h, then diluted with EtOAc and washed with water (2×). The org. phase is dried with MgSO4 and the solvent is removed in vacuo. C8H12BrN3 (M=230.1 g/mol)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:38])=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl {3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.34 g, 3.35 mmol) in 30 mL of CHCl3 was treated with MCPBA (1.45 g, 5.03 mmol, 77% max). After 3 h, the reaction mixture was diluted with 10% Na2CO3 solution and CHCl3 and the phases were separated. The organic portion was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl {3-[(2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.39 g) as an orange foam.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38]([CH3:49])[C:39]([C:41]1[CH2:42]N(C)[C:44](=[O:47])[C:45]=1[OH:46])=[O:40]>>[Cl:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[Cl:53])[CH2:37][N:38]([CH3:49])[C:39]([C:41]1[CH2:42][N:32]([CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[C:44](=[O:47])[C:45]=1[OH:46])=[O:40]
Reactant: CN1CCN(CCN)CC1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN1CCN(CCN2CC(C(=O)N(C)Cc3ccc(Cl)c(Cl)c3)=C(O)C2=O)CC1
Yield: 12 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 2-(4-methyl-piperazine-1-yl)-ethyl amine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber glass (27 mg, 12% yield). 1H NMR (300 MHz, DMSO) δ: 7.63 (d, 1H, J=8.42), 7.52 (s, 1H), 7.25 (d, 1H, J=7.31), 4.59 (s, 2H), 4.24 (m, 10H), 4.11 (s, 2H), 3.58 (s, 2H), 2.98 (s, 3H), 2.78 (s, 3H). HRMS (M−H) calcd for C20H25N4Cl2O3: 439.1303. found: 439.1311.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][NH:6][C@H:7]([C@@H:10]([OH:14])[CH2:11][S:12][CH3:13])[CH2:8][OH:9].[CH2:15]([O:22][CH2:23][N:24]1[C:32]2[C:31]([Cl:33])=[N:30][CH:29]=[N:28][C:27]=2[C:26]([CH:34]=O)=[CH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([O:22][CH2:23][N:24]1[C:32]2[C:31]([Cl:33])=[N:30][CH:29]=[N:28][C:27]=2[C:26]([CH2:34][N:6]([CH3:5])[C@@H:7]([C@H:10]([OH:14])[CH2:11][S:12][CH3:13])[CH2:8][OH:9])=[CH:25]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN[C@@H](CO)[C@@H](O)CSC
Reactant: O=Cc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CSC[C@@H](O)[C@@H](CO)N(C)Cc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Reaction time: 48 h
Yield: 67 %

Procedure:
Sodium cyanoborohydride (68 mg, 1.1 mmol) was added to a stirred solution of (2S,3R)-2-(methylamino)-4-(methylthio)butane-1,3-diol (120 mg, 0.7 mmol) and 5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (263 mg, 0.9 mmol) in methanol (2 ml) and the resulting reaction left for 48 h. The reaction was concentrated in vacuo and the resulting residue purified by flash chromatography on silica gel eluting with 5% MeOH/DCM=>10% MeOH/DCM to afford, presumably, (2S,3R)-2-(((5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)(methyl)amino)-4-(methylthio)butane-1,3-diol B.4 (220 mg, 67% yield) as a syrup which was used in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH3:11])[N+:9]=1[O-])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:15]>C(Cl)Cl>[C:1]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:11][Cl:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(C(C)(C)C)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1oc(C(C)(C)C)nc1CCl
Yield: 75.5 %

Procedure:
30 g of the above prepared 2-tert-butyl-4,5-dimethyl-oxazole 3-oxide (˜115 mmol) was dissolved in 390 ml of CH2Cl2 and treated dropwise with 12.74 ml of POCl3 (139 mmol). The reaction mixture was refluxed over night and then quenched by carefully pouring onto crashed ice/3N NaOH. Separation of the layers, additional extraction of the aqueous phase with CH2Cl2, drying of the combined organic phase over sodium sulfate, evaporation of the solvents, and, finally, flash chromatography (SiO2, hexane/AcOEt=85/15) yielded 16.29 g of the title compound as white crystals of mp. 41–44°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([I:26])[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([I:26])[S:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (380 mg, 2.0 mmol) and 60% sodium hydride (80 mg, 2.0 mmol) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (320 mg, 1.0 mmol) is added and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2% methanol in chloroform to provide 240 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 233–234° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.38 (s, 1H), 7.77 (s, 1H), 7.79 (s, 1H), 8.56 (s, 1H), 9.74 (s, 1H); MS 475.9 (M+H)+.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[C:23]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1.CO>O1CCCC1>[CH3:1][O:20][C:21]1[CH:22]=[C:23]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(O)c3)nc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCOc1ccc(-c2cnc(-c3cccc(OC)c3)nc2)cc1
Yield: 80 %

Procedure:
1.50 g (5.76 mmol) of triphenylphosphine and 0.90 ml (5.76 mmol) of diethyl azodicarboxylste in 40 ml of tetrahydrofuran are stirred at 0° C. for 30 minutes. 1.50 g (3.84 mmol) of 2-(3-hydroxyphenyl)-5-(4-octyloxyphenyl)pyrimidine and 0.23 ml (5.76 mmol) of methanol are subsequently added, and the resultant solution is stirred at room temperature overnight. Evaporation to dryness, chromatographic purification (silica gel/dichloromethane:ethyl acetate=95:5) and recrystallization from acetonitrile give 1.20 g of 2-(3-methoxyphenyl)-5-(4-octyloxyphenyl)pyrimidine. ##STR16##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1.CO>[Ir].ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:15][CH:16]=1
Reactant: COc1ccc(C=C2CCCNC2=O)cc1
Agent: [Ir]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CC2CCCNC2=O)cc1
Yield: 87.4 %

Procedure:
This example describes the preparation of I where n=2 and R1=p-methoxyphenyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(p-methoxybenzylidene)-2-piperidone (250 mg, 1.2 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-p-methoxybenzyl-2-piperidone (230 mg, 92%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak AS, 60% heptane, 39.2% isopropanol, 0.4% trifluoroacetic acid, 0.4% n-hexylamine, 40° C.) indicated that conversion was 100% and the enantiomeric excess was 83%. 13C NMR: δ 21.32, 25.49, 36.72, 42.56, 43.11, 55.40, 113.93, 130.37, 131.99, 158.18, 174.93; 1H NMR: δ 1.44 (m, 1H), 1.62 (m, 1H), 1.68-1.75 (m, 2H), 2.50 (m, 1H), 2.64 (app. dd, 1H), 3.20-3.37 (m, 3H), 3.79 (s, 3H), 6.82 (d, J=9 Hz, 2H), 7.09 (br s, 1H), 7.12 (d, J=9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:17][CH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(C)nc(C(F)(F)F)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Temperature: 100 °C

Procedure:
A mixture of ethyl 6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.1 g, 4.5 mmol, prepared as described in WO 2007/090748), N-bromosuccinimide (2.86 g, 16.1 mmol) and benzoyl peroxide (0.21 g, 0.9 mmol) in carbon tetrachloride (9 mL) was heated in a sealed vessel to 100° C. overnight. The mixture was diluted with dichloromethane (DCM), filtered and the solvent was removed in vacuo. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded the product, which on removal of solvent, was an oil.
Reaction SMILES: [CH:1]1([C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][NH:13]C(=O)OC(C)(C)C)=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[ClH:22]>>[NH2:13][CH2:12][C:8]1[C:9](=[O:11])[NH:10][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:6][C:7]=1[CH3:21].[ClH:22]
Reactant: Cc1cc(C2CCC2)[nH]c(=O)c1CNC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1cc(C2CCC2)[nH]c(=O)c1CN
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl [(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3pyridinyl)methyl]carbamate (2.1 g, 7.2 mmol) in 4 N HCl (in 15 mL 1,4 dioxane) was heated to 60° C. for 1 h. The mixture was cooled to room temperature. The mixture was filtered and dried to give 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone as an HCl salt (1.95 g, 90%). LCMS MH+=193.1 1H NMR (400 MHz, DMSO-d6) δ 11.70 (br s, 1H), 8.01 (s, 3H), 6.04 (s, 1H), 3.74 (d, 2H), 3.32-3.39 (m, 1H), 2.22 (s, 3H), 2.17-2.20 (m, 2H), 2.06-2.11 (m, 2H), 1.85-1.95 (m, 1H), 1.71-1.79 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][C:6]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C(O)(C)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3[C:4](=[CH:5][C:6]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:8]=3)[N:3]=2)=[CH:30][CH:29]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(=O)n(C)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)n(C)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a suspension of methyl 2-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (70.0 mg, 0.28 mmol) in isopropyl alcohol (3 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) and p-chlorobenzylamine (84.2 μL, 0.69 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% MeOH/DCM) to afford methyl 2-[(4-chlorobenzyl)amino]-3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (92 mg, 93%). LC-MS: (FA) ES+ 358.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]1[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(Cl)(=O)C([Cl:26])=O.CN(C=O)C>ClCCl>[O:1]=[S:2]1(=[O:22])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]1[C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:26])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)benzoic acid (0.39 g; 1.0 mmol) in dichloromethane (6 mL) was treated with oxalyl chloride (1 mL), a drop of DMF, and allowed to stir at ambient temperature for a period of 2 hours. The solvent was removed under reduced pressure to afford 4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)benzoyl chloride, 7, (0.3 g, quant.) which was used without further purification.
Reaction SMILES: O.NN.[CH3:4][C@H:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O.[ClH:23]>C(O)C>[ClH:23].[CH3:4][C@H:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:6][NH2:7]
Reactant: C[C@@H](CN1C(=O)c2ccccc2C1=O)CC(F)(F)F
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: C[C@@H](CN)CC(F)(F)F
Yield: 88 %

Procedure:
Hydrazine monohydrate (3.1 ml) was added to a stirred solution of (R)-2-(2-methyl-4,4,4-trifluorobutyl)-1H-isoindole-1,3(2H)-dione (17.1 g) in anhydrous ethanol (85 mL) and heated to reflux. After three hours' reflux, the solution was cooled; ethanol (40 mL) was added; and the solution was acidified to pH 1 by addition of concentrated hydrochloric acid and was filtered. The filtrate was evaporated, and the residue was purified by sublimation (bath temperature 170° C., at 6.6 Pa) to yield (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride as a white solid (9.89 g, 88%); m.p. 187°-191° C.; partial NMR (300 MHz, DMSO-d6 -D2O shake): 1.05 (d, 3H, CH3), 2.06-2.36 (m, 2H, CF3CH2) 2.36-2.54 (m, 1H, CHCH3) 2.73 (dd, 1H, CH2N), 2.87 (dd, 1H, CH2N) 8.20 (br, s, 2H, NH2).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:24][CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7]
Reactant: NCCO
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NCCO)c(O)c2c1

Procedure:
Synthesized from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-amino-ethanol in analogy to example B-5; MS-(+)-ion: M+1=325.1.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3/[C:20](=[N:29]\[O:30][CH3:31])/[C:21](OCCCCC)=[O:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH2:33].O>O1CCCC1>[CH3:32][NH:33][C:21](=[O:22])[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:12][C:9]1[N:10]=[CH:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[N:29][O:30][CH3:31]
Reactant: CCCCCOC(=O)/C(=N/OC)c1ccccc1COc1ncn(-c2ccccc2)n1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1COc1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
1.5 g (3.6 mmol) of the pentyl ester from Example 13 were dissolved in 50 ml of tetrahydrofuran, and the mixture was treated with 10 ml of 40% strength aqueous monomethylamine solution and stirred at room temperature for 16 hours. It was then treated with water, extracted with methyl tert-butyl ether, and the organic phase was washed with water, dried over sodium sulfate and concentrated in a rotary evaporator. As a residue, 1.1 g (86% yield) of the title compound remained as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=[N:11]O)[NH:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1.[OH-].[NH4+]>>[F:1][C:2]([F:14])([F:13])[C:3]1[N:4]=[C:5]2[CH:10]=[N:9][CH:8]=[CH:7][N:6]2[N:11]=1
Reactant: ON=C(Nc1cnccn1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: FC(F)(F)c1nc2cnccn2n1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A mixture of 2,2,2-trifluoro-N′-hydroxy-N-pyrazin-2-ylethanimidamide (10.5 g, 50.97 mmol, from Step B) and polyphosphoric acid (80 mL) was heated to 150° C. with stirring for 18 h. The solution was added to ice and neutralized by addition of ammonium hydroxide. The dark aqueous solution was extracted three times with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography (50% then 100% ethyl acetate/hexane) afforded the title compound as a yellow solid.