Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:15]([CH2:16][CH3:17])[CH2:13][CH3:14]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCN(CC)c1ccnc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 15 h
Yield: 17.4 %

Procedure:
To a mixture of 6-bromo-4-chloro-quinoline (0.900 g, 3.71 mmol) and diethylamine (1.364 g, 18.56 mmol) in ethanol (10 mL) was added potassium carbonate (2.56 g, 18.56 mmol) at room temperature. Then, the reaction mixture was stirred for 15 h in a sealed tube. TLC analysis of the reaction mixture indicated the presence of lot of 6-bromo-4-chloro-quinoline and another 2 mL of diethylamine was added and heated to 100° C. and stirred for 15 h. After cooling to room temperature, the reaction mixture was diluted with water and the solvent was removed under the vacuum. Then, the product was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 0.180 g (17.4% yield) of (6-bromo-quinolin-4-yl)-diethylamine as a light yellow oil: EI-LRMS m/e calcd for C13H15BrN2 (M+) 279.1, found 279.1.
Reaction SMILES: Cl.[CH:2]1([C:6]([NH2:8])=[NH:7])[CH2:5][CH2:4][CH2:3]1.C(O[CH:12]=[CH:13][C:14]#[N:15])C>>[CH:2]1([C:6]2[N:8]=[C:14]([NH2:15])[CH:13]=[CH:12][N:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: N=C(N)C1CCC1
Reactant: CCOC=CC#N
Agent: Cl
Product: Nc1ccnc(C2CCC2)n1

Procedure:
This intermediate was made according to example 2, step A] method from cyclobutanecarboxamidine hydrochloride (0.3 g, obtained from cyclobutanecarbonitrile in analogy to Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (14), 1990, 1969-1972) and 3-ethoxy-acrylonitrile (0.3 g). 2-Cyclobutyl-pyrimidin-4-ylamine was obtained as a light brown solid (0.26 g): 1H NMR (δ, DMSO-d6): 7.98 (d, 1H), 6.66 (br s, 2H), 6.21 (s, 1H), 3.35-3-37 (m, 1H), 2.33-2.23 (m, 2H), 2.19-2.12 (m, 2H), 1.99-1.88 (m, 1H), 1.82-1.74 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].N#N>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH3:14])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNc1cc(Cl)ncc1CO
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
To a 0° C. solution of ethyl 6-chloro-4-(methylamino)nicotinate (4 g, 18.7 mmol) in THF (40 mL) was added LiAlH4 (1.4 g, 37.4 mmol) portionwise under N2 atmosphere. After stirring for 20 min, the reaction was quenched by cautious addition of water followed by aqueous solution of 2 N NaOH. The suspension was filtered and the filtrate was concentrated to afford (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 90.6% yield), which was used in next step without purification. 1HNMR (400 MHz, DMSO-d6): δ 7.96 (s, 1 H), 6.63 (s, 1 H), 6.46 (s, 1 H), 5.04 (s, 1 H), 4.39 (m, 2 H), 2.81-2.68 (m, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][N:13]=1)[CH3:2].B(O)(O)[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[CH:15]=[CH:14][N:13]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OS(=O)(=O)C(F)(F)F)ccn1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(C)cc2)ccn1
Yield: 88 %

Procedure:
Compound II (56 mg, 0.117 mmol), Pd(PPh3)4 (12 mg, 0.011 mmol), p-tolylboronic acid (32 mg, 0.235 mmol) and potassium carbonate (65 mg, 0.47 mmol) were stirred in toluene (3 mL) and water (1.5 mL) at 120° C. under microwave irradiation (300 W) for 30 min. The reaction mixture was then poured onto brine (30 mL) and extracted with EtOAc (2×20 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 80:20) to furnish III as a colourless oil (43 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([C:16]#[N:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[N:12][CH:11]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]2[CH:11]=[N:12][C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:15]=2[C:16]#[N:17])=[CH:4][C:5]([S:23]([Cl:22])(=[O:25])=[O:24])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-(2-chloro-4-methoxy-phenyl)-2-trifluoromethylisonicotinonitrile (0.7 g, 2.24 mmol) in chloroform (6 mL), was added to ClSO3H (0.62 mL). The solution was stirred at rt for 16 hrs. The solvent was removed and MeCN (3 mL) was added, followed by addition of POCl3 (3 mL). The mixture was heated at 60° C. for 16 hrs, then concentrated. The remainder was poured into ice water with stirring. The resulting solid was filtered, dried in vacuo over 2 days to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzenesulfonyl chloride (0.79 g) as a pale yellow solid. tR=2.92 min (method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]3)=[CH:8][C:7]=2[CH:19]=1.P(Cl)(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[Cl:31][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[C:4]([O:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:3]([O:2][CH3:1])=[CH:19][C:7]=3[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCN1CCOCC1
Solvent: Cc1ccccc1
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 2.32 g (6.11 mmol) of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 35 mL of phosphorus oxychloride is heated under reflux for 1 hour, then cooled to room temperature. Excess phosphorus oxychloride is evaporated to yield a residue, to which toluene is added and the resulting solution is reduced in vacuo. Toluene is added and evaporated twice more. The resulting residue is cooled with ice bath, neutralized with cold saturated solution of sodium bicarbonate and stirred. The solid is collected by filtration, is washed with cold water and dried to yield 1.989 g of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([Br:26])=[C:21]([CH3:27])[CH:20]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:6][CH:5]=1.Cl>O1CCCC1.[OH-].[Na+].C(OCC)C.O>[Br:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]([S:18][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:16])([F:17])[F:15])=[CH:20][C:21]=1[CH3:27]
Reactant: COC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(SC(CCCC(F)(F)F)c2ccc(C(=O)O)cc2)cc(C)c1Br
Yield: 92.8 %

Procedure:
Racemic 4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoic acid methyl ester (0.424 g, 0.890 mmol) is dissolved in the tetrahydrofuran (2.5 mL) and sodium hydroxide (2.5 mL, 5N) is added. The reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized with hydrochloric acid (2.5 mL, 5N) and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated. The title compound (0.380 g, 0.826 mmol) is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1
Yield: 77 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (9.59 g, 38 mmol) and excess aq. dimethylamine to give the title compound (7.61 g, 77%) as a white crystalline solid. MS (ISP) 266.1 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][CH:8]=[C:9]([C:15]([O:17]C)=[O:16])[C:10]([C:11]([O:13]C)=[O:12])=[C:5]2[N:4]=[C:3]1[CH3:19].[OH-].[Na+].Cl>>[CH3:1][N:2]1[C:6]2=[CH:7][CH:8]=[C:9]([C:15]([OH:17])=[O:16])[C:10]([C:11]([OH:13])=[O:12])=[C:5]2[N:4]=[C:3]1[CH3:19]
Reactant: COC(=O)c1ccc2c(nc(C)n2C)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c(C(=O)O)c(C(=O)O)ccc2n1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
A mixture of dimethyl 1,2-dimethyl-4,5-benzimidazoledicarboxylate (1.70 g, 6.49 mmol) and 2N sodium hydroxide (25 mL, 12.5 mmol) is stirred for 5 hours at 100° C. The mixture is cooled, acidified to pH 4 with hydrochloric acid and filtered to afford the title product as a white powder (1.32 g, 86.8%), mp 305°-308° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(O)C.C1(C)C=CC=CC=1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h
Yield: 8.4 %

Procedure:
After dissolving 4-[2-(pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (49 mg) in ethanol (2 ml) under a nitrogen atmosphere, D-10-camphorsulfonic acid (53 mg) was added and the mixture was stirred for 5 minutes. A 0.25 M solution of 2-phenylacetyl isothiocyanate in toluene (0.684 ml) was added to the reaction mixture and stirring was carried out for 1 hour. The reaction mixture was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium hydrogencarbonate (30 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate (30 ml), water (30 ml) and brine (30 ml) in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:8). Fractions containing the target compound were concentrated under reduced pressure, and then diethyl ether (1.0 ml) and hexane (1.5 ml) were added to the resultant residue to produce a suspension of the solid. After filtering the solid, it was subjected to aeration drying to provide the title compound (5.8 mg, 8.4%) as white powder.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([O-:27])=[O:26])=[CH:23][CH:22]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Na+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:1][CH:3]3[O:5][CH2:4]3)=[O:26])=[CH:23][CH:22]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClCC1CO1
Reactant: O=C([O-])c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(OCC1CO1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A mixture of 89.0 g. of epichlorohydrin, 92.0 g. of sodium 4-(8-cyclohexyloctylamino)benzoate, and 350 ml. of hexamethylphosphoramide is stirred at 105° C. for 5 hours, allowed to cool, and poured into 1.0 liter of water. The white solid is collected by filtration, recrystallized from acetonitrile and then from hexane-methylene chloride to yield the product.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[H-].[Na+].[CH2:48](I)[CH3:49].O>CN(C)C=O.C(OCC)(=O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:48][CH3:49])[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1
Reactant: CCI
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OCc1ccccc1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
Benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (1.5 g) is dissolved in N,N-dimethylformamide (15 ml), and thereto is sodium hydride (60%) (127 mg) under ice-cooling, and the mixture is stirred for 30 minutes and thereto is added ethyl iodide (255 μl), and the mixture is stirred at room temperature overnight. Thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→17:3) to give benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (1.30 g). MS (m/z): 735/737 [M+H]+
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.Cl.[CH:13]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14]2.C(N(CC)CC)C>C(#N)C>[CH:16]12[N:19]([C:2]3[N:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=3)[CH:13]([CH2:18][CH2:17]1)[CH2:14][CH2:15]2
Reactant: Cc1cc(F)ncc1[N+](=O)[O-]
Reactant: C1CC2CCC1N2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(N2C3CCC2CC3)ncc1N
Temperature: 80 °C
Yield: 82 %

Procedure:
To a solution of 2-fluoro-4-methyl-5-nitropyridine (150 mg, 0.96 mmol) in acetonitrile (5 mL) was added 7-azabicyclo[2.2.1]heptane hydrochloride (153 mg, 1.15 mmol) and triethylamine (335 μL, 2.40 mmol). The reaction was heated at 80° C. for 16 h. The reaction was quenched with water (2 mL) and solvent was evaporated. The residue was dissolved in ethyl acetate (15 mL), washed with 1N HCl (10 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-methylpyridin-3-amine (160 mg, 71% yield) as yellow solid which was used in next step without purification. 1H NMR (400.0 MHz, CDCl3) δ 8.96 (s, 1H), 6.37 (s, 1H), 4.59 (s, 2H), 2.59 (d, J=0.4 Hz, 3H), 1.83-1.80 (m, 4H), 1.61-1.54 (m, 4H).
Reaction SMILES: Cl.NC1NC=C(CO)N=1.C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.Cl.Cl.NCCS.[NH2:32][C:33]1[NH:34][CH:35]=[C:36]([CH2:38][S:39][CH2:40][CH2:41][NH2:42])[N:37]=1.[CH3:43][N:44]=[C:45]=[S:46]>>[CH3:43][NH:44][C:45]([NH:42][CH2:41][CH2:40][S:39][CH2:38][C:36]1[N:37]=[C:33]([NH2:32])[NH:34][CH:35]=1)=[S:46]
Reactant: NCCSCc1c[nH]c(N)n1
Reactant: CN=C=S
Agent: Cl
Agent: NCCS
Agent: Nc1nc(CO)c[nH]1
Product: CNC(=S)NCCSCc1c[nH]c(N)n1

Procedure:
Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which is obtained by treating the picrate salt with hydrochloric acid) with cysteamine hydrochloride and reaction of the resulting 2-amino-4-[(2-aminoethyl)thiomethyl]imidazole with methyl isothiocyanate by the methods of Example 1 gives N-methyl-N'-[2-((2-amino-4-imidazolyl)methylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]2[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]2)[CH:12]=[C:11]([Cl:23])[C:10]=1[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH:24]([C:10]2[C:9]([Cl:8])=[CH:14][C:13]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]3)=[CH:12][C:11]=2[Cl:23])[C:25]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:26])=[CH:29][CH:30]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(c2ccc(Cl)cc2)c2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)CC1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a stirred mixture of 10 parts of 1-methylpiperazine in 45 parts of tetrahydrofuran was added dropwise a solution of 6.7 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetyl chloride in 45 parts of tetrahydrofuran during a period of 5 minutes. Upon complete addition, stirring was continued for 2 hours at room temperature. After evaporation in vacuo, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was boiled in acetonitrile. After cooling, the precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 4.8 parts (62.8%) of 1-[2-(4-chlorophenyl)-2-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]acetyl]-4-methylpiperazine; mp. 261.5° C. (intermediate 36).
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:11][CH:10]=1
Reactant: IC1CCOCC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1ccc(SC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-Iodotetrahydropyran (9 g, 42.45 mmol) was added to a stirred suspension of 4-bromobenzenethiol (7.296 g, 38.59 mmol) and potassium carbonate (10.67 g, 77.18 mmol) in DMF (15 mL) and the reaction stirred at ambient temperature for 3 hours. The mixture was diluted with Et2O and washed with water (×2) and brine (×1). The organic extracts was dried (MgSO4) and concentrated in vacuo. Petroleum ether was added to the residue and the resultant precipitate removed by filtration. The filtrate was concentrated in vacuo to give the sub-title compound as a light yellow oil (9.0 g, 85% Yield). 1H NMR (400.0 MHz, CDCl3) δ 1.63-1.73 (m, 2H), 1.89-1.93 (m, 2H), 3.23-3.30 (m, 1H), 3.45 (td, 2H), 3.99 (dt, 2H), 7.31 (d, 2H) and 7.45 (d, 2H) ppm.
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:27][CH2:28][S:29][CH3:30])[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[OH:25][CH2:24][CH2:23][C@@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:27][CH2:28][S:29][CH3:30]
Reactant: CSCC[C@@H](CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CSCC[C@@H](CCO)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
N-methylmorpholine (3.63 ml) and ethyl chloroformate (3.01 ml) were added to a solution of (R)-3-((tert-butoxycarbonyl)amino)-5-(methylthio)pentanoic acid (7.92 g) in THF (79.2 ml) at −10° C. After stirring at −10° C. for 15 minutes, the generated insoluble matter was filtered off. An aqueous solution of sodium borohydride (1.55 g) (15 ml) was added to the filtrate at −10° C., and the mixture was stirred at −10° C. for 1 hour. A saturated aqueous ammonium chloride solution was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added thereto to separate the organic layer. The organic layer was washed with a 0.5 N aqueous potassium hydrogensulfate solution, water, a 0.5 N aqueous sodium hydroxide solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/ethyl acetate) to obtain the title compound as a light-yellow, oily substance (7.18 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].O[C:28]1[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:32][CH:33]=1>>[CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[CH2:10]1)=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 45 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 3-hydroxybenzotrifluoride. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 45%). MS (m/e): 472.4 (M+H+, 100%).