Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:22]=[C:9]2[N:10]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH2:26][N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[CH2:16][NH:15][C:11]1[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:22]=[C:9]2[N:10]=1
Reactant: Nc1nc(NCC2CCCN2)nc2nc(-c3ccco3)nn12
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nc(NCC2CCCN2Cc2c(Cl)cccc2Cl)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Furan-2-yl-N5-pyrrolidin-2-ylmethyl-[1,2,4]-triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 2,6-dichlorobenzaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.95-7.0 (m, 3H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 2.2-3.2 (m, 8H). MS: m/z: 460[M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=O)[CH2:7][NH:8][C:9]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=3[N:15]=2)=O)[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.FC(F)(F)C([O-])=O.[NH4+:40]>O>[S:1]1[CH:5]=[C:4]([C:6]2[NH:40][C:9]([C:11]3[S:12][C:13]4[C:19]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=4[N:15]=3)=[N:8][CH:7]=2)[C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2
Reactant: [NH4+]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3csc4ccccc34)nc12
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3ncc(-c4csc5ccccc45)[nH]3)nc12
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 0.15 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-benzo[b]thiophen-3-yl-2-oxo-ethyl)-amide and 0.43 g ammonium triflouroacetate was melted at 210° C. for 30 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 1:1 gave 0.10 g (69%) 2-(5-benzo[b]thiophen-3-yl-1H-imidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole as yellow solid; M.p.: 161–162° C.; MS (ISP): m/e=449 (M+H+).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[NH:16][C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[CH2:2][CH2:3][CH3:4].[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[N:40]=[C:41]=[O:42]>CCCCCC>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[NH:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:16]=1)[C:41]([NH:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[F:32])=[O:42])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCCCCC
Product: CCCCN(CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Yield: 50.1 %

Procedure:
Part C. To a solution of N-butyl-8-(4,5-diphenyl-1H-imidazol-2-ylthio) octanamine (0.2 g, 0. 00045 mol) in 5 hexane (15 mL) was added, dropwise, a solution of 2,4-difluorophenylisocyanate (0.065 mL, 0.085 g, 0.00055 mol) in hexane (5 mL) and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed with 7:3 hexane-ethyl acetate and the resulting solid was recrystallized from acetonitrile and triturated with hexane to give the title compound (0.138 g, 0.00023 mol) as a white solid, mp 114°-115°. 1H NMR (CDCl3) δ 8.1-7.9(m, 1H), 7.6-7.2(m, 11H), 6.95-6.75 (m, 2H), 6.5-6.4 (m, 1H), 3.4-3.1 (m, 6H), 1.8-1.3 (m, 16H), 1.0 (t, 3H, J=8 Hz).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([F:37])[CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:31]1[CH:32]=[C:33]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1, 100 mg, 1.0 eq.), anhydrous copper(II) acetate (90 mg, 2.0 eq.), 3,5-difluorophenylboronic acid (123 mg, 3 eq.) and pyridine (80 uL, 4 eq.) in dichloromethane (2.5 mL) was stirred at room temperature for 2 days, evaporated to dryness and purified on silica gel, eluting with a 98:2 to 95:5 gradient of dichloromethane/methanol, to yield 79 mg (61%) from the desired product as light yellow foam. MS (m/e): 518.4 (MH+, 100%).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[S:6][C:7]=1[C:8](=[O:10])[CH3:9].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:8]([C:7]1[S:6][C:5]([N:11]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:18](=[O:20])[CH3:19])=[N:4][C:3]=1[CH3:2])(=[O:10])[CH3:9]
Reactant: CC(=O)c1sc(Nc2cnccn2)nc1C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)c1sc(N(C(C)=O)c2cnccn2)nc1C
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
In a tube, 1-[4-Methyl-2-(pyrazin-2-ylamino)-1,3-thiazol-5-yl]ethanone, hydrochloride salt (500 mg; 1.85 mmol; 1 eq.) is mixed with acetic anhydride (2.16 ml; 22.90 mmol; 12.40 eq.). The tube is sealed and is heated at 150° C. with an oil bath. After 15 min, the mixture becomes yellow. The reaction is complete. The solvents are removed and N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N-pyrazin-2-ylacetamide is used as such without further purification (510.3 mg; quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of methyl 2-chloro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate (Step 3, 1.10 g, 2.56 mmol) in tetrahydrofuran (7.0 mL) and methanol (5.0 mL) was added a solution of lithium hydroxide (0.245 g, 10.2 mmol) in water (3.0 mL). The mixture was stirred at room temperature for 2 h. and concentrated under reduced pressure to a volume of about 3 mL. The residue was diluted with water (3 mL), and adjusted with 1N HCl to pH of about 4-5. The precipitate was filtered out, washed several times with water and dried in air overnight. The precipitate was then triturated sequentially with ether and dichloromethane (DCM)-Hexane (1:1). The desired product (638 mg, 60%) was obtained. LCMS (M+H)+: m/z=415.9/417.9.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][NH2:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:49][O:48][CH3:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NOC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with methoxyamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H46Cl2N5O4 [(M+H)+] 694.2922, observed 694.2919.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=O)[CH:5]=[CH:4][C:3]1=2.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(OCC)(=O)C.CCCCCC>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:1])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Reactant: Nc1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(F)cc3)ccc21
Yield: 60.7 %

Procedure:
In a manner analogous to Example 1, 2 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxylic acid and 1 g of 4-fluoroaniline were used to obtain 1.7 g of 4'-fluoro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxanilide in colorless crystals, m.p. 163°-165° C. (from ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:10])[C:7]=1[CH2:8][CH3:9].O.[NH2:13][NH2:14]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[C:6]([CH3:10])[C:7]=1[CH2:8][CH3:9]
Reactant: CCc1c(Cl)nnc(Cl)c1C
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CCc1c(Cl)nnc(NN)c1C
Reaction time: 1 h

Procedure:
3,6-Dichloro-4-ethyl-5-methylpyridazine (W4.007; 1 g) was initially charged in dioxane (8 ml) with addition of hydrazine monohydrate (2 ml) in a microwave vessel at RT. Thereafter, the reaction mixture was kept at 140° C. in the microwave for 1 h. In the course of standing overnight, a solid precipitated out, which was filtered off with suction, washed and dried. 345 mg of (6-chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine were obtained as the free base. The mother liquor was concentrated to dryness and the residue was purified by means of preparative HPLC (met. F). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 340 mg of 6-chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic acid salt and 239 mg of (6-chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine as the trifluoroacetate were obtained.
Reaction SMILES: C[C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([C:15]3[CH:20]=[N:19][C:18]([NH:21][C:22](=[O:31])[C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])=[CH:17][N:16]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:32](O)=[O:33].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[CH2:48]([O:50][CH:51]([O:54][CH2:55][CH3:56])[CH2:52][NH2:53])[CH3:49]>C(Cl)Cl.CN(C=O)C>[CH2:48]([O:50][CH:51]([O:54][CH2:55][CH3:56])[CH2:52][NH:53][C:32]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:15]3[CH:20]=[N:19][C:18]([NH:21][C:22](=[O:31])[C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])=[CH:17][N:16]=3)[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][C:10]=2[CH:2]=1)=[O:33])[CH3:49]
Reactant: CCOC(CN)OCC
Reactant: Cc1c(C(=O)O)ccc2c1nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CNC(=O)c1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (xiii) (50 mg, 0.11 mmol, 1.00 equiv) in DCM (15 ml) and DMF (1 drop). To the above stirred solution was added oxalyl dichloride (70 mg, 0.55 mmol, 5.00 equiv) dropwise at 0° C. The resulting solution was allowed to stir at 0° C. for 4 hours then was concentrated by evaporation under vacuum using a rotary evaporator. The residue was then taken up by DCM (10 ml) and then add dropwise to a stirred solution of Et3N (40 mg, 3.00 equiv) and 2,2-diethoxyethanamine (15 mg, 0.11 mmol, 1.00 equiv) in DCM (10 mL) at 0° C. The resulting solution was allowed to stir overnight at room temperature, then washed with H2O (2×100 mL) and dried over Na2SO4. Removal of the solvent and volatile components afforded the crude product 1-[5-(2,6-difluoro-benzoylamino)-pyrazin-2-yl]-2-trifluoromethyl-1H-benzoimidazole-5-carboxylic acid (2,2-diethoxy-ethyl)-amide (xiv) (50 mg, 64% yield) as a yellow solid that was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([O:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:15])/[CH2:11][CH2:12][CH2:13]I)=[O:4].C(N(CC)CC)C.[CH3:25][C:26](C)(C)[C:27](Cl)=O>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([O:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:15])/[CH2:11][CH2:12][CH:13]=[C:26]([CH3:27])[CH3:25])=[O:4]
Reactant: C/C(=C\CCCOC(=O)C(C)(C)C)CCCI
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)=CCC/C(C)=C/CCCOC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 10.00 g (54.94 mmol) of Example 2 Part D alcohol in 50 mL of dichloromethane at 0° C. was added 0.67 g (5.50 mmol) of 4-dimethylaminopyridine (DMAP) and 11.49 mL (82.41 mmol) of triethylamine followed by the addition of 8.12 mL (65.93 mmol) of trimethylacetyl chloride over 15 min. The reaction mixture was stirred for 1 h at 0° C. and 2.5 h at room temperature. The suspension was diluted with 200 mL of dichloromethane and 300 mL of water. The layers were separated and the organic fraction was washed with solutions of KHSO4, NaHCO3 and NaCl, dried (MgSO4) and concentrated to provide title compound as a colorless liquid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:15]1([NH:14][C:4]2[N:3]=[C:2]([N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1c(Cl)nc(NC2CC2)nc1NCCO
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NC2CC2)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-cyclopropylamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 47a) was treated with the 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield the 2-cyclopropylamino-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=398.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:16][CH:17]([F:19])[F:18])[C:11]=1[CH3:12])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:16][CH:17]([F:18])[F:19])[C:11]=1[CH3:12])[CH:5]=[O:6]
Reactant: COC(=O)c1cc(Br)c(C)c(CCCOC(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(Br)cc(C=O)cc1CCCOC(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dichloromethane (0.07 M) solution of methyl 3-bromo-5-[3-(difluoromethoxy)propyl]-4-methylbenzoate (1 eq.) from the previous step was added DIBAL-H (1.5 M solution in toluene, 2.2 eq.). The resulting solution was stirred at RT for 1.5 h and then carefully quenched with 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The crude alcohol thus obtained was taken up again in dichloromethane (0.07 M) and then added Dess-Martin periodinane (1.0 eq.) and sodium bicarbonate (1.2 eq.). After stirring at RT for 40 min, the reaction mixture was diluted with ether and washed sequentially with sat. aq. NaHSO3, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:26][C:27](=O)[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:26]=[C:27]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(NC(N)=S)ncc2Br)c1
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)c1
Temperature: 70 °C
Yield: 96.4 %

Procedure:
A flask was charged with ethyl 3-(5-bromo-2-thioureidopyridin-4-yloxy)-4-chlorobenzoate (0.200 g, 0.464 mmol), 1-bromo-4-phenylbutan-2-one (0.105 g, 0.464 mmol) and triethylamine (0.0470 g, 0.464 mmol). Ethanol (5 mL) was added and the reaction was heated at 70° C. for 6 hours, and then concentrated to provide ethyl the desired product (0.250 g, 95 yield) as white solid. LC/MS (apci) M+2H: 560 (100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Cl)[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1.ClC1C=CC(Cl)=CC=1CO>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Agent: OCc1cc(Cl)ccc1Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)nc(N)c1-c1cc(Cl)ccc1Cl

Procedure:
This compound was made in an analogous manner to the compound of Example 6 from 2,5-dichlorobenzylalcohol (Lancaster Synthesis). Mp. 226°-228° C.: TLC (SiO2 : CHCl3 /MeOH, 9:1) Rf=0.24.
Reaction SMILES: [Na+].[C:2]1([CH2:8][C:9]([O:11][CH2:12][C:13]([F:19])([F:18])[S:14]([O-:17])(=[O:16])=[O:15])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].FC(F)(F)S([O-])(=O)=O.[C:29]1([CH:35]([SH+:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:36]1([CH:35]([SH+:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1.[F:19][C:13]([F:18])([S:14]([OH:17])(=[O:16])=[O:15])[CH2:12][O:11][C:9](=[O:10])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)OCC(F)(F)S(=O)(=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [Na]
Product: O=C(Cc1ccccc1)OCC(F)(F)S(=O)(=O)O

Procedure:
<2> The reaction described in <3> of Synthesis Example 1 was performed under the same conditions, except that the phenylacetyloxymethyl difluoromethanesulfonic acid sodium salt (2.97 g) produced in <1> above was used instead of the benzoyloxymethyldifluorosulfonic acid sodium salt in the reaction with diphenylmethylphenylsulfonium trifluoromethanesulfonic acid sodium salt, and thus 3.87 g (yield 99.5%) of phenylacetic acid 2,2-difluoro-2-sulfoethyl ester diphenylmethylphenylsulfonium salt as shown in the following reaction scheme 7 was obtained. The structure of the product was confirmed by 1H-NMR (see FIG. 6).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.O[C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:17]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]2)=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Tetrahydrofuran (200 ml) was added to 2,6-dichloropurine (6 g, 31.8 mmol), tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (5.94 g, 31.8 mmol), and triphenylphosphine (9.2 g, 34.9 mmol) and the resulting mixture was made uniform. Diisopropyl azodicarboxylate (6.9 ml, 35 mmol) was added with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. The reaction mixture was cooled, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=7:3 to 6:4 to 5:5 to 4:6) to give the title compound (10.5 g, 92%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>S(Cl)(Cl)=O>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)c1ccc(C(=O)OCc2ccccc2)nc1

Procedure:
Analogously to Example 1, 20 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride with 160 ml of thionyl chloride and this is reacted with 25.9 g of benzyl alcohol. The product is recrystallized from ethyl acetate, with the addition of active charcoal.
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)#[N:9].BrN1C(=[O:31])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O>[C:8]([N:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]([OH:31])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CN1c2ccccc2CCc2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 87.5 °C
Yield: 52.2 %

Procedure:
190 ml of chlorobenzene and 25 g of (I) are loaded into a 500 ml pyrex round-bottom flask, under nitrogen. Afterwards, 21.2 g of N-bromosuccinimide and 2.2 g of dibenzoylperoxide are added and the mixture is heated to 85-90° C., keeping this temperature for 1.5 hours. 150 ml of water and 5 g of PEG 6000 are added, heating to 85°-90° C. for 2 hours. After decanting at 60° C., water is removed and the organic phase is washed with further water (2×100 ml). Chlorobenzene is evaporated off under vacuum at 5 mm/Hg and the residue is taken up with 50 ml of ethyl acetate. The mixture is cooled to 0° C. for 2 hours, filtered and dried at 60° C. for 4 hours, to obtain 14 g of (VI), m.p. 111-112° C., with good purity.