Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]P(=O)(OCC)OCC)[N:6]=1.[H-].[Na+].[CH3:18][O:19][CH2:20][O:21][C:22]1[C:26]([CH:27]=O)=[CH:25][N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]=1.O>O1CCCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5](/[CH:7]=[CH:27]/[C:26]2[C:22]([O:21][CH2:20][O:19][CH3:18])=[N:23][N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[N:6]=1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1csc(C)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C)n1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of diethyl [(2-methyl-1,3-thiazol-4-yl)methyl]phosphonate (2.32 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.32 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1, v/v) to give 2-methyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (2.72 g, yield 83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][C:32]1([CH3:38])[CH2:36][O:35][C:34](=[O:37])[NH:33]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[C:32]([CH3:38])([CH3:31])[CH2:36][O:35][C:34]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CC1(C)COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OCC4(C)C)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 24.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and 4,4-dimethyloxazolidin-2-one (57.6 mg), the title compound (63.6 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:15]Br.O>C(O)(=O)C>[Br:15][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([NH2:8])=[N:4][CH:5]=1
Reactant: Nc1nccnc1Cl
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Br)nc1Cl
Temperature: 25 °C

Procedure:
3-Chloro-pyrazin-2-ylamine (0.750 g, 5.79 mmol) is suspended in acetic acid (7 ml) with stirring at room temperature and sodium carbonate (0.675 g, 6.37 mmol) is added. When all the gas has evolved bromine (0.171 ml, 3.34 mmol) in acetic acid (4 ml) is added dropwise. Sodium carbonate (0.675 g, 6.37 mmol) is added and a gas evolves. Once all gas has evolved bromine (0.171 ml, 3.34 mmol) in acetic acid (4 ml) is added. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is poured onto iced water and left to stir for 30 minutes. A pale yellow suspension has formed. This solid is filtered off and rinsed with cold water to give 5-Bromo-3-chloro-pyrazin-2-ylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)ccc1F
Yield: 91.9 %

Procedure:
Heat a solution of 5-bromo-2-fluorobenzoic acid (20 g, 92 mmol) and p-toluenesulfonic acid monohydrate (52 g, 275 mmol) in methanol (200 mL) at reflux overnight. Concentrate and dissolve the residue in ethyl acetate, wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate to give the title compound as a clear liquid (19.7 g, 92%).
Reaction SMILES: [CH:1]1([CH:6]([OH:18])[CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[C:27]([F:28])=[CH:26][C:23]([C:24]#[N:25])=[C:22](F)[CH:21]=1>CN(C)C=O>[Cl:19][C:20]1[C:27]([F:28])=[CH:26][C:23]([C:24]#[N:25])=[C:22]([CH:21]=1)[O:18][CH:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: CN(CCC(O)C1CCCC1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CN(CCC(Oc1cc(Cl)c(F)cc1C#N)C1CCCC1)C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-cyclopentyl-3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: [CH:1](OCC#N)=[O:2].[CH:7]1([NH:10][C:11]([C:13]2[C:21]3[CH:20]=[C:19]([C:22]4[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[N:23]=4)[S:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1>CN(C=O)C.C(OCC)(=O)C>[CH:7]1([NH:10][C:11]([C:13]2[C:21]3[CH:20]=[C:19]([C:22]4[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]5[CH2:34][CH2:35][N:36]([CH:1]=[O:2])[CH2:37][CH2:38]5)[N:23]=4)[S:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:8][CH2:9]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Cl)cc12
Reactant: N#CCOC=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CN1CCC(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reaction time: 18 h
Yield: 74.8 %

Procedure:
Cyanomethyl formate (10 mg, 0.11 mmol) is added to a stirred suspension of 2-[5-chloro-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (50 mg, 0.11 mmol) in DMF (1 mL) and stirred for 18 hours to form a thick suspension. The mixture is diluted with ethyl acetate (1 mL) then filtered to give the title compound as a solid (41 mg). ES+(m/z) 498 (35Cl) and 500 (37Cl) [M+H].
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:18][CH3:19])(=[O:17])[CH2:12][CH2:13][C:14]([O-])=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([NH:9][NH:10][C:14](=[O:15])[CH2:13][CH2:12][C:11]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: COC(=O)CCC(=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
The mixture of benzhydrazide (1.5 g, 11.0 mmol), butanedioic acid, monomethyl ester (2.0 g, 15 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.4 g, 12 mmol), N,N-diisopropylethylamine (3.8 mL, 22 mmol) and 4-dimethylaminopyridine (0.87 g, 7.2 mmol) in DMF (30 mL) was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed by brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the desired product (900 mg, 32.6%). LCMS calculated for C12H15N2O4(M+H): 251.1; found: 251.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[N:9][C:10]1=[O:14]
Reactant: Cc1cc(-c2cc[nH]c(=O)n2)ccn1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccn(CCCCCl)c(=O)n2)ccn1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 26.3 %

Procedure:
To a solution of 4-(2-methyl-pyridin-4-yl)-1H-pyrimidin-2-one (256 mg, 1.37 mmol) in dry DMF (45 ml), 60% NaH (71 mg, 1.78 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (305 mg, 1.78 mmol) was added and the mixture was stirred at room temperature for 1.5 hours and heated at 60° C. for 2 hours. Water was added and the mixture extracted with diethyl ether and with ethyl acetate. The organic layers were mixed together, dried (Na2SO4) and evaporated to afford 100 mg of the title compound that was used in the next step without further purification in the next step (27% yield).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15](O)[CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]([N:20]3[CH2:21][CH2:22][O:18][C:19]3=[O:23])[CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NCCO1
Reactant: CC(O)c1ccc(C#Cc2ccccc2)cn1
Product: CC(c1ccc(C#Cc2ccccc2)cn1)N1CCOC1=O

Procedure:
The title compound, white solid, MS: m/e=293.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from rac-1-(5-phenylethynyl-pyridin-2-yl)-ethanol (example 42, step 1) and oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].C1C[O:13][CH2:12]C1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl>O>[Cl:1][C:2]1[C:3]2[NH:9][C:12](=[O:13])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1N
Reactant: C1CCOC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Product: O=c1[nH]c2cccc(Cl)c2[nH]1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a solution of 3-chloro-benzene-1,2-diamine (0.820 g, 5.75 mmol) and THF (25 mL), was added carbonyl diimidazole (1.12 g, 6.90 mmol) at 0° C. The mixture was stirred for 16 h and allowed to warm to 23° C. A solution of 1M aqueous HCl (25 mL) was added to the reaction mixture at 0° C., followed by water (100 mL) and the mixture was stirred for 1 h. The precipitated solid was filtered and dried under high vacuum for 18 h to yield the titled compound, which was used in the next step without further purification (0.800 g, 83%). MS (ESI/CI): mass calcd. for C7H6ClN2O, 168.0; m/z found, 169.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 11.13 (s, 1H), 10.88 (s, 1H), 7.00-6.86 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:17](O)=O>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[CH:17][NH:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: O=CO
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Product: N#Cc1ccccc1-c1ccc2nc[nH]c2c1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (0.04 moles, 8.3 g) was refluxed in 100 ml formic acid for 3 hours. The solution was concentrated in vacuo, triturated with toluene, and dissolved in water. The pH of the solution was adjusted to 7.5 with 2N sodium hydroxide. The intermediate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The solid was triturated with 25% ethyl acetate/75% hexane, filtered and purified by HPLC on silica gel eluted with a gradient of 50-75% ethyl acetate in hexane. The reaction yielded 7.3 g of 5-(2-Cyanophenyl)benzimidazole. (MS)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3cc(Cl)ccc3Cl)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and 2,5-dichlorophenylboronic acid (191 mg, 1.0 mmol) to afford after chromatographic purification the title compound (105 mg, 47%). 1H NMR (CDCl3, 300 MHz) δ 7.30–7.36 (m, 2H), 7.15–7.19 (m, 1H), 7.01 (s, 1H), 3.82–4.22 (m, 2H), 3.82–3.96 (m, 1H), 2.82–3.52 (m, 7H), 1.82–1.90 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 445 [M+H+].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>>[N:15]1([CH2:14][CH2:13][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][C:2]2=[NH:10])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1nc2ccccc2s1
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: N=c1sc2ccccc2n1CCN1CCOCC1
Yield: 25.9 %

Procedure:
Benzothiazol-2-ylamine (1.0 g, 6.6 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (1.2 g, 6.6 mmol) and triethylamine (2.8 mL, 20 mmol) were heated at 80° C. for 16 hours. The solid was recrystallized from ethyl acetate, collected by filtration, dried under vacuum to provide 0.45 g (26%) of the title compound. MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:15](Br)=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:12]1)=O)(C)(C)C.[ClH:29].C=O.[OH-].[Na+]>C(O)C>[Cl:29][C:15]1[N:11]2[CH2:10][CH2:9][NH:8][CH2:6][C:12]2=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1
Reactant: Cl
Reactant: CCOC(=O)c1cn(CCNC(=O)OC(C)(C)C)c(Br)c1-c1cccc(F)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of 38.4 g (84.3 mmol) of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-5-bromo-4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in 80 ml of ethanol are added slowly 271 ml (949 mmol) of aqueous 3.5N hydrochloric acid solution. The formation of a white precipitate is rapidly observed and then, after 45 minutes, the medium becomes clear, while the mixture is heated to 70° C., and 3.00 g (31.2 mmol) of paraformaldehyde are added. Heating is continued at 70° C. for 1 hour. After cooling, the reaction medium is poured into a mixture of ice and aqueous 4N sodium hydroxide solution. The product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a brown oil, which is chromatographed on a column of 330 g of silica gel, eluting with a mixture of 3% methanol in dichloromethane, to give 14.3 g of ethyl 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate after crystallizing from 50 ml of diisopropyl ether.
Reaction SMILES: CC1C2C(=CC=CC=2)CCN1.C(O)C(O)C.[Cl:17]C1C(C)=C(C)N=C(NC2C=CC(F)=CC=2)N=1.[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]>C(N(CC)CC)C>[ClH:17].[CH3:34][C:35]1[C:36]([N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]2[CH3:60])=[N:37][C:38]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:39][C:40]=1[CH3:41]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Agent: CC1NCCc2ccccc21
Agent: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Solvent: CC(O)CO
Solvent: CCN(CC)CC
Product: Cl

Procedure:
75 ml of triethylamine and 65 g(442 mmole) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 100 ml of 1,2-propylene glycol. 100.9 g(0.40 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 120° C. for 64 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 91 g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[C:14](Cl)=[N:13][CH:12]=[CH:11][N:10]=1.C[O-].[Na+]>C(O)C>[Cl:8][C:9]1[C:14]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1nccnc1Cl
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1nccnc1Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
22 g (0.2 mol) of thiophenol and 29.8 g (0.2 mol) of 2,3-dichloropyrazine are successively added dropwise to a solution of 10.8 g (0.2 mol) of sodium methylate in 200 ml of ethanol and the mixture is stirred for 1 hour. The reaction mixture is then cooled to 0° C. and the reaction product which has precipitated is filtered off and washed with ethanol and water. After drying, 2-chloro-3-phenylthio-pyrazine, melting point 100°-111° C., is obtained.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[C:44]2[N:45]([CH:49]=[N:50][CH:51]=2)[CH:46]=[CH:47][CH:48]=1>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.S1C=CC=C1C([O-])=O.[Cu+]>[CH:51]1[N:50]=[CH:49][N:45]2[CH:46]=[CH:47][CH:48]=[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:35][CH2:34][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]5)=[CH:26][C:9]=4[N:10]=3)[C:44]=12
Reactant: Brc1cccn2cncc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cccn5cncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 72.8 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (132 mg, 0.19 mmol), 8-bromoimidazo[1,5-a]pyridine (45 mg, 0.23 mmol), Pd(PPh3)4 (22 mg, 0.02 mmol) and copper(I) thiophene-2-carboxylate (7 mg, 0.04 mmol) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 202 as a yellow solid (72 mg, 73%). LCMS (Method G): RT 5.12 min; [M+H]+ 521. 1H NMR (400 MHz, CHCl3-d): δ 8.33 (s, 1 H); 8.21 (s, 1 H); 8.04 (d, J=6.9 Hz, 1 H); 7.93 (d, J=6.9 Hz, 1 H); 7.36 (s, 1 H); 7.07 (m, 1 H); 6.74-6.69 (m, 1 H); 5.19 (s, 1 H); 4.07 (t, J=4.7 Hz, 4 H); 3.96-3.86 (m, 4 H); 3.88-3.83 (m, 2 H); 2.61 (s, 8 H); 1.25 (s, 6 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16](O)[N:15]([CH3:19])[N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16]([SH:29])[N:15]([CH3:19])[N:14]=1
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S
Reaction time: 3 h
Yield: 53 %

Procedure:
A suspension of 1.0 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxy-1-methylpyrazole (6) and 0.7 g of Lawesson's reagent in 10 ml of toluene were refluxed with stirring for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/6), giving 0.3 g of the desired compound in the form of colorless crystals (yield 27.3%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:4])=[O:3].BrBr.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[NH:27][C:28]([NH2:30])=[S:29]>O1CCOCC1.C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:29][C:28]([NH:27][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[N:30][C:12]=2[CH3:13])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:4])=[O:3]
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Reactant: NC(=S)Nc1cnccn1
Agent: BrBr
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-propan-2-one (Example 59c) (0.60 g, 2.14 mmol) is dissolved in dioxan (50 ml) and the solution is cooled to 10° C. at which point the mixture is semi frozen. Bromine (0.088 ml, 1.7 mmol) is added slowly and the mixture is stirred for an additional 30 min in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil. This material is dissolved in ethanol and pyrazin-2-yl-thiourea (1a) is added in one portion. The mixture is stirred at 60° C. for 30 minutes then allowed to cool whereupon the titled product precipitates and is removed by filtration.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=O)=[CH:8][C:5]=2[C:6]=1[CH3:7].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][C:18](=[O:20])[O:19][C:14](=[O:16])[CH2:13]3)=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1oc2ccc(C(CC(=O)O)CC(=O)O)cc2c1C
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(C3CC(=O)OC(=O)C3)cc2c1C

Procedure:
27.6 g (0.1 mol) of 3-(2,3-dimethyl-5-benzofuranyl)-glutaric acid are refluxed in 120 ml of acetic anhydride for one hour. The excess reagent and the acetic acid formed are then evaporated off in a rotary evaporator. The brownish residue is dissolved in ether, and hexane is added until crystallisation starts. The crystals are filtered off with suction, washed with ether/hexane and dried. The 3-(2,3-dimethyl-5-benzofuranyl)-glutaric anhydride thus obtained as pale sand-coloured crystals melts at 107°-110°, and after recrystallisation from methylene chloride/hexane, at 111°-112°.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].CCOCC.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:5][CH2:4][CH:2]1[O:3][CH2:1]1)=[O:15]
Reactant: O=C(Cl)c1ccccc1F
Reactant: OCC1CO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCC1CO1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture containing 37 g (0.5 mole) of glycidol, 500 ml of anhydrous ether, 500 ml of pyridine and 80 g (0.5 mole) of o-fluoro-benzoyl chloride was stirred at 0° C. for 1 hour and 25° C. for 2 hours. The mixture was filtered and the ethanol filtrate was washed with 100 ml of 5% HCl. Evaporation of the ether gave an oil which was distilled to give 69.5 g (71%) of product, b.p. 115° C./0.5 mmHg. The NMR and IR spectra were consistent with the assigned structure.