Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:28]([F:31])([F:30])[F:29])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:32]([O:1][CH:2]([C:28]([F:30])([F:31])[F:29])[CH:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(O)C(F)(F)F)cc2)nc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(OC(=O)CCC)C(F)(F)F)cc2)nc1
Reaction time: 4 h
Yield: 93.1 %

Procedure:
1.0 g of (-)-2-(4-(3-hydroxy-4,4,4-trifluoro-1-butenyl)phenyl)-5-decyloxypyrimidine was dissolved in 20 ml of pyridine. The solution was added with 0.5 g of butyryl chloride and stirred at 25°-30° C. for 4 hours. The reaction mixture was diluted with 100 ml of toluene and washed with 4N hydrochloric acid, water, a 5% sodium bicarbonate solution and water successively in that order, and then the toluene layer was concentrated under reduced pressure. The residue was purified by subjecting it to silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 1.08 g of (+)-2-(4-(3-butyryloxy-4,4,4-trifluoro-1-butenyl)phenyl)-5-decyloxypyrimidine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.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>[CH3:21][S:18]([C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[N:3]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1cccc(Nc2nc(Cl)nc3scnc23)c1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(S(C)(=O)=O)c3)c3ncsc3n2)c1
Yield: 57.7 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3-(methylsulfonyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.59 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (183 mg, 0.7 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol) and Na2CO3 (127 mg, 1.2 mmol) in 5 mL of water was added into the mixture solvent of 5 mL of water and 50 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give methyl 3-(7-(3-(methylsulfonyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (150 mg, 58%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 10.76 (s, 1H), 9.45 (s, 1H), 8.99-8.98 (m, 1H), 8.93 (s, 1H), 8.73 (d, 1H, J=7.8 Hz), 8.21-8.18 (m, 1H), 8.09 (d, 1H, J=7.8 Hz), 7.69-7.65 (m, 3H), 3.91 (s, 3H), 3.26 (s, 3H). LC-MS: 441 [M+H]+, 903 [2M+Na]+, 439 [M−H]−, tR=1.61 min. HPLC: 98.78% at 214 nm, 97.72% at 254 nm, tR=8.14 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([O:1][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:11]=1
Reactant: Cc1cc(O)nc2ccccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OC(=O)N(C)c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
A mixture of 2-hydroxy-4-methylquinoline (0.48 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 50° C. for 4 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.24 g, 27% yield) as a white solid.
Reaction SMILES: CCN=C=NCCCN(C)C.[I:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19].[CH:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[CH:35]1([C:38]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][C:15]4[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([I:12])[CH:14]=4)=[O:34])=[CH:23][N:24]=3)[CH2:33][CH2:32]2)=[O:39])[CH2:37][CH2:36]1
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)C4CC4)CC3)nc2)cc1I

Procedure:
6-(4-Cyclopropanecarbonyl-piperazin-1-yl)-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized by the EDCI coupling of N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and cyclopropanecarboxylic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester, above. LCMS calcd for C21H23IN4O2 (m/e) 490, obsd 491 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[C:9]([O:13][C:14]([N:16]([CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH3:17])=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:20]1[CH2:21][CH2:22][CH:18]([N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH3:17])[CH2:19]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: Brc1ccccc1Br
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccccc2Br)C1

Procedure:
The title compound was prepared from dibromobenzene and 3-(N-t-butyloxycarbonyl-N-methylamino)pyrrolidine as for Example 110 (a).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:11][S:12](O)(=[O:14])=[O:13].O=S(=O)=O>O>[N+:1]([C:4]1[CH:9]=[C:8]([S:12]([OH:14])(=[O:13])=[O:11])[C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reaction time: 2.8 h
Yield: 99.15 %

Procedure:
After 2.8 hours of operation, the cascade reaction train was shut down, including 4-nitrotoluene, oleum, and water flows. The molten sulfonation mass in the first three reactors was allowed to solidify. Several days later, the reactors were heated to about 105°-115° C. The reactant feeds were restarted using oleum with an 82.7% free SO3 assay. The 4-nitrotoluene and oleum flows were set at 4.18 g/min and 3.4 g/min (SO3 excess 15%). The water flow to the fourth cascade vessel was started at 13.9 g/min. After operating the systems for five hours, samples were taken from the first three reactors and analyzed. The conversion in R-1, R-2 and R-3 were 97.0, 99.4, and 99.98 respectively. After 5.8 hours running, samples were again taken and analyzed. Conversion was 97.4% in the first reactor, 99.4% in the second and 100% in the third. The final sample collected at the overflow from the dilution vessel (#4 ) for 68 minutes showed 4-nitrotoluene conversion to be 99.7% with a yield of 99.15% of 4-nitrotoluene-2-sulfonic acid. 0.73% of theory yield was lost to sulfone formation. The final solution contained only 0.02% of unreacted 4-nitrotoluene and 16% sulfuric acid relative to 4-nitrotoluene-2-sulfonic acid. The dilute 30% 4-nitrotoluene-2-sulfonic acid solution is ready for use in other processes without any further treatment.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[S:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[S:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Reactant: ClCc1csc(-c2cccs2)n1
Product: c1csc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)cs2)c1
Yield: 82 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with 4-chloromethyl-2-(2-thienyl)thiazole to obtain 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)thiazole. The yield was 82%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 108-109° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.[CH3:54][O:55][C:56]1[CH:57]=[C:58]([CH2:64][NH2:65])[CH:59]=[CH:60][C:61]=1[O:62][CH3:63]>CN(C=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:65][CH2:64][C:58]2[CH:59]=[CH:60][C:61]([O:62][CH3:63])=[C:56]([O:55][CH3:54])[CH:57]=2)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CN)cc1OC
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(I)c2n1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 322.6 %

Procedure:
To a solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (5 g, 15.72 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (10.43 g, 23.58 mmol) in anhydrous DMF (250 mL) at room temperature under a nitrogen atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.23 mL, 28.3 mmol) and the reaction mixture was stirred for 2.5 hours. (3,4-Dimethoxyphenyl)methanamine (20 mL, 94 mmol) was added and the mixture was warmed to 40° C. for 3 hours. The reaction mixture was evaporated in-vacuo and the resulting oil partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated in-vacuo to yield as a semi-crystalline yellow oil (23.7 g). The residue was absorbed onto Florosil, loaded onto a 330 g silica pre-conditioned cartridge and purified by chromatography using cyclohexane over 1 column volume followed by 0-100% ethyl acetate in cyclohexane gradient over 14 column volumes followed by ethyl acetate over 4 column volumes. Appropriate fractions containing only the desired material by LC-MS analysis were combined and evaporated in-vacuo to yield the title compound as a pale yellow foam (4.58 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1>>[CH:13]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc(Br)cc1F
Product: COC(=O)c1ccc(C2CC2)cc1F

Procedure:
The title compound was prepared from methyl 4-bromo-2-fluorobenzoate and cyclopropylboronic acid according to the procedure for the preparation of EXAMPLE 152, part A. 1H NMR (400 MHz, CDCl3): δ 0.74-0.78 (2H, m), 1.04-1.09 (2H, m), 1.87-1.94 (1H, m), 3.90 (3H, s), 6.75-6.79 (1H, m), 6.86-6.89 (1H, m), 7.79-7.82 (1H, m).
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.CO>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1)(=[O:5])[CH:4]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CCCc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 0.40 g of sodium hydroxide in 6 ml of water, a solution of 1.00 g of methyl 4-(4-acetylphenyl)butyrate in 2 ml of methanol was added under ice-cooling. Then, a solution of 0.48 g of benzaldehyde in 2 ml of methanol was added dropwise and stirring was continued at room temperature for 3 hours. The reaction mixture was diluted with water and acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration, washed successively with water and n-hexane to yield 0.94 g of colorless crystals. Recrystallization from 80% aqueous methanol gave colorless needles, mp 111°~112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[CH:18][N:17]=[N:16]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:16]2[N:17]=[CH:18][CH:19]=[N:15]2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1c[nH]nn1
Product: C[C@@H](n1nccn1)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (202 mg) and 1H-1,2,3-triazole (0.17 ml), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-1,2,3-triazol-2-yl)ethyl]oxirane (172 mg) was obtained by the same way as in Reference Example 10.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:13]([O:17][C:18]([N:20]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:27]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:20]([CH3:21])[C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:31][CH:30]=2)=[O:28])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: CN(Cc1ccc(C(=O)O)cc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(=O)NNC(=O)c2nc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
3-amino-6-bromo-pyrazine-2-carbohydrazide (12.91 g, 55.64 mmol), 4-[[tert-butoxycarbonyl(methyl)amino]methyl]benzoic acid (14.76 g, 55.64 mmol) and triethylamine (12.39 g, 17.07 mL, 122.4 mmol) were suspended in N,N-dimethylformamide (200 mL) and stirred at ambient temperature for 30 minutes. A further 3-amino-6-bromo-pyrazine-2-carbohydrazide (3 g, 12.93 mmol) was added and left to stir for 18 hours at ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the N,N-dimethylformamide. The residue was then diluted with ethyl acetate and water. The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution followed by a brine wash. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to a yellow sticky solid. The solid was triturated with ethyl acetate to give a beige solid (this is the hydrazide starting material), the crude mother liquors were concentrated and purified by column chromatography (ISCO Companion XL, 330 g gold column) dry loaded and eluted with 30 to 70% ethyl acetate/petroleum ether to give a yellow sticky gum. This gum was then crystallised from petroleum ether to give tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carbonyl)hydrazinecarbonyl)benzyl(methyl)carbamate as a yellow powder (14.16 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.20 (m, 1H), 1.38-1.45 (br d, 9H), 2.80 (br s, 3H), 4.02-4.04 (m, 1H), 4.45 (s, 2H), 7.34 (d, 2H), 7.69 (br s, 2H), 7.89 (d, 2H), 8.44 (s, 1H) ppm.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([NH:18][CH3:19])=[O:17])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:23].[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>C1COCC1>[CH3:19][NH:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][CH:22]=[C:13]([S:12][C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:37][C:34]4[CH:33]=[CH:32][C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:36][CH:35]=4)[C:4](=[O:23])[NH:5]3)=[CH:10][CH:9]=2)[CH:14]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CNC(=O)c1cccc(Sc2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(Sc2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 68 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A small screw cap test tube was charged with 3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylsulfanyl)-N-methyl-benzamide (as prepared below; 20 mg, 0.062 mmol) and THF (1 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (12 mg, 0.062 mmol), and the mixture was stirred for 24 h at 68° C. Subsequently, the reaction mixture was cooled to room temperature and then concentrated in vacuo. Purification of the crude residue via flash silica gel chromatography (10% MeOH in CHCl3) afforded the title compound in 39% yield (12 mg, 0.024 mmol).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]/[C:11](=[CH:16]\[N:17](C)C)/[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:20]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=1)N.C(O)(=O)C.C([O-])(O)=O.[Na+]>C(O)C>[Si:1]([O:8][CH2:9][CH2:10]/[C:11](=[CH:16]\[NH:17][NH:20][C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=1)/[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/N(C)C)CCO[Si](C)(C)C(C)(C)C
Reactant: N#Cc1ccnc(NN)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)/C(=C/NNc1cc(C#N)ccn1)CCO[Si](C)(C)C(C)(C)C
Temperature: 90 °C
Yield: 68.9 %

Procedure:
Charged methyl (2E)-4-[tert-butyl(dimethyl)silyl]oxy-2-(dimethylaminomethylidene)butanoate (7.33 g, 50%, 12.72 mmol), 2-hydrazinopyridine-4-carbonitrile (1.70 g, 12.72 mmol), acetic acid (10 mL) and ethanol (50 mL) to a flask, the mixture was heated to 90° C. for 30 min, cooled to r.t. and basified with NaHCO3 at 0° C. to pH=8. It was then extracted with ethyl acetate twice, concentrated and purified by silica gel chromatograph (PE/EA=10/1) to give the title compound (3.3 g, 34%). 1H NMR (400 MHz, CDCl3): δ 0.04 (6H, d, J=1.6 Hz), 0.89 (9H, s), 1.96-2.17 (2H, m), 3.59 (1H, q, J=6.4 Hz), 3.69 (2H, d, J=6.0 Hz), 3.74 (3H, s), 6.91-6.92 (1H, m), 7.19 (1H, d, J=6.0 Hz), 7.38 (1H, s), 8.22 (1H, d, J=5.2 Hz), 8.33 (1H, s). [M+H] Calc'd for C18H28N4O3Si, 377. Found, 377.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>ClCCl>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:2]2[C:1]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:5][CH2:4][CH2:3]2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a solution of tetrahydroisoquinoline (3.99 g, 30 mmol) in triethyl amine(6 g, 60 mmol) and dichloromethane(150 mL) cooled in ice bath was added p-nitrophenyl chloroformate (6.06 g, 30 mmol) drop wise over a period of 1 h. The reaction mixture was srirred at room temperature for 3 h and then washed with water (3×100 mL), dried over sodium sulfate and concentrated to afford an oil which was triturated with ether:hexane to afford the titled compound as yellow solid (5.9 g, 65%).
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][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:3]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown powder; MS: [M+H]+=449.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:30][CH3:31]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([CH2:30][CH3:31])[N:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(CC)n1
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a solution of 10.0 g (0.028 mole) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate [prepared in Example 2] in 75 mL of N,N-dimethylformamide was added 1.2 g of 60% sodium hydride (0.03 mole) in mineral oil was added. After stirring for 0.5 hour, the sodium hydride had dissolved and 8.5 g (0.056 mole) of iodoethane was added. The solution was stirred at room temperature for 16 hours, diluted to 400 mL with water and extracted with CH2Cl2. The extracts were dried and concentrated in vacuo. The residue was triturated with hexane to remove mineral oil. The residue was absorbed onto silica gel by dissolving in CH2Cl2 and adding dry silica gel, then concentrating in vacuo to a dry powder. This material was transferred to the top of a silica gel column and eluted with 10% (v/v) ethyl acetate in hexane to give 4.9 g (45.5%) of the title compound; m.p.= 113°-114.5° C.
Reaction SMILES: CC(C)=O.[C@@H:5]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10]2.[C:16]([O:21][CH2:22][CH2:23][OH:24])(=[O:20])[C:17]([CH3:19])=[CH2:18]>CN(C)C1C=CN=CC=1.O>[C:16]([O:21][CH2:22][CH2:23][O:24][C:11]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[C:14]([OH:13])=[O:15])=[O:12])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: C=C(C)C(=O)OCCO
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(=O)OCCOC(=O)C1CCCCC1C(=O)O
Reaction time: 1 h

Procedure:
To acetone (1,000 mL) were added cis-1,2-cyclohexanedicarboxylic anhydride (308.3 g), 2-hydroxyethyl methacrylate (273.3 g), and 4-dimethylaminopyridine (4.9 g). This mixture was heated with refluxing for 5 hours, and the acetone was distilled off under reduced pressure. Thereafter, 1N hydrochloric acid (500 mL) and ethyl acetate (2,000 mL) were added to the residue to extract it. The resulting organic phase was washed twice with saturated aqueous sodium chloride solution (500 mL), and anhydrous magnesium sulfate (100 g) was then added thereto. This mixture was allowed to stand for 1 hour to dehydrate the organic phase. Subsequently, the magnesium sulfate was removed by filtration and the ethyl acetate was distilled off under reduced pressure to obtain a white solid. The solid was pulverized and then added to water (2,000 mL). After this mixture was stirred for 2 hours, the particles were taken out by filtration and dried. As a result, 2-[2-(methacryloyloxy)ethoxy-carbonyl]cyclohexanecarboxylic acid was obtained as a white solid (518.9 g).