Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:42][C:37]1[CH:36]=[C:35]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:21]2)[CH:40]=[CH:39][C:38]=1[Cl:41]
Reactant: COc1ccccc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: COc1ccccc1C(=O)N1CC[C@@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(2-methoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: CS[C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[CH:4][N+:5]([O-:7])=[O:6].O.[NH2:21][NH2:22]>C(O)C>[NH:21]([C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[CH:4][N+:5]([O-:7])=[O:6])[NH2:22]
Reactant: CSC(=C[N+](=O)[O-])Nc1ccc(OC(F)(F)F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=C[N+](=O)[O-])Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
3.00 g of 1,1-bis(methylthio)-2-nitroethene, 3.38 g of 4-trifluoromethoxyaniline and 30 ml of ethanol were reacted for 5 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration and washed with a small amount of ethanol and dried to obtain 3.40 g of crystals, to which 1.81 g of 4-trifluoromethoxyaniline and 30 ml of ethanol were added and reacted for 6.5 hours under heating and refluxing. After completion of the reaction, the solution was cooled to room temperature, and precipitated crystals were collected by filtration, washed with a small amount of ethanol and dried to obtain 2.51 g of N-(1-methylthio-2-nitroethenyl)-4′trifluoromethoxyaniline (Intermediate No. 30) having a melting point of from 114 to 115° C. (2) To 2.00 g of N-(1-methylthio-2-nitroethenyl)-4-trifluoromethoxyaniline (Intermediate No. 30) obtained in the above step (1), 40 ml of ethanol was added at room temperature, and then 0.36 g of hydrazine monohydrate was dropwise added thereto. Thereafter, the reaction was carried out for 1 hour under heating and refluxing. After completion of the reaction, the solution was cooled to room temperature, and precipitated crystals were collected by filtration, washed with a small amount of ethanol and dried to obtain 1.36 g of the desired product (Compound No. 61) having a melting point of 161° C. (decomposition point).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[CH3:14][Si:12]([CH3:15])([C:8]([CH3:11])([CH3:10])[CH3:9])[O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: OCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCO
Reaction time: 16 h

Procedure:
To a stirred solution of 1,3-propanediol (4.8 mL, 66 mmol) in THF (100 mL) was added sodium hydride (60% dispersion in mineral oil, 2.6 g, 66 mmol) followed by tert-butyldimethyl chlorosilane. The solution was allowed to stir for 16 h, and concentrated to an oily residue. Purification by chromatography (40% ethyl acetate in hexanes) afforded title compound (12.3 g). MS (M+H): 191.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([Cl:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])c(Cl)c3)ccc2n1)C1CC1
Yield: 111.4 %

Procedure:
Using N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.92 mmol), 4-fluoro-2-chloro-1-nitrobenzene (315 mg, 1.79 mmol), dimethyl sulfoxide (4 mL) and cesium carbonate (675 mg, 2.07 mmol), and in the same manner as in Reference Example 101, the title compound (382 mg, 74%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.323 g. of caproic acid chloride as in Example 1. The 0.613 g. of yellowish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.555 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl hexanoate obtained melts at 56.1° and has a clearing point of 70.7° UV (EtOH): ε 273 = 26400.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]Br>C(OCC)C>[CH2:11]([O:10][C:8]([C:3]1[CH2:4][CH2:5][CH2:6][CH:7]([Br:13])[C:2]=1[OH:1])=[O:9])[CH3:12]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: BrBr
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)C(Br)CCC1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
Ethyl 2-oxocyclohexanecarboxylate (30 g, 176 mmol, 28 mL) was dissolved in diethyl ether (30 mL) and cooled to 0° C. under nitrogen. Bromine (28 g, 176 mmol, 9.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to RT over 90 min. The mixture was slowly poured into ice-cold saturated aqueous potassium carbonate (250 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo and dried on the vacuum line for 18 h to afford 41.4 g (94%) of 3-Bromo-2-hydroxy-1-enecarboxylic acid ethyl ester (4) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.1, 17.7, 21.8, 32.0, 60.0, 60.8, 99.7, 166.3, and 172.8.
Reaction SMILES: [N:1]#[N:2].C([O:7][C:8](=[O:36])[CH2:9][N:10]([C:15](=[O:35])[C@H:16]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][CH2:13][CH3:14])(C)(C)C.[ClH:37].C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:1]#[N:2].[ClH:37].[S:18]([NH:17][C@H:16]([C:15]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:8]([OH:36])=[O:7])=[O:35])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2.0 g of N2 -tosyl-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry ethyl ether to give 1.5 g of N2 -tosyl-L-arginyl-N-butylglycine hydrochloride as an amorphous solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c7) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[C:21]([N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH3:37])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(Cl)(Cl)(Cl)Cl>[C:21]([N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH2:37][Br:8])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(CBr)nc2ccccc21
Reaction time: 21 h

Procedure:
NBS (8.43 g, 47.4 mmole) and AIBN (2.1 g, 12.8 mmole) were added to a solution of 1-BOC-2-methylbenzimidazole (10.0 g, 43.1 mmole) in CCl4 (120 mL) at reflux. After 21 hr, the reaction was cooled and filtered. The filtrate was concentrated, and the resulting brown oil was chromatographed on silica gel (15% EtOAc/hexanes) to afford the title product: 1H NMR (400 MHz, CDCl3) δ 7.94-8.01 (m, 1 H), 7.70-7.75 (m, 1 H), 7.31-7.44 (m, 2 H), 4.96 (s, 2 H), 1.75 (s, 9 H),
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]=O)=[CH:8][CH:7]=2.[NH2:15][C:16]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:17]=1[C:18]([NH2:20])=[O:19].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:20][C:18](=[O:19])[C:17]3[C:16](=[CH:24][C:23]([O:25][CH3:26])=[CH:22][C:21]=3[O:27][CH3:28])[N:15]=1)=[CH:8][CH:7]=2
Reactant: O=Cc1ccc2[nH]c(CCO)cc2c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCO)cc4c3)nc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-hydroxy-ethyl)-1H-indole-5-carbaldehyde (0.300 g, 1.58 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.370 g, 1.90 mmol) in N,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt %) (0.350 g, 1.90 mmol) and p-toluenesulfonic acid monohydrate (60 mg, 0.32 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen and cooled to room temperature. The solvent was evaporated under reduced pressure. Water (20 mL) was added and the solid was separated by filtration, washed with water (30 mL) and dried under vacuum. Crude compound was purified by the Simpliflash system (5:20:75 methanol/ethyl acetate/CH2Cl2 as eluent) to give the title compound as an off-white solid. Yield: 0.22 g (38%). MP 237-238° C. 1H NMR (400 MHz, DMSO-d6): δ 11.83 (br s, 1H), 11.20 (s, 1H), 8.34 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 6.73 (d, J=1.9 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 6.30 (s, 1H), 4.81 (t, J=5.1 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.75 (q, J=6.63 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C(C)=O.[Na].O>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:11])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
4-Methoxyphenylacetyl chloride (76 g, 0.413 mole) was added to a stirred suspension of ethyl acetoacetate, sodium salt (62.8 g, 0.413 mole) in ether (250 ml) over a period of 1.5 hours and the reaction was allowed to sit for 3 days. The reaction mixture was treated with water (100 ml) and extracted with ether. The ether extract was cooled in an ice bath and ammonia gas was bubbled into the solution for 2.5 hours while the reactants were allowed to warm to room temperature. The reaction was washed with water, filtered and the ether fraction was stirred with 3N hydrochloric acid (100 ml) for 16 hours. The ether layer was washed with water, 5% sodium bicarbonate, brine and dried with sodium sulfate. The solvent was removed and the residue was distilled on a kugelrohr apparatus to give the product as a yellow oil (19.7 g, 20%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=3[Cl:53])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1cc(Cl)c(CBr)cc1F
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(F)c(F)cc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4,5-difluorobenzene and isolated as colorless gum (8.3 mg, 45%). MS(m/e): 443.4 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]4[CH:28]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cncnc4)c3)cnc2c1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and pyrimidine-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(pyrimidin-5-yl)phenyl]-imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (7 mg, 6%): m/z (ES+) 367 [MH+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]#[N:17])[C:10]=2[CH:9]=[N:8]1.N>CO.[Ni]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: N#Cc1cccc2c1cnn2C1CCCCO1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 198 (430 mg, 1.89 mmol) in a 7N solution of NH3 in MeOH (20 mL) was added Raney nickel (50 mg), and the mixture was stirred under hydrogen (1 atm) at RT overnight. The Raney nickel was removed by filtration. The filtrate was concentrated to afford 340 mg (79%) of (1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) methanamine (199) as yellow syrup: MS (ESI) m/z=232.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:24][CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 4-isopropylaniline gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.30 (s, 1H), 10.50 (s, 1H), 8.22 (d, 1H, J=5.4 Hz). 7.37 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=3 Hz), 7.18 (s, 1H), 7.15 (s, 1H), 7.06 (dd, 1H, J=3.3 and 8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 2.85 (sept., 1H, J=7.2 Hz), 1.17 (d, 6H, J=6.9 Hz); LCMS: ret. time: 24.91 min.; purity: 95%; MS (m/e): 381 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14]CC=C)[N:10]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:9](=[O:23])[CH2:8][CH2:7]2)[CH:2]=[CH2:3].[CH2:24]1[C:33]2C(=CC=CC=2)CC[CH2:25]1>>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:33][CH:24]=[CH2:25])[C:13]=1[OH:14])[N:10]([CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])[C:9](=[O:23])[CH2:8][CH2:7]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc2c(cc1CC=C)CCC(=O)N2CC=C(C)C
Reactant: c1ccc2c(c1)CCCC2
Product: C=CCc1cc2c(c(CC=C)c1O)N(CC=C(C)C)C(=O)CC2
Reaction time: 3 h
Yield: 78 %

Procedure:
10 Grams of 6-allyl-7-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone obtained in Example 20 was dissolved in 50 ml of tetralin and stirred at 200° to 230° C. for 3 hours. After cooling, the reaction mixture was subjected to purification by passing through a silica gel column, there was obtained 7.8 g (78%) of 6,8-diallyl-3,4-dihydro-7-hydroxy-1-prenyl-2(1H)-quinolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([CH3:28])[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)C1=C(C)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Temperature: 70 °C
Reaction time: 12 h
Yield: 47.9 %

Procedure:
A mixture of ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 5.3 mmol), iodomethane (0.97 g, 6.84 mmol) and potassium carbonate (1.47 g, 10.6 mmol) in acetonitrile (50 mL) was stirred at 70° C. for 12 hours, and cooled to 25° C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a tawny solid (1.0 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[N:11]>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:12](\[C:10]#[N:11])/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=Cc1ccc(Br)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)/C(C#N)=C/c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromobenzaldehyde (1 eq), t-butyl cyanoacetate (1 eq) and NH4OAc (1 eq) in benzene (1M) was reflux for 4 h while removing water with a Dean-Stark trap. The mixture was cooled to rt, diluted with hexane and triturated. The title compound was isolated after filtration as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]=2.[C:28](OC)(OC)(OC)[CH2:29][CH2:30][CH3:31]>>[C:22]1([C:7]2[CH:8]=[CH:9][C:10]3[C:11]4[N:12]([CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])[CH3:15])[C:28]([CH2:29][CH2:30][CH3:31])=[N:1][C:2]=4[CH:3]=[N:4][C:5]=3[CH:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)(CNc1c(N)cnc2cc(-c3ccccc3)ccc12)NS(C)(=O)=O
Product: CCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Yield: 81.8 %

Procedure:
N-[2-(3-Amino-7-phenylquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide (2.20 g, 5.04 mmol) was treated with trimethyl orthobutyrate (0.90 mL, 5.5 mmol) according to the method described in Part G of Example 1. The chromatographic purification was carried out eluting with 92.5:7.5 dichloromethane:methanol to provide 1.8 g of N-[2-(7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a tan solid.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Si:13]([O:20][CH:21]([C:50]1[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[CH:52][CH:51]=1)[C:22]([O:24][CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1)=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C([SiH](CC)CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Si:13]([O:20][CH:21]([C:50]1[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[CH:52][CH:51]=1)[CH2:22][O:24][CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.27 mmol of titanium tetrachloride in 1.5 ml of dichloromethane is added to a solution of 2.61 mmol of trimethylsilyl trifluoromethanesulphonate in 1 ml of dichloromethane at 0° C. The mixture is stirred at room temperature for 4 hours and then cooled to 0° C. A solution of 0.83 mmol of 1-trityl-1H-imidazol-4-ylmethyl (tert-butyldimethylsilyloxy)(4-cyanophenyl)acetate and 4.17 mmol of triethylsilane in 2 ml of dichloromethane is added, and the reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate (2×). The combined organic phases are washed with water and brine; dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).