Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[OH:28])[CH:22]=[CH:23][CH:24]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1O
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CC(c2cccc(-c3ccccc3O)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Yield: 53.3 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (748.1 mg, 1.67 mmol), 2-hydroxy-phenylboronic acid (276.0 mg, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (193.0 mg, 0.17 mmol) in dioxane (5.0 mL) was added 2 M sodium carbonate solution in water (1.7 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(2′-hydroxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (412.1 mg, 53.4%) as a white solid: MS (ESI) M+1=463.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[C:12]([CH2:14][C:15]([O:17]CC)=[O:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)c(Cl)c2)oc1-c1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1nc(-c2ccc(Cl)c(Cl)c2)oc1-c1ccoc1
Yield: 81.2 %

Procedure:
7.0 g of ethyl 2-[2-(3,4-dichlorophenyl)-5-(3-furyl)-4-oxazolyl]acetate, 70 ml of methanol, 7 ml of water and 2.0 g of potassium hydroxide are treated in the same manner as described in Example 16. 5.25 g of 2-[2-(3,4-dichlorophenyl)-5-(3-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 81.0%
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:16][C:7]1[C:6]([CH:4]=[O:5])=[CH:11][CH:10]=[C:9]([C:12]([F:14])([F:13])[F:15])[N:8]=1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1C=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a cooled (−78° C.) solution of N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide (615 mg, 2.48 mmol) in THF (10 mL) was added lithium aluminum hydride (LAH, 1 N/THF, 1.23 mL). The mixture was stirred for 15 minutes, and then warmed to −10° C. After additional stirring for 30 minutes, the mixture was quenched with saturated potassium hydrogen sulfate solution (1 mL) and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-methyl-6-trifluoromethyl-3-pyridinecarboxaldehyde quantitatively as oil. The crude product was used directly in the following reaction.
Reaction SMILES: C[Si]([CH:5]=[CH:6][CH2:7][NH2:8])(C)C.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C(OCC)C>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])/[CH:5]=[CH:6]\[CH2:7][NH2:8])[CH2:24][CH2:25][CH3:26]
Reactant: C[Si](C)(C)C=CCN
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](/C=C\CN)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a solution of N-trimethylsilylallylamine (21.0 mL, 125. mmol) in diethyl ether (323 mL) at 0° C. under an atmosphere of nitrogen was added 2.5M n-butyllithium in hexanes (100. mL, 250. mmol). The solution was stirred at 0° C. for 15 minutes then the reaction was allowed to warm to room temperature and stirred for 16 hours. To the reaction mixture was added a solution of tributyltin chloride (33.6 mL, 124. mmol) in diethyl ether (158 mL) slowly at 0° C., then the reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution then extracted twice with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified using column chromatography on silica gel (400 gr Analogix column, gradient DCM to 10% MeOH in DCM over 30 minutes) to give the product (30.6 g, 71%). 1H NMR (400 MHz, CDCl3) δ: 6.81-6.37 (m, 1H), 6.03-5.76 (m, 1H), 3.31-3.17 (m, 2H), 1.60-1.22 (m, 12H), 1.00-0.79 (m, 15H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[C:17]12([CH2:27][CH2:28][C:29](OC)=[O:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>O1CCCC1.CCCCCC.C(O)(=O)C>[O:30]=[C:29]([CH2:28][CH2:27][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)CCC12CC3CC(CC(C3)C1)C2
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CCC12CC3CC(CC(C3)C1)C2)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A solution of 24.8 g (0.200 moles) dimethyl methyl-phosphonate (Aldrich) in 250 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atomsphere. To the stirred phosphonate solution was added 92 ml of 2.38 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 30 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 22.2 g (0.100 mole) methyl 3-(1-adamantyl)propionate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 55 ml acetic acid and rotary evaporated to a white gel. The gelatenous material was taken up to 50 ml water, the aqueous phase extracted with 100 ml portions of methylene chloride (4X), the combined organic extracts were backwashed with water (4 × 100 ml), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 195-200° (<0.02 mm) to give dimethyl 2-oxo-4-(1-adamantyl)butylphosphonate (2b) weighing 36.6 g (100% yield).
Reaction SMILES: ClCCl.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([Cl:18])=[C:11]([CH2:13][NH:14]C(=O)C)[CH:12]=1)(=[O:6])[CH3:5].S(=O)(=O)(O)O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:14][CH2:13][C:11]1[CH:12]=[C:7]([C:4](=[O:6])[CH3:5])[CH:8]=[CH:9][C:10]=1[Cl:18]
Reactant: CC(=O)NCc1cc(C(C)=O)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Cl)c(CN)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 199.8 kg of a dichloromethane solution of N-[(5-acetyl-2-chlorophenyl)methyl]acetamide obtained in Example 3-(B), 90 kg of water and 46 kg (0.45 kmoles) of 98% sulfuric acid were added. Dichloromethane was distilled off under normal pressure over 1.5 hours until the inner temperature reaches 100° C., followed by aging for 6 hours. After the completion of the reaction, the reaction solution was cooled to 50° C. over 20 minutes and 90 kg of water and 105 kg of toluene were added. After cooling, 212 kg of an aqueous 25% sodium hydroxide solution was added dropwise at 15 to 25° C. over 2.5 hours. After heating to 40° C. over 30 minutes, the organic layer was partitioned to obtain a toluene solution of 1-[3-(aminomethyl)-4-chlorophenyl]ethan-1-one.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.Cl.[F:24][C:25]1([F:31])[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]1>>[F:24][C:25]1([F:31])[CH2:29][CH2:28][CH:27]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:26]1
Reactant: NC1CCC(F)(F)C1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC(F)(F)C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 3,3-difluorocyclopentylamine hydrochloride instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.73-2.27 (m, 9H), 2.36 (s, 3H), 3.30-3.34 (m, 2H), 4.30-4.40 (m, 1H), 7.73 (t, J=6.4, 1H), 7.84 (d, J=8.1, 1H), 8.28 (t, J=6.7, 1H), 8.70 (d, J=5.1, 1H); MS (ESI) m/z 334 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 47 %

Procedure:
As described for example 147, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol) was converted, using thiomorpholine instead of cyclopropylmethylamine, to the title compound (56 mg, 47%) which was obtained as an off white solid. MS: m/e=397.3 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=4)[C@@H:7]1[C@@H:6]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:5][C:4]2=[O:28].[CH3:29]OC(OC)(C)C>>[CH3:29][O:20][C:13]1[CH2:14][CH2:15][C@H:16]2[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:17]2[CH2:18][CH2:19][C@@:3]2([CH2:2][CH3:1])[C@H:7]3[C@@H:6]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:5][C:4]2=[O:28])[CH:12]=1
Reactant: COC(C)(C)OC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)C(C)(C)C)CC2=O
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)C(C)(C)C)CC2=O

Procedure:
In analogy to Direction II(b), 5.6 g of 18-methyl-15α-trimethylacetoxy-4-estrene-3,17-dione is reacted with dimethoxypropane and worked up, thus obtaining 4.9 g of 3-methoxy-18-methyl-15α-trimethylacetoxy-3,5-estradien-17-one.
Reaction SMILES: COC([N:6]1[N:10]=[N:9][C:8]([CH3:11])=[N:7]1)(C)C.C([Li])CCC.[C:17]1([C:23]2[CH:28]=[CH:27][C:26]([N:29]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][CH:43]=3)[C:30]([NH:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=3)=[O:31])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C(O)(=O)C>C1COCC1>[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([N:29]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([CH:48]([OH:49])[CH2:11][C:8]4[N:9]=[N:10][NH:6][N:7]=4)=[CH:46][CH:47]=3)[C:30]([NH:32][C:33]3[CH:34]=[C:35]([Cl:40])[CH:36]=[C:37]([Cl:39])[CH:38]=3)=[O:31])=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: COC(C)(C)n1nnc(C)n1
Reactant: O=Cc1ccc(CN(C(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)N(Cc1ccc(C(O)Cc2nn[nH]n2)cc1)c1ccc(C2=CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1-methoxy-1-methylethyl)-5-methyl-2H-tetrazole (1000 mg, 6.41 mmol) in THF (5 ml) cooled to −78° C. on a dry-ice-acetone bath was added dropwise a solution of n-butyl lithium in hexanes (4.0 ml, 1.6 M, 6.4 mmol). The mixture was stirred at −78° C. for 30 min, and at 0° C. for an additional 30 min, then recooled to −78° C. 1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)-1-(4-formylbenzyl)urea (250 mg, 0.52 mmol, from step 2, example 12) was then added as a solid, and the mixture was maintained at −78° C. for 20 min. Reaction temperature was raised to 0° C. and the mixture was stirred for 20 min before addition of acetic acid (2 ml). Upon standing, a white solid starts to precipitate, which is collected and washed with cold acetonitrile. The solid is oven dried under vacuum, to yield 582 mg (95%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=[C:13]([NH2:24])[N:12]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][OH:34]>CN(C=O)C>[NH2:24][C:13]1[N:12]=[C:11]([C:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:10][N:9]=2)[N:16]=[C:15]([N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:32][CH2:33][OH:34])[N:14]=1
Reactant: OCCBr
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3ccco3)n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2noc(-c3ccco3)n2)nc(N(CCO)c2ccccc2)n1
Reaction time: 18 h
Yield: 12 %

Procedure:
6-(5-Furan-2-yl-[1,2,4]oxadiazol-3-yl)-N-phenyl-[1,3,5]triazine-2,4-diamine (prepared in an analogous manner to Example 2, 100 mg, 310 μmol) and potassium carbonate (86 mg, 620 μmol) were stirred together in a sealed tube in DMF (5 ml). 2-Bromoethanol (26 μL, 310 μmol) was added and the reaction was heated at 110 C for 18 h. Potassium carbonate (43 mg, 310 μmol) and 2-bromoethanol (26 μL, 310 μmol) were added and the reaction stirred at 110 C for a further 18 h. After cooling and evaporation of the solvent the crude residue was dissolved in water (30 mL) and extracted twice with DCM (30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified using prep HPLC method B to give the desired title compound (14 mg, 12%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[C:4]([C:8]3[C:9]4[CH:23]=[CH:22][NH:21][C:10]=4[N:11]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=4)[N:13]=3)[CH:5]=[N:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(-c3cncc(N4CCN(C)CC4)c3)c3cc[nH]c3n2)n1

Procedure:
To a solution of 4-(5-bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Example 16) (1 eq, 0.81 mmol, 300 mg) in THF (5 ml), 1-methylpiperazine (Sigma-Aldrich, St. Louis, USA) (1.25 eq, 1.01 mmol, 0.114 ml), Pd2(dba)3 (0.04 eq, 0.032 mmol, 29.7 mg), and 2-(dicyclohexylphosphino)biphenyl (0.08 eq, 0.065 mmol, 25.5 mg) are added. After addition of LHMDS (1 M in THF, 2.2 eq, 1.8 mmol, 1.8 ml) the mixture is refluxed for 5 h, cooled down and quenched by addition of aqueous HCl solution (2M, 5 ml). The mixture is adjusted to pH 6 using aqueous NaOH solution and washed with ethyl acetate. The aqueous layer is adjusted to pH 12 and extracted with EtOAc. The organic layer is washed with brine, dried with MgSO4, filtered, and concentrated. Purification by reversed phase HPLC is giving the title compound, [M+H]+=422; 1H-NMR (400 MHz, CD3OD): δ 9.20 (s, 1H), 9.06-9.03 (m, 2H), 8.74 (d, 1H), 8.67 (t, 1H), 8.04 (d, 1H), 7.99 (d, 1H), 7.23 (d, 1H), 4.41 (m, 2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.43 (m, 2H), 3.04 (s, 3H), 3.03 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][N:29]=1
Reactant: COCCN(C)c1ncc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C19H18F3N5O3 (m/e) 421, obsd 422 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH2:33])=[CH:30][CH:31]=2)[CH:26]=[N:25]1>>[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:2]3[C:3]4[C:10]5[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=5[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:30][CH:31]=2)[CH:26]=[N:25]1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2C1

Procedure:
In analogy to Example 22A, ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (100 mg, 0.35 mmol) and 1-(3-fluorobenzyl)-1H-indazol-5-amine from Example 8A (89 mg, 0.37 mmol) were reacted to the title compound to yield 120 mg (68%).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][O:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][O:15][CH2:16][CH:8]12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCOCC12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)C3COCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
3-(hydroxymethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one (70.0 mg, 0.298 mmol) was suspended in propionitrile (0.74 mL) and (cyanomethyl)trimethylphosphonium iodide (87.0 mg, 0.357 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (115 ul, 0.893 mmol). To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile (56.0 mg, 0.298 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with methanol (5 mL) and dried in vacuum to afford the title compound (72.5 mg, 60.1%) as a white solid. 1H NMR (CHLOROFORM-d) δ: 8.41 (d, J=1.8 Hz, 1H), 8.20 (br. s., 1H), 7.80 (d, J=2.0 Hz, 1H), 7.61 (dd, J=9.0, 2.4 Hz, 1H), 6.99 (br. s., 1H), 6.59 (d, J=9.1 Hz, 1H), 4.42 (dd, J=11.5, 3.7 Hz, 1H), 4.26 (dd, J=13.3, 1.6 Hz, 1H), 3.95-4.12 (m, 2H), 3.58-3.80 (m, 6H), 3.45 (s, 2H), 2.92-3.08 (m, 1H), 2.53 (br. s., 4H). [M+H] calc'd for C, 21; H, 23; N, 7; O, 2, 406; found, 406.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH:10]3[CH2:15][CH2:14][N:13](C(OCC)=O)[CH2:12][CH2:11]3)[C:4]=2[CH:3]=[CH:2]1>Cl>[NH:13]1[CH2:12][CH2:11][CH:10]([C:5]2[C:4]3[CH:3]=[CH:2][S:1][C:9]=3[CH:8]=[CH:7][N:6]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)N1CCC(c2nccc3sccc23)CC1
Agent: Cl
Product: c1cc2sccc2c(C2CCNCC2)n1

Procedure:
A solution of 0.57 g of the product obtained in Step F in 4 ml of HCl (5N) is heated at reflux for 12 hours and then cooled, washed with ether, rendered basic by the addition of 20% sodium hydroxide solution and extracted with dichloromethane. Drying, filtration and concentration of the organic phase under reduced pressure, followed by chromatography on silica gel (CH2Cl2/MeOH/NH4OH: 90/10/1), enables the expected product to be isolated.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.CI.[C:31](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:31][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), methyl iodide (0.1 mL), potassium carbonate (0.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.52 g, 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCc1ccc(Cl)cc1
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1ccc(Cl)cc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 4-chlorobenzylamine to provide yellow solid 4-(4-chlorobenzylamino)-3-nitroquinoline, the melting point of the crude product being 168°-173° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])=[CH:12][CH:11]=1
Reactant: CCc1ccncc1
Reactant: BrCCc1ccc(Br)cc1
Product: CC(CCc1ccc(Br)cc1)c1ccncc1
Yield: 40.5 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.47 g (9.35 mmol) of 4-bromophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.10 g of the desired compound (yield: 40.7%).