Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29].C=O.[BH4-].[Na+].[C:34](O)(C(F)(F)F)=O>C1COCC1.CC(=O)OCC>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH:24]4[CH2:28][CH2:27][N:26]([CH3:34])[CH2:25]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNC1)C3
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C)C1)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A mixture of Example 68 (150 mg; 0.36 mmol; 1 eq.), formaldehyde (0.27 mL; 3.64 mmol; 10 eq.) and NaBH4 (69 mg; 1.82 mmol; 5 eq.) in THF (12 mL) was cooled to 0° C. and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with EA. The organic phase was washed with 0.1M NaOH (2×), dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM/MeOH/TEA) afforded the title compound (75 mg, 48%) as white foam. 1H NMR (DMSO-d6) δ 7.47-7.38 (m, 1H), 7.33-7.25 (m, 1H), 7.09-6.99 (m, 2H), 4.99-4.89 (m, 1H), 4.82 (m, 2H), 4.65-4.42 (m, 2H), 2.88-2.75 (m, 4H), 2.62 (s, 1.5H), 2.60-2.52 (m, 2.5H), 2.37-2.20 (m, 2H), 2.19 (s, 1.5H), 2.18 (s, 1.5H), 1.80-1.66 (m, 1H), 1.46-1.31 (m, 1H). HPLC (max plot) 95.6%, Rt 2.63 min. UPLC/MS: (MS+) 426.5 ([M+H]+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]#[N:12])[C:2]1=2.CC([OH:17])(C)C.[OH-].[K+]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]([NH2:12])=[O:17])[C:2]1=2
Reactant: CC(C)(C)O
Reactant: N#CCc1cccc2ccsc12
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)Cc1cccc2ccsc12

Procedure:
Add benzo[b]thiophene-7-acetonitrile (1.9 g, 11.0 mmol) to 2-methyl-2-propanol (20 mL). Heat to reflux under nitrogen and add potassium hydroxide pellets (7.4 g, 132 mmol). Stir and reflux under nitrogen for 30 minutes. Pour solution off of the excess potassium hydroxide and dilute with ethyl acetate. Wash with a 1:1 mixture of aqueous saturated sodium chloride, aqueous saturated sodium hydrogen carbonate. Dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Rinse the solid with cold diethyl ether and dry under vacuum to obtain the title compound as an off-white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and-saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (532 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:25][CH2:26][CH:27]1[O:29][CH2:28]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[CH2:28][CH:27]([CH2:26][Cl:25])[O:29][C:7]3([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: ClCC1CO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN1C(=O)CN2CC(CCl)OC2(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
A mixture of 10 g. (35 mmole) of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 10 g. of aluminum chloride, and 200 ml. of dried benzene was treated with 30 ml. of 1-chloro-2,3-epoxypropane in 100 ml. of benzene. The reaction mixture was stirred overnight. Work-up as in Method A, Example 5, above gave 32 g. of a crude oil. The oil was dissolved in benzene, filtered over Florisil, evaporated to dryness and crystallized from ether-petroleum ether to give the above-titled product as colorless needles, m.p. 140°-142°.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][CH:20]([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(#N)C.C(=O)(O)[O-].[Na+]>>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:26][C:25]4[CH:27]=[CH:28][C:22]([O:21][CH:20]([F:19])[F:29])=[CH:23][CH:24]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 160 °C
Yield: 76.5 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.103 g, 0.000366 mol) and 4-(difluoromethoxy)aniline (0.091 mL, 0.00073 mol) in acetonitrile (3 mL, 0.06 mol) was heated via microwave in a sealed tube at 160° C. for 10 minutes. After cooling to room temperature, the mixture was added to saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Concentrated to leave an oil. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.113 g of a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N#N.[H][H]>CCO.[Pd]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2cccc(N3CCNCC3)c2ccn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: O=C1c2cccc(N3CCNCC3)c2CCN1Cc1ccccc1
Yield: 15.6 %

Procedure:
2-Benzyl-5-piperazin-1-yl-2H-isoquinolin-1-one (0.05 g, 0.16 mmol) from step 5 was added to a small (100 mL) Parr bottle, dissolved in 10 mL of EtOH, and a catalytic amount (25 mg) of palladium (10%) on charcoal was added (under N2 atmosphere). The vessel was then exposed to 60 psig hydrogen for 24 hours. Preparative HPLC gave the desired product, 2-benzyl-5-piperazin-1-yl-3,4-dihydro-2H-isoquinolin-1-one (8 mg, 0.025 mmol); M+H=322.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]#[N:19].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].C([NH+](CC)CC)C.Cl>C1(C)C=CC=CC=1.O>[NH:20]1[C:18]([C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]=2[NH2:1])=[N:19][N:22]=[N:21]1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1nnn[nH]1
Temperature: 61 °C

Procedure:
4-Amino-4′-trifluoromethyl-biphenyl-3-carbonitrile (8.3 g) was dissolved in toluene (100 mL), to the solution was added sodium azide (3.1 g) and triethylammonium chloride (6.6 g). The reaction mixture was heated at 60-62° C. overnight, then cooled to room temperature and added water (40 mL), then hydrochloric acid (4 M, 13 mL) was added until pH=1. The product precipitated and was isolated by filtration, the precipitate was washed with cold water and dried on the filter by sucking air through the compound. Yield 10.2 g of white powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.Br[CH:20]([C:22](=[O:25])[CH2:23][CH3:24])[CH3:21].C(N(CC)C(C)C)(C)C>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5](=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:6]([CH:20]([C:22](=[O:25])[CH2:23][CH3:24])[CH3:21])[CH:7]=1
Reactant: CCC(=O)C(C)Br
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)C(C)n1cc(I)ccc1=NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
To a stirred solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (3 g) and 2-bromopentan-3-one (3.3 g) in THF (50 ml) was added N,N-diisopropylethylamine (5.6 ml) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, poured into saturated NaHCO3 solution and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (hexane/EtOAc) to afford the title compound (1.6 g) as a yellow solid.
Reaction SMILES: N[C@H]1CCCC[C@H]1N[C:9]1[N:14]=[N:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=2)[CH:10]=1.N[C@@H]1CCOC[C@@H]1NC(=O)OC(C)(C)C.[Cl-:45].[Na+].O>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:45][C:9]1[N:14]=[N:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=2)[CH:10]=1
Reactant: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1C(C)C
Reactant: [Cl-]
Agent: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C(C)C
Temperature: 140 °C

Procedure:
To a solution of 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (199 mg, 618 μmol, prepared as described in example 32) in NMP (2.06 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (536 mg, 2.47 mmol) in four portions approximately every 12 h and the mixture heated at 140° C. After 48 h total heating time the mixture was cooled and then diluted with ethyl acetate and brine. The phases were separated then the organic phase was washed with brine (2×), then concentrated in vacuo and the residue obtained was purified by chromatography (silica, 10 to 50% methanol in dichloromethane) to give 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (199 mg, 618 μmol, quantitative) as a light brown solid. MS (EI/CI) m/z: 502.2 [M+H].
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C@H:6]([C:8]1[N:15]2[C:11]([S:12][CH:13]=[CH:14]2)=[CH:10][N:9]=1)[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.C(OC(=O)C)(=O)C>CO.O.C(O)=O>[CH:3]([NH:5][C@H:6]([C:8]1[N:15]2[C:11]([S:12][CH:13]=[CH:14]2)=[CH:10][N:9]=1)[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)C(F)(F)F)c1ncc2sccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C[C@H](NC=O)c1ncc2sccn12
Temperature: 25 °C
Reaction time: 14 h
Yield: 93 %

Procedure:
To a solution of 1.108 of the above-obtained 5-[(S)-1-(trifluoroacetylamino)ethyl]imidazo[5,1-b]thiazole in 20 ml of methanol was added a solution of 2.70 g of potassium carbonate in 20 ml of water, and the mixture was stirred at room temperature under argon atmosphere for 14 hours. To the reaction solution was added 50 ml of methylene chloride. To this mixture was added with ice-cooling a mixture of 0.50 g of formic acid and 0.25 g of acetic anhydride, which had been heated to 50° C. for 10 minutes and then cooled to room temperature, and the resulting mixture was stirred for an additional 30 minutes. 2.70 g of potassium carbonate was added to this reaction solution to obtain a solution, to which was added again with ice-cooling a mixture of 0.50 g of formic acid and 0.25 g of acetic anhydride, which had been heated to 50° C. for 10 minutes and then cooled to room temperature, and the resulting mixture was stirred for 30 minutes. Insoluble matters were removed by filtration. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (30 ml×2). The combined organic layers were dried over anhydrous potassium carbonate, concentrated under reduced pressure, and purified by flash column chromatography using silica gel, eluting first with ethyl acetate and then with a 20:1 mixture of ethyl acetate and methanol to give 0.763 g (yield 93%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[CH:33]1([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>CC(N(C)C)=O>[CH:33]1([NH:39][CH2:40][CH2:41][CH2:42][NH:43][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:3]3[C:2](=[O:1])[C:6]4[N:7]=[N:8][C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:5]=4[NH:4]3)=[CH:16][CH:17]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NCCCNC1CCCCC1
Reactant: O=C(Cl)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NCCCNC1CCCCC1)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-(3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)benzoyl chloride (97 mg, 0.30 mmol) was dissolved in anhydrous DMA (2 ml). Diisopropylethylamine (39 mg, 53 μl, 0.60 mmol) was added followed by N-cyclohexyl-1,3-propanediamine (52 mg, 0.60 mmol). The mixture was stirred for 30 min. Water (5 ml) was added to give a dark red suspension. The mixture was extracted with n-butanol (2×20 ml). The combined organic phases were washed with water and concentrated under vacuum until precipitation was observed. Hexane (20 ml) and ethyl acetate (10 ml) were added, the solids were collected by filtration and dried under vacuum. The product was isolated as a dark red powder (82 mg, 0.18 mmol, 62%). LCMS: m/z 445 [M+H]+.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[O:10][CH:9]=[C:8]([CH:11]=O)[CH:7]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:8]1[CH:7]=[C:6]([CH3:5])[O:10][CH:9]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1cc(C=O)co1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1coc(C)c1)CC(=O)O
Yield: 30.5 %

Procedure:
Sodium ethylate (16 g, 0.23 mol) was added under vigorous stirring to a solution of 5-methyl-3-furaldehyde (21 g 80% purity, 0.19 mol) and diethyl succinate (50 g, 0.286 mol) in ethanol (400 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 300 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 700 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture (1:1). Fractions with the target product were collected, evaporated in vacuum and crystallized from ether/hexane mixture, 1:3 to give the desired product 14 g (58 mmol, 31%) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:30][CH2:29][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: NCc1ncccn1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
In DMF (60 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio) pyrimidine-5-carboxylic acid (1.0 g, 2.95 mmol), pyrimidine 2-ylmethylamine (570 mg, 5.22 mmol) and HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 2.64 g, 6.96 mmol), then DIEA (152 mg, 1.2 mmol) was added dropwisely. The reaction mixture was stirred at 60° C. overnight, extracted with DCM after water was added and washed with brine. The organic phase was dried over sodium sulfate. The solvent was removed by rotary evaporation, then the solid obtained was purified by silica gel column chromatography (DCM/methanol=50/1) to give 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (350 mg, 13% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.CO.C(Cl)(Cl)Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:29][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2cc3c(Nc4cccc(Br)c4)c(C#N)cnc3cn2)cc1
Yield: 45 %

Procedure:
To 1 g of 4-(3-bromo-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 25 mL of absolute ethanol was added 2 ml of 4-methoxy-benzylamine. The reaction was refluxed for eight days, stripped of solvents, and passed through a plug of silica gel with 5% methanol/chloroform. Fractions containing product were pooled and further purified by flash chromatography on silica gel with a gradient of 1-2% methanol/chloroform to give 595 mg (45%) of 4-(3-bromo-phenylamino)-6-(4-methoxy-benzylamino)-[1.7]naphthyridine-3-carbonitrile, which was sufficiently pure for further transformations. The product was recrystallized by dissolving in a minimum amount of warm chloroform, diluting with ether, and then adding hexanes to give 195 mg: melting point 82-86° C. (decomposed); mass spectrum (m/e): M+H 460.2, 462.2.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1ccc(I)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(I)cc1

Procedure:
To a suspension of 10 g (40.32 mmol) of 4-iodobenzoic acid in 100 ml absolute ethanol was added 2 ml thionyl chloride and the mixture was then heated at reflux for 3 hours. Solvent was removed in vacuo and the residue was dissolved in 100 ml ether. The ether solution was washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was then removed in vacuo an the residue kugelrohr distilled (100 degrees C.; 0.55 mm) to give the title compound as a colorless oil, PMR (CDCl3): & 1.42 (3H, t, J~7 Hz), 4,4 (2H, q, J~7 Hz), 7.8 (4H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][C:6]([O:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[N:20]=[CH:19][N:18]=3)=[CH:7][CH:8]=2)[N:3]=1.CC(O)=O.O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.[Zn]>[F:15][C:12]([F:13])([F:14])[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=4)[N:20]=[CH:19][N:18]=3)=[CH:7][CH:8]=2)[N:3]=[CH:2][CH:11]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Oc3ccc4c(C(F)(F)F)cc(Cl)nc4c3)ncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4c(C(F)(F)F)ccnc4c3)ncn2)cc1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
To a 100-mL, round-bottomed flask containing a solution of 2-chloro-4-trifluoromethyl-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline, (Example 22(b)), (0.25 g, 0.53 mmol) in EtOAc (20 mL) was added Zn (0.87 g, 13 mmol, Aldrich), AcOH (61 mg, 1.1 mmol), and water (40 mg, 1.1 mmol). The mixture was heated at 70° C. with stirring for 2.5 h. After cooling to room temperature, 5% aq. Na2CO3 was added and the reaction mixture was extracted with EtOAc (30 mL). The organic phase was washed with water (2×10 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Purification of the residue by silica gel chromatography (gradient: 3:1 hexanes:EtOAc) gave the title compound. Mp: 129-131° C. MS (ESI, pos. ion) m/z: 436 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.Br[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[C:22](\[CH3:28])/[CH2:23][O:24][CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=1.CCCCCC.C([Li])CCC.[CH:40]1[CH:45]=[N:44][CH:43]=[C:42]([CH:46]=[O:47])[CH:41]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[N:44]1[CH:45]=[CH:40][CH:41]=[C:42]([CH:46]([OH:47])[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[C:22](\[CH3:28])/[CH2:23][O:24][CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=2)[CH:43]=1
Reactant: C/C(=C\c1ccc(Br)cc1)COCCO
Reactant: O=Cc1cccnc1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C(=C\c1ccc(C(O)c2cccnc2)cc1)COCCO

Procedure:
In 10 ml of anhydrous tetrahydrofuran was dissolved 910 mg of tetrahydropyranyl ether of 2-[(E)-3-(4-bromophenyl)-2-methylallyloxy]ethanol, and 1.9 ml of 1.5M n-butyl lithium hexane solution was dropped into the resulting solution at a temperature of -70° C. to -65° C., after which the resulting mixture was subjected to reaction at the same temperature for one hour. To the reaction mixture was dropwise added 1 ml of anhydrous tetrahydrofuran containing 0.27 ml of nicotinic aldehyde at a temperature of -70° C. to -65° C., and the resulting mixture was subjected to reaction at the same temperature for one hour. Subsequently, the solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 50 ml of ethyl acetate and 20 ml of a saturated aqueous ammonium chloride solution, after which the organic layer was separated, washed successively with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene:ethyl acetate (1:3 by volume)] to obtain 230 mg (yield 23.4%) of colorless, oily tetrahydropyranyl ether of 2-[(E)-3-[4-(pyridin-3-yl-hydroxymethyl)phenyl]-2-methylallyloxy]ethanol.