Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[N:21][C:20]=1[NH2:26].O>CN(C)C=O>[CH3:6][O:5][C:3]([C:2]1[N:21]2[N:22]=[C:23]([CH3:25])[CH:24]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[C:20]2=[N:26][C:7]=1[CH2:8][CH3:9])=[O:4]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Cc1ccc(-c2cc(C)nnc2N)c(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(-c3ccc(C)cc3C)cc(C)nn2c1C(=O)OC
Temperature: 140 °C

Procedure:
Methyl 2-chloro-3-oxopentanoate (7 mL) was added to a solution of the resulting 4-(2,4-dimethylphenyl)-6-methyl-3-pyridazinamine in N,N-dimethylformamide (60 mL), and the mixture was heated at 140° C. for 6 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried-over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid methyl ester as a crude product.
Reaction SMILES: [CH3:1][C:2]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].[CH3:11][C:12]1[C:13]([CH:19]=O)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:11][C:12]1[C:13]([CH2:19][NH:10][C:2]([CH3:3])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:1])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: CC(C)(N)c1ccccn1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNC(C)(C)c2ccccn2)c(C)c1
Yield: 36 %

Procedure:
Using General Procedure B: Reaction of 1-methyl-1-pyridin-2-yl-ethylamine, 3,5-dimethylpyridine-2-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave (3,5-dimethyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amine as a light brown oil (94 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2C=NC=CC=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([CH3:29])[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Product: CC1NC(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 205-206° C.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:15])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1([N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:17]1([N:23]2[CH2:24][CH2:25][CH:26]([NH:29][C:7](=[O:15])[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC1CCN(c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NC1CCN(c2ccccc2)CC1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Pyridine (24 μL) and phenyl chlorocarbonate (32 μL) were added to a solution of 1-phenyl-4-piperidylamine (35 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/chloroform=1/1) to give the title compound (37 mg).
Reaction SMILES: ClC(OC)=O.[CH2:6]([O:8][C:9](=[O:38])[C:10]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:22])[CH:21]=1)([CH3:14])[C:11](O)=[O:12])[CH3:7].CCN(CC)CC.[BH4-].[Na+].Cl>C1COCC1.C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:38])[C:10]([CH2:11][OH:12])([CH3:14])[CH2:15][C:16]1[CH:17]=[N:18][C:19]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:22])[CH:21]=1)[CH3:7]
Reactant: CCOC(=O)C(C)(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)O
Agent: COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(CO)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Reaction time: 0.83 h
Yield: 48 %

Procedure:
Methyl chloroformate (338 μL, 4.4 mmol) was added dropwise to a solution of crude 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl methyl)-2-methyl-malonic acid monoethyl ester (1.9 g) and Et3N (641 μL, 4.6 mmol) in THF (30 mL) at −20° C. The reaction mixture was stirred for 50 min., filtered and added dropwise to a suspension of NaBH4 (182 mg, 4.8 mmol) in THF (30 mL) at −20° C. The reaction was stirred for 16 h at room temperature. 0.5 M HCl was added followed by methylene chloride. The organic phase was washed with brine and dried. Concentration under reduced pressure followed by chromathography (toluene/EtOAc, 10:1→1:3) gave 3-(6-[N,N-bis(tert-butoxycarbonyl)-amino]-5-methyl-pyridin-3-yl)-2-hydroxymethyl-2-methyl-propionic acid ethyl ester (885 mg, 49%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]1=2.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[CH:22][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:24]=1[CH3:25].Cl.[OH-].[Na+]>COCCOC.O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:15])[N:12]([CH2:19][C:20]3[N:21]=[CH:22][NH:23][C:24]=3[CH3:25])[CH2:13][CH2:14][C:3]1=2
Reactant: Cn1c2c(c3ccccc31)C(=O)NCC2
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 6 h
Yield: 94.1 %

Procedure:
A suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (400 mg) in dry DME (50 ml) was treated with sodium hydride (60% dispersion in oil; 100 mg), and the mixture was stirred at 60° under nitrogen for 6 h. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (474 mg) was added and the reaction mixture was stirred at 60° under nitrogen overnight. 2N Hydrochloric acid (10 ml) and water (10 ml) were then added, and the mixture was heated at reflux for 6 h. After cooling, the mixture was basified with 2N sodium hydroxide and the resulting mixture was extracted with ethyl acetate (2×50 ml). The combined, dried organic extracts were concentrated onto FCC silica and purified by FCC eluting with System A (150:8:1) to give the title compound (352 mg) as a solid, t.l.c. (System A, 100:8:1) Rf 0.28. 1H-N.m.r.: δ2.2 (3H,s), 3.04 (2H,t), 3.62 (2H,t), 3.72 (3H,s), 4.53 (2H,s), 7.1-7.28 (2H,m), 7.43 (1H,s), 7.47-7.55 (1H,dd), 7.94-8.03 (1H,dd).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Li])CCC.[C:12]1([CH2:18][CH2:19]C(Cl)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(CCC(O)=O)C=CC=CC=1>O1CCCC1.S(Cl)(Cl)=O>[O:6]=[C:4]([CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:1]#[N:2]
Reactant: N#CCC(=O)O
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C(O)CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: N#CCC(=O)CCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of cyanoacetic acid (1.0 g, 11.8 mmol) in tetrahydrofuran (20 mL) was cooled to −78° C. and treated with 1.6 M n-butyl lithium in hexanes (14.7 mL, 23.5 mmol). The mixture was warmed to −20° C. over 2 hours, cooled to −78° C. and treated with 3-phenylpropionyl chloride (prepared by refluxing a solution of 3-phenylpropionic acid (1.0 g, 6.7 mmol) in thionyl chloride (4 mL) for 3 hours, evaporating and drying). The mixture was stirred at −78° C. for 1 hour and 20% hydrochloric acid added until the pH=3. The mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate, and the organic layer separated and concentrated. The crude product was purified by flash chromatography on silica gel using 0-50% ethyl acetate/hexanes to provide the title compound. MS (ESI) m/e 191 (M+H+NH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[N:17]=1)[CH:13]=[CH:12][O:11]2.Cl>O1CCOCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:17]=1)[CH:13]=[CH:12][O:11]2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccc(-c3c(-c4ccccc4Cl)nc4occn34)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Clc1ccccc1-c1nc2occn2c1-c1ccnc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 167.4 %

Procedure:
The tert-butyl 4-({4-[6-(2-chlorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (1.8 g, 3.6 mmol) is dissolved in 20 ml of dioxane and treated with 40 ml of anhydrous a four molar HCl in dioxane at room temperature (RT). The reaction mixture is stirred at room temperature for three hours. The mixture is then diluted with 100 ml of ether and stirred until product separates as a solid. Solid product is filtered and washed with ether. The product is dried at high vacuum to yield 1.3 g of pale yellow solid (94%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([OH:9])=O.S(Cl)([Cl:12])=O>CN(C=O)C>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([Cl:12])=[O:9]
Reactant: O=C(O)CCOCCCl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCOCCCl

Procedure:
Prepared analogously to Example 90c from 3-(2-chloro-ethoxy)-propionic acid and thionyl chloride with DMF.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[I:12]N1C(=O)CCC1=O>FC(F)(F)S(O)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[I:12]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OCc2cc(Br)ccc21
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2c1ccc(Br)c2I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 5-bromo-2-benzofuran-1(3H)-one (50 g, 0.235 mol) in trifluoromethanesulfonic acid (400 mL) was added N-iodosuccinimide (55.5 g, 0.247 mol). The resulting mixture was stirred at room temperature overnight, then poured slowly into ice water (2 L), filtered and the filtrate extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated to give 5-bromo-4-iodo-2-benzofuran-1(3H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7]([NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[O:24][C:23]([F:22])([F:33])[F:34])=[O:8]
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: O=C(Cl)c1cc(Br)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C(NCc1ccccc1OC(F)(F)F)c1cc(Br)ccc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
This compound was prepared using the procedure described in Example 70, using 5-bromo-2-(4-chloro-benzenesulfonylamino)-benzoyl chloride instead of 5-bromo-2-(4-trifluoromethoxy-benzenesulfonylamino)-benzoyl chloride, and 2-trifluoromethoxybenzyl amine instead of 2-methoxy benzyl amine. M/Z of [M−H]−=563.8. 1H NMR (DMSO) δ=4.4 (sd, 2H), 7.3–7.4 (5H), 7.5 (2H), 7.65–7.7 (3H), 7.9–8.0 (1H), 9.4 (br, 1H), 11.5 (br, 1H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH:19][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Li+]>O1CCCC1.CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:29])=[O:3])[CH2:7][CH2:8]2)=[C:13]([NH:19][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:14]=1
Reactant: CCOC(=O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 0.590 g (1.35 mmol) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid ethyl ester in a mixture of tetrahydrofuran (10 mL) and methanol (4 mL) is added water (2 mL) followed by 0.16 g (6.8 mmol) of lithium hydroxide. The mixture is stirred overnight at room temperature. The mixture is concentrated under reduced pressure to remove volatile organics and the pH of the resulting solution is adjusted to approximately pH 4 by the addition of concentrated hydrochloric acid. A green oil forms at the bottom of the mixture. The aqueous layer is removed by decanting and the green oil is concentrated under reduced pressure to provide 0.46 g (83%) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid as a green solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[NH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Product: O=C(Cc1ccc(Br)cc1F)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 36 %

Procedure:
Following the procedure outlined for Example 627, (2-(4-bromo-2-fluorophenyl)acetic acid) (10.8 g, 30.7 mmol) reacted with (S)-(+)-4-benzyl-2-oxazolidinone (5.44 g, 30.7 mmol) to obtain the desired product (4.5 g, 36%) as white solid. ESI MS nm/393 [C18H15BrFNO3+H]+
Reaction SMILES: N.[OH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[N:10])[CH2:5][CH2:4]1>CO.[Ni]>[NH2:10][CH2:9][C@@H:6]1[CH2:7][CH2:8][C@H:3]([OH:2])[CH2:4][CH2:5]1
Reactant: N#C[C@H]1CC[C@@H](O)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NC[C@H]1CC[C@@H](O)CC1
Reaction time: 8 h

Procedure:
To a 2 N solution of NH3 in MeOH (40 mL) in a high pressure autoclave was added cis-4-hydroxy-cyclohexanecarbonitrile (6.6 g, 52.7 mmol) and Raney Ni (1.0 g, 17 mmol, 0.3 equiv.) The mixture was placed under 45 psi H2 and shaken overnight. The pressure was released and the reaction filtered through a pad of Celite. The filter pad was washed with EtOAc and the mixture was concentrated under reduced pressure to provide a yellow oil as cis-4-aminomethyl-cyclohexanol (6.3 5g, 49.1 mmol, 93.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]O.C[CH2:12][N:13](CC)CC.CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:12]#[N:13]
Reactant: CCN(CC)CC
Reactant: OCCc1ccccc1F
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: N#CCCc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-fluoro-phenyl)-ethanol (10.00 g, 71.50 mmol) in CH2Cl2 at 0° C. was added Et3N (20.00 mL, 0.14 mol) followed by MsCl (19.00 mL, 0.25 mol). The resulting mixture was stirred for 1 hour, then washed with H2O (3×100 mL) and brine (1×150 mL), dried over MgSO4 and concentrated. The residue was dissolved in DMF and KCN (9.30 g, 0.14 mol) was added. The resulting mixture was stirred at 75° C. for 14 hours. After cooling to room temperature, the reaction mixture was quenched into water and extracted with Et2O (3×300 mL). The combined organic extracts were washed with H2O (2×200 mL), brine (1×200 mL), dried over MgSO4 and concentrated to give the title compound.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: CN1CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 380 mg (3.80 mmol) of N-methylpiperazine to give 36 mg (30% of theory) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.C(N(CC)CC)C.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH:59]1[CH2:64][CH2:63][CH:62]([N:65]2[CH2:70][C:69]3[CH:71]=[N:72][CH:73]=[CH:74][C:68]=3[NH:67][C:66]2=[O:75])[CH2:61][CH2:60]1>O1CCCC1>[O:75]=[C:66]1[NH:67][C:68]2[CH:74]=[CH:73][N:72]=[CH:71][C:69]=2[CH2:70][N:65]1[CH:62]1[CH2:61][CH2:60][N:59]([C:35]([NH:1][C@@H:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]2=[O:24])=[O:36])[CH2:64][CH2:63]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=C1Nc2ccncc2CN1C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2Cc3cnccc3NC2=O)CC1
Reaction time: 1 h
Yield: 24.4 %

Procedure:
A solution of (3R) 3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluorethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.030 g, 0.090 mmol) and 4-nitrophenylchloroformate (0.018 g, 0.090 mmol) in dry tetrahydrofuran (2 mL) was cooled to 0° C. under argon. Triethylamine (0.013 mL, 0.090 mmol) was added and the reaction stirred for 1 h. Solid 3-piperidin-4-yl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one bisTFA salt (0.90 mmol) followed by triethylamine (0.065 mL) were added. The reaction was allowed to come to room temperature and stirred for 1 h. The reaction was quenched with 1N NaOH and concentrated. The crude product was purified by chromatography (silica gel, 0 to 15% methanol in methylene chloride gradient elution) to give the title compound (0.013 g, 24% yield). MS 592.2286 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][N:13]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:9]2)=[N:4]1)[CH3:2].NN.O>CO>[CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][NH2:13])=[CH:9]2)=[N:4]1)[CH3:2]
Reactant: CCn1cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Agent: NN
Solvent: CO
Solvent: O
Product: CCn1cc2cc(CN)ccc2n1
Temperature: 50 °C
Yield: 52 %

Procedure:
To a suspension of 2-((2-ethyl-2H-indazol-5-yl)methyl)isoindoline-1,3-dione (step-3 of Example 13, mixture) in MeOH (7 mL) was added hydrazine-H2O (0.5 mL), and the mixture was heated at 50° C. for 4 hrs. The mixture was concentrated, the residual white solid was added 2 M aqueous NaOH, and extracted with DCM, dried over Na2SO4, filtered and concentrated. The residual oil was diluted with MeOH and applied onto a strong cation exchange cartridge (BondElute (registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with MeOH (6 mL). The crude mixture was eluted with 1 M NH3 in MeOH (6 mL) and concentrated to give 68 mg (52% yield in 2 steps) of the titled compound as a colorless oil.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([CH:33]2[CH2:35][CH2:34]2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:23]=[CH:24][CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.[Cl-].[Na+].O>[CH:33]1([CH:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][OH:18])[CH:21]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:34][CH2:35]1
Reactant: CCOC(=O)CC(c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
To a solution of ethyl 3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)-3-cyclopropylpropanoate (4.54 g) in THF (20 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (18.7 mL), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.94 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5][O:4]1.Cl[C:11]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][N:19]=2)[CH:14]=[C:13]([Cl:21])[N:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:21][C:13]1[N:12]=[C:11]([NH:1][CH2:2][CH:3]2[CH2:8][NH:7][C:6](=[O:9])[CH2:5][O:4]2)[C:20]2[C:15](=[N:16][CH:17]=[CH:18][N:19]=2)[CH:14]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: NCC1CNC(=O)CO1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1COC(CNc2nc(Cl)cc3nccnc23)CN1
Yield: 34 %

Procedure:
A solution of 6-(aminomethyl)morpholin-3-one (130 mg, 1 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (200 mg, 1 mmol) and DIEA (260 mg, 2 mmol) in THF (20 mL) was stirred at reflux overnight. After concentration, the residue was purified by column chromatography to give product as yellow solid (100 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:17]1([CH2:23][C:24]([CH:26]2[C:31](=O)[CH2:30][CH2:29][O:28][CH2:27]2)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:23]([C:24]1[C:26]2[CH2:27][O:28][CH2:29][CH2:30][C:31]=2[N:15]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: O=C1CCOCC1C(=O)Cc1ccccc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)COCC3)cc1
Yield: 11.5 %

Procedure:
4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (42.0 mg, 11.5%) was obtained from 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine and 3-(2-phenylacetyl)dihydro-2H-pyran-4(3H)-one by general procedure for the preparation of pyrimidines. The crude product was purified by preparative HPLC twice. Purification using ammoniumacetate buffer was followed by purification using a 0.1% TFA. MS (ES+) m/z 398.1 (M+H)+
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH:34](=O)[C:35]1[CH:42]=[CH:41][CH:40]=[C:37]([CH:38]=[O:39])[CH:36]=1.CCCCCC>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH:38]([C:37]1[CH:36]=[C:35](/[CH:34]=[CH:8]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:42]=[CH:41][CH:40]=1)=[O:39]
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cccc(/C=C/c2ccccn2)c1
Yield: 374.8 %

Procedure:
3.9 g of (2-pyridyl)methyltriphenylphosphonium chloride was suspended in 20 ml of tetrahydrofuran, and with stirring, 5.3 ml of a 20% aqueous solution of potassium carbonate and 0.13 g of isophthalaldehyde were added. The mixture was stirred overnight at room temperature. Hexane was added, and the resulting aqueous layer was discarded, and concentrated under reduced pressure. Hexane was added to the residue. The insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [column: Lobar column, size B, Lichroprep Si 60 (a product of E. Merck Co.); eluting solvent: hexane/ethyl acetate=7/1→4/1]to give 0.76 g (yield 36%) of (E)-2-[2-(3-formylphenyl)vinyl]pyridine.