Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]([C:16]1[C:26]2[NH:25][C:24]3[N:27]=[CH:28][CH:29]=[CH:30][C:23]=3[CH2:22][NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:15].[CH3:31]CCCCC.[H-].[Na+].CI>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]([C:16]1[C:26]2[NH:25][C:24]3[N:27]=[CH:28][CH:29]=[CH:30][C:23]=3[CH:22]([CH3:31])[NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: Cn1ccc(-c2ccc(C(=O)c3cccc4c3Nc3ncccc3CN4)c(Cl)c2)n1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1Nc2cccc(C(=O)c3ccc(-c4ccn(C)n4)cc3Cl)c2Nc2ncccc21
Reaction time: 2 h
Yield: 47 %

Procedure:
Under anhydrous conditions, a solution of [2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-phenyl]-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-10-yl)-methanone of Example 19 (0.382 g, 0.92 mmol) in 10 mL of tetrahydrofuran was added dropwise to a stirred slurry of hexane washed sodium hydride (0.025 g, 1.02 mmol) in 2 mL of tetrahydrofuran. After the gas evolution ceased, methyl iodide (1 mL) was added and stirring was continued for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed and the crude product purified by flash chromatography (on silica Merck-60, dichloromethane-ethyl acetate 2:1) to give the title compound (0.18 g, 47%). Crystallization from diethylether provided a light yellow solid (0.16 g), m.p. 249-250° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C@H:6]([C@@H:8]([CH:18]=[CH2:19])[C@@H:9]([OH:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4][O:3]1.[H-].[Na+].[CH3:23]I>C1COCC1>[CH3:1][C:2]1([CH3:20])[O:7][C@H:6]([C@@H:8]([CH:18]=[CH2:19])[C@@H:9]([O:17][CH3:23])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:5][CH2:4][O:3]1
Reactant: CI
Reactant: C=C[C@H]([C@@H]1CCOC(C)(C)O1)[C@@H](O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@H]([C@@H]1CCOC(C)(C)O1)[C@@H](OC)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a cold (0° C.) solution of (2R,3S)-t-Butyl 3-((S)-2,2-dimethyl-1,3-dioxan-4-yl)-2-hydroxypent-4-enoate (0.12 g, 0.40 mmol) in THF (5 mL) was added sodium hydride (20.0 mg, 0.8 mmol) followed by methyl iodide (50.0 μL, 0.80 mmol). The reaction was allowed to stir for 2 h at 23° C. then quenched with saturated ammonium chloride (5 mL). The reaction mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was reduced under vacuum and the residue was purified on silica gel to obtain 7 (0.12 g, 96% yield) as a colorless oil. Rf=0.54 (20% ethyl acetate/hexanes. 1H NMR (300 MHz, Chloroform-d) δ 5.74 (dt, J=17.2 Hz, 10.1 Hz, 1H), 5.22-4.93 (m, 2H), 4.29 (d, J=11.9 Hz, 1H), 3.95 (td, J=12.0 Hz, 2.8 Hz, 1H), 3.83-3.73 (m, 2H), 3.35 (s, 3H), 2.26 (td, J=9.9 Hz, 2.2 Hz, 1H), 1.79-1.71 (m, 1H), 1.43 (s, 9H), 1.41 (s, 3H), 1.35 (s, 3H), 1.19-1.07 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 171.3, 132.9, 119.8, 98.2, 81.5, 80.5, 65.9, 60.0, 58.1, 52.3, 29.8, 28.4, 28.1, 19.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[OH:23]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(O)c(OC)c1OC
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (5 g) was suspended in anhydrous methylene chloride (50 ml), followed by addition of m-chloroperbenzoic acid (10 g; purity of 70%) to heat and stir the resulting mixture at 50° C. for 3 hours. After distilling off the solvents under reduced pressure, the residue was dissolved in ethyl acetate (100 ml) and washed in an aqueous saturated sodium hydrogen carbonate solution, in water and in an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Then, the solvents were distilled off under reduced pressure. To the residue were added dioxane (15 ml) and a 3N sodium hydroxide solution (15 ml), prior to stirring at room temperature for 30 minutes and adjustment to acidity with dilute hydrochloric acid, followed by ethyl acetate extraction three times. The organic phase was washed in water and in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, followed by distillation of the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=3:1), to recover 2,3,4-trimethoxyphenol (2.4 g; yield of 51%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [Br:1]Br.Cl.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH2:17])=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:15])[CH3:14])(=[O:6])[CH3:5].N>C(O)(=O)C>[C:4]([C:7]1[CH:8]=[C:9]([Br:1])[C:10]([NH2:17])=[C:11]([CH:16]=1)[CH2:12][N:13]([CH3:14])[CH3:15])(=[O:6])[CH3:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc(N)c(CN(C)C)c1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Product: CC(=O)c1cc(Br)c(N)c(CN(C)C)c1

Procedure:
9.0 gm of bromine were added dropwise to a solution of 12.8 gm of 5-acetyl-2-amino-N,N-dimethyl-benzylamine hydrochloride in 100 ml of 80% acetic acid. Subsequently, the reaction mixture was made alkaline with 2 N ammonia, extracted twice with chloroform, and the organic extract was evaporated. By recrystallization of the residue from ethanol/water, 5-acetyl-2-amino-3-bromo-N,N-dimethyl-benzylamine, m.p. 92°-95°C, was obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:43])[C:7](=[CH2:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC>CO>[CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:31])[CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
3.5 g of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in 30 ml of absolute methanol in the presence of 20 mg of [Ru2Cl4 ((S)-Binap)2 ].NEt3 at room temperature and 25 bar for 5 hours. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is purified by FC (200 g of silica gel, hexane/ethyl acetate=1:1). Title compound: Rf (hexane/ethyl acetate=1:1)=0.16; FAB-MS (M+H)+ =599.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14](OCC)(=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)C.Cl>>[Cl:1][C:2]1[C:3]2[N:4]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NNc1ncc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nnc2c(Cl)cc(C(F)(F)F)cn12
Temperature: 140 °C

Procedure:
A mixture of 3-chloro-2-hydrazinyl-5-(trifluoromethyl)pyridine (600 mg), diethyl oxalate (1.15 mL) and 2M hydrogen chloride ethanol solution (9 mL) was heated with microwave irradiation at 140° C. for 2 hr. The reaction mixture was allowed to be cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium 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 (290 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[C:10]1=[O:19].[OH-:20].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:11](=[O:18])[C:10]([OH:19])=[O:20]
Reactant: [OH-]
Reactant: O=C1C(=O)N(c2c(Cl)cccc2Cl)c2ccccc21
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 5.8 g of 1-(2,6-dichlorophenyl)indole-2,3-dione (m.p. 174°-175° C.) in 40 ml of ethanol were added 22 ml of a 1 N aqueous sodium hydroxide solution and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated at a bath temperature of not more than 40° C. under a reduced pressure of 5 mmHg. To the residue were added 50 ml of water and the mixture was extracted with 30 ml of ether. The ether extract was separated out. The remaining aqueous layer was acidified with a 5% aqueous hydrochloric acid solution under ice-cooling and the solid thus precipitated was extracted with ether. The ether extract was washed with water and dried over sodium sulfate and concentrated at 10 mmHg without heating. The residue was recrystallized from dichloromethane-hexane to give 6.0 g of 2-(2,6-dichloroanilino)phenylglyoxylic acid as a yellow powder. m.p. 159°-159.5° C. Yield: 97% of theoretical amount
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]2[CH2:12][C:13]3[C:25]4[NH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]=4[C:16]4[C:26](=[O:29])[NH:27][CH2:28][C:15]=4[C:14]=3[C:8]=2[CH:7]=1)CCC.[I:38]I.OS([O-])=O.[Na+]>C(Cl)Cl>[I:38][C:6]1[CH:11]=[CH:10][C:9]2[CH2:12][C:13]3[C:25]4[NH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]=4[C:16]4[C:26](=[O:29])[NH:27][CH2:28][C:15]=4[C:14]=3[C:8]=2[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)-c1c3c(c4c([nH]c5ccccc54)c1C2)C(=O)NC3
Reactant: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(I)cc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 3-tributylstannyl-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Step-1) (16 mg, 0.026 mmol) in dry CH2Cl2 (4 mL) was added a solution of I2 (8 mg, 2 mL CH2Cl2) dropwise. The mixture was stirred at ambient temperature 2 h., then a solution of 10% NaHSO3 was added. After stirring for 10 min. the mixture was filtered. The solid was collected and washed with water, CH2Cl2 and dried under vacuum (100° C., 6 h) to give 6 mg (53%) of Compound I-40, 1H NMR (DMSO-d6, 300 MHz) d 4.29 (s, 2H), 4.96 (s, 2H), 7.33-7.50 (m, 3H), 7.66-7.79 (m, 2H), 8.29 (s, 1H), 8.62 (s, 1H), 8.42 (d, 1H), 12.08 (s, 1H). MS (m/e)=437 (m+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([Cl:12])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[C:4]([CH:13]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[C:10]2[C:5]=1[C:4]1[CH:13]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[S:22][C:3]=1[N:2]2[CH3:1]
Reactant: Cn1c(Cl)c(C=O)c2c(Cl)cc(Cl)cc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3c(Cl)cc(Cl)cc3n(C)c2s1
Yield: 32.5 %

Procedure:
Prepared from (48) (6.5 g), K2CO3 (9.59 g) and methyl 2-mercaptoacetate (3.82 ml) yielding (53) 2.5 g (32.5%). M.p. 231°-232° C. The product was purified by cromatography on silicagel using toluene as eluent. The compound was crystallized by trituration with methanol.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:13]=1)=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH2:2][CH3:3].[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:13]=1)=[N:8][C:9]([NH:12][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:11]=2)[CH2:2][CH3:3]
Reactant: CCCc1nc2nc(N)ccc2[nH]1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2nc(NC(=O)C(C)C)ccc2[nH]1

Procedure:
2.62 g (15 mMol) of 2-n-propyl-5-amino-imidazo[4,5-b]pyridine are suspended in 100 ml of absolute methylene chloride and 3.16 g (30 mMol) of isobutyric acid chloride are added, with stirring and cooling with ice. Then, at -5° C., a solution of 3.03 g (30 mMol) of triethylamine in 5 ml of methylene chloride is added dropwise. After one hour at ambient temperature the reaction mixture is combined with 100 ml of 2N hydrochloric acid and the mixture is stirred for a further hour. Then the solution is poured onto ice water and mixed with saturated sodium hydrogen carbonate solution. The aqueous phase is extracted 3 times with 100 ml of ethyl acetate, the combined organic phases are then washed with saline solution, dried over sodium sulphate and concentrated by evaporation. The crude product is taken up in methylene chloride and purified over a silica gel column (particle size 0.063-0.2 mm), using as eluant methylene chloride to begin with, followed by mixtures of methylene chloride and ethanol of increasing polarity (25:1 and 19:1). The unified fractions are concentrated by evaporation and the residue is triturated with petroleum ether/ether=1:1 and suction filtered.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:22][OH:23])([CH2:24][OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:13]([C:18]([F:20])([F:19])[F:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(O)c(C(F)(F)F)c1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(CCC(CO)(CO)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Compound 9-6 (360 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (263 mg) and 1-bromooctane (0.198 ml) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (490 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.BrC1C=CC([C:19]2([O:22]C)CC2)=CC=1.[Li]CCCC.CN(C=O)C>>[CH3:19][O:22][C:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: COC1(c2ccc(Br)cc2)CC1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COC1(c2ccc(C=O)cc2)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 1-bromo-4-(1-methoxycyclopropyl)-benzene (250 mg, 1.10 mmol), n-BuLi (722 μl, 1.6M solution in hexane, 1.16 mmol) and DMF (171 μl, 2.20 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1-methoxycyclopropyl)-benzaldehyde (90 mg, 58%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 10.0 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 3.29 (s, 3H), 1.35-1.30 (m, 2H), 1.09-1.05 (m, 2H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:14][CH2:15][O:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:17][O:16][CH2:15][CH2:14][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccc2c(c1)NCCC2
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCCc2ccc(CO)cc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (1,2,3,4-tetrahydroquinolin-7-yl)methanol (370 mg, 1.496 mmol), 1-bromo-2-methoxyethane (0.141 ml, 1.496 mmol) and Cs2CO3 (731 mg, 2.244 mmol) in DMF (10 ml). was stirred for 16 hr at 80° C. Additional 1-bromo-2-methoxyethane (0.070 ml, 0.748 mmol) was added and stirring was continued for 16 hr at 80° C. A third batch of 1-bromo-2-methoxyethane (0.070 ml, 0.748 mmol) was added and stirring was continued for 1 additional hour at 80° C. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound. HPLC (Method A) Rt=1.173 min; MS (Method A) [M+H]+=221.9
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:29][N:30]=[C:31]=NCCCN(C)C.Cl.CNC.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([N:30]([CH3:31])[CH3:29])=[O:23])[CH:18]=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cc(C(=O)O)cn3)nc2N1C1CCCC1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cc(C(=O)N(C)C)cn3)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44, 0.14 g, 0.378 mmol) was dissolved in 2 mL of DCM and EDCI (79 mg, 0.415 mmol), dimethylamine hydrochloride (46 mg, 0.567 mmol), HOAt (5 mg, 0.0379 mmol) and triethylamine (115 mg, 1.13 mmol) were added. The resulting solution was stirred at rt for 48 hours after which the reaction mixture was diluted with DCM and washed with 0.1 N aqueous HCl then 1 N aqueous NaOH, dried with Na2SO4, filtered, concentrated under vacuum and purified by preparative HPLC to give the title compound. 1H NMR (CDCl3) δ: 7.55-7.57 (s, 1H), 7.40-7.51 (m, 2H), 4.26-4.51 (m, 2H), 3.11-3.39 (m, 9H), 1.64-2.18 (m, 10H), and 0.97 ppm (m, 3H); LCMS: 398.1 m/z (M+H)+; ret. Time: 3.267 min (Analytical Method A).
Reaction SMILES: C(O)C.[CH3:4][C:5]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:6]=1[CH:7]=O.C([O-])(=O)C.[Na+].Cl.[NH2:21][OH:22]>O>[CH3:4][C:5]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:6]=1[CH:7]=[N:21][OH:22]
Reactant: NO
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C=NO)c(C)c1
Yield: 85 %

Procedure:
To 120 ml of ethanol and 60 ml of water were added 29.6 g (0.2 mole) of 2,4,6-trimethylbenzaldehyde, 32.8 g (0.4 mole) of sodium acetate and 20.7 g (0.3 mole) of hydroxylamine hydrochloride, and the mixture was heated under reflux for 2 hours. After the reaction, the reaction mixture was added to 500 ml of water. The precipitated crystals were collected by filtration to give 28 g (0.17 mole) of 2,4,6-trimethylbenzaldoxime.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=[O:11])[C:7](F)(F)F)=[O:4].N1C=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:3]1(=[O:4])[O:5][C:6](=[O:11])[C:7]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Solvent: ClCCl
Product: O=C1OC(=O)c2ccccc21
Reaction time: 2 h

Procedure:
22.4 g (0.08 mol) of the 4-(maleinamidyl)-phthalic acid manufactured according to Example 3, paragraph 1, are suspended in 150 ml of anhydrous methylene chloride and 37.8 ml of trifluoroacetic anhydride are added. The reaction mixture is stirred for 2 hours at 20°-25° C., whilst excluding atmospheric moisture. 30.5 g of pyridine are then added dropwise whilst cooling with ice (internal temperature 20°-25° C.). The reaction mixture is then stirred for a further 2 hours at 20°-25° C. and filtered, and the filter residue is washed with a little methylene chloride and dried under a high vacuum. 14.7 g (75% of theory) of 4-isomaleinimidyl)-phthalic anhydride are obtained in the form of slightly yellowish crystals; decomposition at 195°-207° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:21][CH:22]([CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=1)=[O:24]>>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:36]1[CH2:37][CH2:38][CH:33]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:39])[CH:31]=[CH:30][C:29]=2[CH3:32])[CH2:34][CH2:35]1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccc(O[C@@H](CCCl)c2ccccc2)c1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cc(NC(=O)C(C)C)ccc3C)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure G and Scheme AI using 1-(3-{[(1S)-3-chloro-1-phenylpropyl]oxy}phenyl)ethanone and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 513.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[CH:20]=[C:19]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=4[F:30])[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:2]1.CCN(C(C)C)C(C)C.[C:40](O)(C(F)(F)F)=[O:41]>CN(C=O)C>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][NH:21][C:19]1[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:4][N:1]([CH:40]=[O:41])[CH2:2]3)=[CH:6][CH:7]=2)[CH:20]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CNC3)cc2)cc1NCc1cccc(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Nc2ccc(C3CN(C=O)C3)cc2)cc1NCc1cccc(F)c1F

Procedure:
Compound 6-(4-(azetidin-3-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide (Example 212) (35 mg, 0.08 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for three days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (11 mg). MS found for C23H21F2N5O2 as (M+H)+ 438.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 8.02 (1H, s), 7.44 (2H, dt, J=8.0; 1.6 Hz), 7.24 (1H, m), 7.17 (2H, dt, J=8.4; 1.6 Hz), 7.14 (1H, m), 7.11 (1H, m), 5.82 (1H, s), 4.68 (1H, t, J=8.0 Hz), 4.56 (2H, s), 4.46 (1H, m), 4.27 (1H, m), 4.05 (2H, m) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8]1)=[O:28]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2C(=O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 1G and 3-chlorobenzoyl chloride by procedures analogous to those described in Example 160. HPLC; 100% at 6.3 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 452 [M+1]+. Chiral HPLC 100% e.e.; retention time=50.4 min; Conditions: AD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 70 min at 1 mL/min.