Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>S(=O)(=O)(O)O>[N:21]1([C:19]2[N:20]=[C:15]([C:12]3[CH:13]=[N:14][C:9]([NH2:8])=[N:10][CH:11]=3)[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[C:17]=3[N:18]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccncc3)cn2)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cn1
Temperature: 40 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
To the obtained bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine, TFA (3 ml) and concentrated sulfuric acid (a few drops) were added, followed by stirring at 40° C. for 6 hours. This was concentrated under reduced pressure, and water was added, followed by neutralization with 1N aqueous sodium hydroxide solution. The resulting solid was purified by silica gel column chromatography (dichloromethane/2N ammonia methanol=40/1 to 10/1), to obtain the desired compound as a colorless solid (32.3 mg, yield 26%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:25])=[N:9][C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:12]=1[C:13]([O:15]CC)=[O:14].[OH-].[K+]>>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:25])=[N:9][C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cc(Cc2ccccc2)nc(C)c1OCCCN(C)C
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(Cc2ccccc2)cc(C(=O)O)c1OCCCN(C)C

Procedure:
Hydrolysis of 2-methyl-4-carbethoxy-6-benzyl-pyridin-3-yl 3-dimethylaminopropyl ether (Example 19) with methanolic potassium hydroxide solution at 60° C. gives 2-methyl-4-carboxy-6-benzyl-pyridin-3-yl 3-dimethylaminopropyl ether, of melting point 157° C. N determination: calculated 8.5%, found 8.6%.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:17])[CH3:16]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2Sc2ccccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
20 g (0.1 mol) of phenothiazine followed by 14.3 ml (2 eq.) of acetyl chloride are added to a 500 ml flask containing 200 ml of toluene. The heterogeneous reaction mixture is stirred for 1 hour at 50° C. After concentration to dryness, the precipitate is taken up in a minimum of isopentane and filtered. After drying, 24 g of a beige solid is obtained with a quantitative yield. Melting point: 210-211° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][CH:8]=[C:9]2[C:14](=[O:15])[CH:13]=[CH:12][CH:11]=[C:10]2[CH2:16][CH2:17]C(OCC)=O)=[N:3]1.[C:23]1([O:29]C2C=CC=CC=2)C=CC=CC=1>>[OH:29][C:23]1[C:5]2[C:4](=[N:3][N:2]([CH3:1])[CH:6]=2)[N:7]=[CH:8][C:9]=1[C:14]([C:13]1[CH:12]=[CH:11][CH:10]=[CH:16][CH:17]=1)=[O:15]
Reactant: CCOC(=O)CCC1=CC=CC(=O)C1=CNc1ccn(C)n1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: Cn1cc2c(O)c(C(=O)c3ccccc3)cnc2n1

Procedure:
310 g. of 2-[[(1-methyl-1H-pyrazol-3-yl)amino]methylene]-3-oxobenzenepropanoic acid, ethyl ester (1.04 mol.) are heated with stirring for 15 minutes at 250° in 1 liter of diphenyl ether, while the alcohol formed is continuously distilled off. The solution is cooled and the diphenyl ether removed in vacuo. The residue is crystallized with methanol to obtain (4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]-pyridin-5-yl)phenylmethanone, yield 156 g. (59.2%); m.p. 286°-290° (DMF).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example AX from 4-bromophenyl methyl sulfone and N-Boc-piperazine (31%, white solid, MS (m/e): 241.2 (M−Boc, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]>CO.O>[OH:5][CH:4]([C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1])[C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(C(=O)c2ccccc2Cl)CCCC1
Solvent: CO
Solvent: O
Product: CCOC(=O)C1(C(O)c2ccccc2Cl)CCCC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 80.3 %

Procedure:
tBuBisP*RuBr2 (28 mg) was placed in a reactor and deaerated and substituted with argon. A mixture of deaerated methanol/water (10/1) (33 ml) and ethyl 1-(2-chlorobenzoyl)cyclopentanecarboxylate (3.2 g, 11.4 mmol) was added. Under a hydrogen pressure (6 atm), the mixture was stirred at 70° C. for 7 h and concentrated to dryness. This was dissolved in ethyl acetate, dried over anhydrous sodium sulfate and purified by silica gel column chromatography to give the title compound (2.59 g, yield; 80.9%) as a colorless oil. The enantiomer excess of this product was measured by high performance liquid chromatography (Condition F) and found to be 90% ee.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][O:11][N:12]=1)[CH2:4][CH2:5][CH3:6]>CC(C)=O>[I-:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH2:14][N:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:10][O:11][N:12]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCOc1nonc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCCOc1nonc1C1=CC=CN(C)C1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and 3-(4-butyloxy-1,2,5- oxadiazol-3-yl)pyridine (1.9 mmol) in acetone (10 ml) was stirred at room temperature for 18 h and evaporated.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][C:38](O)=[O:39])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][C:38]([NH:27][C@H:24]3[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]4[CH2:17][CH2:18][N:13]([C:12]5[C:7]6[O:6][CH2:5][O:4][C:8]=6[CH:9]=[CH:10][CH:11]=5)[CH2:14][CH2:15]4)[CH2:22][CH2:23]3)=[O:39])=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (26 mg, 64.6%), MS (ISP) m/z=494.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(benzo[d][1,3]dioxol-5-yl)acetic acid.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]3[CH:16]=[C:17]([O:20][C@H:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C@@H:24]([NH:31][C:32]([NH:34][C:35]5[N:36]([C:44]6[CH:49]=[CH:48][C:47]([CH2:50][OH:51])=[CH:46][CH:45]=6)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=5)=[O:33])[CH2:23][CH2:22]4)[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)[CH2:7][CH2:6]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.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>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:32]([NH:31][C@@H:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]4[N:15]([C:11]([N:8]5[CH2:9][CH2:10][CH:5]([OH:4])[CH2:6][CH2:7]5)=[N:12][N:13]=4)[CH:16]=3)[CH2:22][CH2:23]2)=[O:33])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH2:50][OH:51])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: C=CCOC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5-c5ccc(CO)cc5)c5ccccc54)cn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(O)CC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
Ar was bubbled through a solution of Intermediate 57c (93.0 mg, 0.135 mmol) and 1,3-dimethyl barbituric acid (63.0 mg, 0.404 mmol) in DCM (5 mL) at RT under Ar for 30 min, then Pd(PPh3)4 (15.6 mg, 0.0135 mmol) was added and the orange solution was stirred at RT for 1 h, and then at reflux for 17 h. The suspension was concentrated in vacuo, the residue redissolved in DCE (10 mL) and Ar bubbled through the mixture for 30 min. Pd(PPh3)4 (15.6 mg, 0.0135 mmol) was added and the opaque orange-red solution stirred at 75° C. under Ar for 2 h. The cooled solution was concentrated in vacuo to ˜3 mL volume, then applied to an SCX-2 cartridge (5 g) and washed with MeOH (25 mL). The product was eluted with 2M NH3 in MeOH (20 mL); concentration in vacuo left an orange solid. FCC, using 5-15% MeOH in DCM, gave a pale orange solid (46.0 mg). Further purification by HPLC (XBridge C18 column, 20-80% MeCN in H2O, 0.1% NH4OH) gave the title compound as a white powder after freeze-drying (27.1 mg, 31%). LCMS (Method 5): Rt 3.59 min, m/z 651 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.23 (9H, s), 1.56-1.67 (2H, m), 1.76-1.92 (4H, m), 1.95-2.11 (2H, m), 2.91-2.97 (2H, m), 3.31-3.35 (2H, m), 3.64-3.71 (1H, m), 4.51 (2H, d, J 4.2), 4.70 (1H, d, J 3.9), 4.77 (1H, m), 5.25 (1H, t, J 5.3), 5.50 (1H, t, J 4.4), 6.29 (1H, s), 7.05 (1H, d, J 8.5), 7.10 (1H, dd, J 9.9, 2.1), 7.21-7.25 (2H, m), 7.28-7.34 (2H, m), 7.39 (2H, d, J 9.1), 7.40 (2H, d, J 9.1), 7.56 (1H, dd, J 9.9, 0.8), 7.61 (1H, dd, J 2.1, 0.9), 8.04 (1H, s).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[C:10]([F:18])=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:12][NH2:13].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[NH2:8][C:9]1[C:10]([F:18])=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:12][NH:13][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(F)c(N)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (400 μL, 2.86 mmol) followed by pivaloyl chloride (60 μL, 0.52 mmol) are added to 3-amino-2,4-difluoro-benzylamine (120 mg as HCl salt) in THF (10 mL) and the mixture is stirred at rt overnight. The reaction mixture is diluted with EtOAc and sat NaHCO3-solution, the organic layer is washed with water and brine, dried and concentrated to give the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:32]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[C:74]([Br:75])=[CH:73][C:69]([C:70]([OH:72])=[O:71])=[C:68]([O:76][CH3:77])[CH:67]=1>C(Cl)Cl>[CH3:32][O:71][C:70](=[O:72])[C:69]1[CH:73]=[C:74]([Br:75])[C:66]([NH:65][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:67][C:68]=1[O:76][CH3:77]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(N)c(Br)cc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA (0.30 mL, 1.72 mmol) and 4-amino-5-bromo-2-methoxy-benzoic acid (Aldrich, 179 mg, 0.69 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 7.3 mg.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[NH:9][N:8]=[N:7][C:6]=2[CH:12]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[O:11])[NH:9][N:8]=[N:7][C:6]=3[CH:12]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=c1[nH]nnc2cc(F)ccc12
Product: O=c1[nH]nnc2cc(N3CCOCC3)ccc12

Procedure:
32.5 g (0.196 mol) of 7-fluoro-3H-benzo[d]-1,2,3-triazin-4-one were heated at 120° C. for 5 hours in 300 ml of morpholine with stirring. The precipitated product was filtered off with suction at 50° C., the precipitate was washed with water, filtered off with suction and dried in a vacuum drying cabinet for 48 hours, giving 30.5 g of 7-morpholin-4-yl-3H-benzo[d]-1,2,3-triazin-4-one as solid; 1H NMR (500 MHz, DMSO) δ 8.00 (d, J=9.0, 1H), 7.52 (dd, J=9.0, 2.6, 1H), 7.39 (dd, J=22.8, 2.6, 1H), 3.78 (dd, J=17.1, 12.3, 4H), 3.45 (dd, J=17.1, 12.3, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: NCCCCC(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C(O)CCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 72.4 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and 5-aminopentanoic acid (0.30 g, 0.0026 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.55 g (73%) 123 as pale yellow flat crystals: mp=158-160° C.; Rf0.69 (A): Rf0.90 (C): Rf0.73 (D): 1H NMR (DMSO-d6) δ1.53 (m, 2H), 1.58 (m, 2H), 2.24 (t, J=7.1 Hz, 2H), 3.57 (t, J=6.7 Hz, 2H), 8.04 (dd, J=8.0, 7.5 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H); IR (cm−1): 2800-3130 (OH), 3096 (C═CH), 2691 (C—H), 1774 (C═O), 1723 (bs, C═O), 1616 (C═C), 1543 (N═O), 1466 (C═C), 1443 (C═C), 1396 (C—O), 1358 (N═O), 1209 (C—O), 1050 (C—O), 722 (C═CH); MS m/z (rel intensity) 291 (92), 247 (31), 191 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29]([OH:31])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][NH2:33]>>[CH:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]([NH:13][C@@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C@H:9]([CH2:28][C:29]([NH:33][CH3:32])=[O:31])[CH2:10]2)=[O:15])=[N:17]1)([CH3:27])[CH3:26]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: CN
Product: CNC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 1 of Example 13) and methylamine.
Reaction SMILES: [CH2:1](S)C.[H-].[Na+].C[O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([C:14]2[CH2:15][C:16]3[C:21]([C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[C:18]([O:29]C)[CH:17]=3)=[O:13])=[CH:10][CH:9]=1.Cl>CN(C=O)C>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:14]2[CH2:15][CH2:1][C:16]3[C:21]([C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[C:18]([OH:29])[CH:17]=3)=[O:13])=[CH:31][CH:32]=1
Reactant: CCS
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccc(OC)cc3C2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(C1=C(c2ccccc2)c2ccc(O)cc2CC1)c1ccc(O)cc1
Temperature: 60 °C

Procedure:
To 300 ml. of DMF were added under nitrogen and with ice bath cooling, 9.3 gms. of ethyl mercaptan. To the mixture then were added 7.2 gms. of a 50 percent sodium hydride-oil mixture. The mixture represents 0.15 mole of sodium hydride. To the resulting mixture then were added 11.1 gms. (0.03 mole) of the product from Example 1. The mixture was heated at 60° C. for 1 hour. Analysis of the reaction mixture by TLC indicated the presence of starting material plus another component, probably the mono-hydroxy compound. The temperature of the reaction mixture was raised to 110° C., and this temperature was maintained for one hour. TLC showed no starting material; however, the presence of two components was noted. The reaction mixture therefore was heated for an additional one hour at 125° C. after which a single spot was noted by TLC analysis. The reaction mixture then was acidified by addition of cold 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate was washed with water and evaporated. The resulting residue was recrystallized from a mixture of methanol and acetone to give 8 g. of the title compound, m.p. 205°-207° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][NH:24]C(OC(C)CC)=O)[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH:2]([CH2:23][NH2:24])[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CCC(C)OC(=O)NCC(C)C(=O)N(Cc1cc(Cl)c2c(c1)OCCCO2)CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above (±)-2-Methyl-3-(methylpropan-2-yl)oxycarbonylamino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide was dissolved in dichloromethane (3 ml) and treated with trifluoroacetic acid (3 ml). After stirring for two hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane (10 mL) and aq. sodium carbonate (sat., 10 mL). The aqueous layer was extracted with dichloromethane (10 ml×2). After washing with brine, the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to yield a resin: MS (m+1)=355.5.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.[Cl:10][C:11]1[CH:12]=[C:13]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][C:34]=3[O:36][CH2:37][CH2:38][NH:39][CH3:40])[N:29]=[CH:28][N:27]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][C:34]=3[O:36][CH2:37][CH2:38][N:39]([CH3:40])[C:4](=[O:6])[C@@H:3]3[CH2:7][CH2:8][CH2:9][N:2]3[CH3:1])[N:29]=[CH:28][N:27]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN1CCC[C@H]1C(=O)O
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)[C@@H]1CCCN1C
Yield: 38 %

Procedure:
The procedure described in Example 1 was repeated using 1-methylproline and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 38% yield; NMR spectrum (DMSO-d6) 1.55-1.68 (m, 3H), 1.92-2.03 (m, 2H), 2.12 (s, 2H), 3.29 (s, 6H), 3.87-4.03 (m, 2H), 4.40-4.61 (m, 2H), 5.31 (s, 2H), 7.17 (d, 1H), 7.22 (d, 1H), 7.33 (d, 1H), 7.35-7.39 (m, 1H), 7.57-7.63 (m, 2H), 7.69-7.75 (m, 1H), 7.86-7.91 (m, 1H), 8.05 (d, 1H), 8.43 (s, 1H), 8.60 (d, 1H), 9.76 (s, 1H); Mass spectrum MH+ 547.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl.CCOC(C)=O>[C:28]([NH:2][CH2:3][CH:4]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:20][CH:21]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:30])[CH3:29]
Reactant: COC(=O)C(CN)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C(CNC(C)=O)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-[1-(aminomethyl)-2-methoxy-2-oxoethyl]benzoate hydrochloride (600 mg, 1.90 mmol) in CH2Cl2 were added pyridine (0.38 mL, 4.75 mmol) and acetyl chloride (0.20 mL, 2.85 mmol). After stirring for 2 h at room temperature, the reaction mixture was diluted with EtOAc, washed (sat. CuSO4, sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica gel (50-100% EtOAc/hexanes) afforded tert-butyl 4-{1-[(acetylamino)methyl]-2-methoxy-2-oxoethyl}benzoate as a thick, colorless oil. 1H NMR (CDCl3) δ7.94 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 5.87 (t, J=5.5 Hz, 1H), 3.96 (dd, J=8.8, 5.9 Hz, 1H), 3.71-3.60 (m, 2H), 3.67 (s, 3H), 1.93 (s, 3H), 1.57 (s, 9H). MS (ESI) calcd [M+H]+ 322.1, found 322.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.Cl.[Cl-].[Na+]>N1C=CC=CC=1>[Cl:16][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCOCc1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: ClCCCCOCc1ccccc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 4-benzyloxybutanol (64.8 g, 0.36 mol) in dry pyridine (200 ml) is stirred and heated to 50°-60° C. A solution of thionyl chloride (43 g, 0.36 mol) in pyridine (100 ml) is added slowly, and the mixture is kept at 60° C. for one more hour. After cooling to room temperature, the reaction mixture is poured into a mixture of ice and 2 N HCl. The mixture is saturated with sodium chloride, extracted with ether, and washed successively with water, 10% sodium bicarbonate, and water. Evaporation of solvent gives a yellow oil (49.7 g) which is distilled under vacuum to give the pure title compound (47 g), bp0.03-0.05 85°-90° C.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:19]([C:12]1[N:13]([CH3:18])[C:14]2[C:10]([CH:11]=1)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=2)=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: NCc1ccccc1
Product: Cn1c(C(=O)NCc2ccccc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and benzylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=281.