Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH2:24][O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 10.5 %

Procedure:
Using cyclohexyl{3-(methoxymethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (1.2 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.94 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.19 g, 10%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:9]=1)(=[O:3])[CH3:2].[F:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1.CCOC(C)=O>CC(O)C>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22][N:34]2[CH2:35][CH2:36][CH:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:38][CH:37]=3)[CH2:32][CH2:33]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)nc(-c2ccccc2)n1

Procedure:
This compound was prepared from chloroacetamide 6 (77 mg; 0.221 mmol) and 4-(4-fluorobenzyl)-piperidine (7.9) (47 mg; 0.24 mmol) in a manner analogous to 8.8 yielding a white crystalline solid (80.5 mg; 72%) after silica gel chromatography (12-8:1 EtOAc:i-PrOH). LC (method B) tR=13.1 min; 1H NMR (200 MHz, CDCl3) δ 9.51 (brs, 1H), 8.37 (m, 2H), 7.48 (m, 3H), 7.22 (s, 1H), 7.11 (m, 2H), 6.98 (m, 2H), 6.58 (brs, 1H), 5.45 (brt, J=5.4 Hz, 1H), 3.68 (m, 2H), 3.53 (m, 2H), 3.11 (s, 2H), 2.89 (m, 2H), 2.57 (m, 2H), 2.20 (m, 2H), 1.86 (s, 3H), 1.80-1.30 (m, 5H); ESIMS 505.0 (42) [MH+], 253.1 (100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:6]1=[C:5]2[CH3:16].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:6]1=[C:5]2[CH3:16]
Reactant: Cc1c2n(c3ccc(Br)cc13)CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c2n(c3ccc(Br)cc13)CCCC2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a solution of 2-bromo-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one (5.56 g, 20 mmol, described in Example 17, Step 1), in methanol (350 mL) was added sodium borohydride (2.5 g) portionwise, upon cooling. The reaction mixture was stirred at room temperature for 1 hour, and evaporated. The residue was partitioned between water and methylene chloride, the organic layer separated, dried (MgSO4), filtered, and evaporated to obtain the title compound 3.4 g (61%), m.p. 120°-123° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1.Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][N:26]=1>>[Cl:31][C:30]1[C:25]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:5]4[C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][O:7][C:6]4=[O:9])=[CH:11][CH:12]=3)=[O:17])[CH2:23][CH2:22]2)=[N:26][CH:27]=[C:28]([Cl:32])[CH:29]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)cc1
Yield: 66 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-methoxymethyl-3-[4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (473 mg) described in Preparation Example 165 and 2,3,5-trichloropyridine (405 mg), the title compound (455 mg) was obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.CN(C)C=O.[Br:17][CH2:18][CH2:19][CH2:20]Br>O>[Br:17][CH2:18][CH2:19][CH2:20][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: BrCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
To sodium hydride (0.9 g, 30 mmol, 80% oil dispersion) and indole (2.81 g, 24 mmoles) was added anhydrous dimethylformamide (50 mL). The resultant mixture was stirred at room temperature under argon for 1 h. Then neat 1,3-dibromopropane (7.3 mL, 72 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into water (120 mL) and the resultant slurry was extracted with diethyl ether (3×100 mL). After the organic extracts were combined and concentrated in vacuo, the crude material was purified by dry column chromatography (350 mL funnel filled with Silica 10–40μ, Sigma cat. S-6628) using as eluent a mixture of ethyl acetate and hexanes (1:49 v/v, containing 0.2% v/v isopropylamine) to yield 1.43 g of N-(3-bromopropyl)indole.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[N:29]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:37]([C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]([CH3:27])[N:29]=3)=[O:38])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC(=O)c2nn(C)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (0.53 g) was dissolved in dimethylformamide (20 ml). 1-Methylindazole-3-carboxylic acid (0.27 g) and 1-hydroxybenzotriazole (0.25 g) were added, and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.35 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.20 g of N-(5-(4-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)piperidin-1-yl)pentyl)-1-methyl-1 H-indazole-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](O)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.ON1C2C=CC=CC=2N=N1.[CH2:31]([C@H:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C1COCC1>[CH2:31]([C@H:33]([NH:40][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[OH:1])=[O:13])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: CC[C@H](N)c1ccccc1
Reactant: O=C(O)c1c(O)c(-c2ccccc2)nc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
2.49 g (9.4 mmol) of 3-hydroxy-2-phenylquinoline-4-carboxylic acid (CAS [485-89-2]) were suspended in 150 ml of a 7/3 mixture of THF/CH3CH; 1.40 g (10.3 mmol) of 1-hydroxybenzotriazole (HOBT) and 1.27 g (9.4 mmol) of (S)-α-ethylbenzylamine dissolved in 20 ml of CH2Cl2 were added and the reaction mixture was stirred at room temperature for 30 minutes. 2.13 g (10.3 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 20 ml of CH2Cl2 were added dropwise. The reaction was left at room temperature overnight, quenched with 20 ml of H2O, evaporated in-vacuo to dryness and dissolved in EtOAc. The precipitated dicyclohexylurea was filtered off and the organic layer was washed with H2O, 20% citric acid, sat. sol. NaHCO3, sat. sol. NaCl. The organic layer was separated, dried over Na2SO4 and evaporated in-vacuo to dryness; the residue was purified by gradient column chromatography on 60-240 mesh silica gel using a mixture of hexane/EtOAc 9:1 as starting eluent and a mixture of hexane/EtOAc 7:3 as final eluent. The crude product was recrystallized from i-PrOH to yield 1.75 g of the title compound as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Si:12]([N:19]1[CH:22]([CH2:23][C:24](=[O:29])[Si](C)(C)C)[CH:21]([C@H:30]([OH:32])[CH3:31])[C:20]1=[O:33])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[Si:12]([N:19]1[C@H:22]([CH2:23][C:24]([OH:9])=[O:29])[C@@H:21]([C@H:30]([OH:32])[CH3:31])[C:20]1=[O:33])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1CC(=O)[Si](C)(C)C
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)O

Procedure:
m-Chloroperbenzoic acid (1.00 mmol) is added to a solution of (3S,4R)-1-(t-butyldimethylsilyl-3-[(R)-1-hydroxyethyl]-4-(2-oxo-2-trimethylsilylethyl)azetidin-2-one (1.00 mmol) in chloroform (4 ml). The resulting solution is heated at reflux for 4 hr, then cooled, concentrated in vacuo, and the residue chromatographed on silica gel (2% glacial acetic acid in methylene chloride). (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carboxymethyl-azetidin-2-one, 238 mg (83%) is isolated as a colorless solid, Rf =0.25. n.m.r. (CDCl3 and D2O) δ3.6-4.3 (2H, m, H-5, H-8), δ2.98 (1H, dd, J=7, 2.1 H-6), δ 2.7 (2H,d of ABq)-CH2CO2H), δ1.29 (3H, d, J=6, CH3 --)δ 0.95 (9H, S, Si±), δ 0.25 (6 H, S, (CH3)2 --Si).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:26][S:27][CH2:28][CH2:29][NH2:30].O>C(#N)C>[CH3:26][S:27][CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CSCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in acetonitrile (5 mL) was added potassium carbonate (321 mg, 1.55 mmol) and 2-(methylthio)ethylamine (127 mg, 1.39 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (373 mg, 98% yield) as red crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: NCC(=O)[O-]
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NCC(=O)[O-])cc1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-4-fluoro-5-nitrotoluene (2.080 g, 10.97 mmol, as prepared above) in DMF (11.0 mL) at 70° C., was added dropwise, a solution of sodium glycinate (1.065 g, 10.97 mmol, Aldrich, used as received) in water (11.0 mL). The resulting suspension was stirred overnight at 70° C., cooled to room temperature, and the resulting red solid was filtered, washed with acetone (35 mL), and dried under vacuum to give 1.005 g (37%) of the pure (1H NMR) title compound as a red powder; 1H NMR (DMSO-d6): δ 2.184 (s, 3H), 3.396 (d, 2H, J=4.2 Hz), 6.852 (s, 1H), 7.991 (s, 1H), 8.671 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH2:11][CH2:12][OH:13])=[CH:5]2.CSC.C(=O)(O)[O-].[Na+].[OH-].[NH4+:23]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([CH:7]=[C:6]([CH2:11][CH2:12][OH:13])[N:23]=[CH:5]2)=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: OCCC1=Cc2cc(Br)ccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: CO
Product: OCCc1cc2ccc(Br)cc2cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Example 52D (0.85 g, 3.5 mmol) in methanol (15 mL) at −70° C. was ozonated until a bluish color developed (˜10 minutes). The mixture was treated with dimethylsulfide (0.7 mL, excess) and sodium bicarbonate (0.2 g) and allowed to warm to room temperature. After stirring for 3 hours, the mixture was treated with aqueous ammonium hydroxide (7.4 mL, 28%). After stirring an additional 4 hours, the reaction mixture was concentrated under vacuum and then diluted with dichloromethane (20 mL). The organic layer was separated and evaporated to provide the title compound which was used without further purification in the next step. 1H NMR (CDCl3) δ 3.13 (t, J=5.6 Hz, 2H); 4.07 (t, J=5.6 Hz, 2H); 7.47 (s, 1H); 7.61 (d, J=8.7 Hz, 1H); 7.71 (dd, J=1.9, 8.7 Hz, 1H); 9.04 (s, 1H); Anal. Calcd. for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C, 52.51; H, 3.94; N, 5.42.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:36])[NH:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]([C:25]([O:27]C)=[O:26])[CH2:16][CH:15]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:13])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>O.CO>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:36])[NH:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:17]([C:25]([OH:27])=[O:26])[CH2:16][CH:15]2[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)O)C2c2ccccc2)c1
Yield: 45 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.6 g of 2-tert-butyl 4-methyl (2RS,4RS,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate and 0.18 g of potassium hydroxide in 20 cm3 of distilled water and 60 cm3 of methanol. After treatment, there is obtained 0.7 g of 2-tert-butyl hydrogen (2RS,4SR,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate, melting at 160° C.
Reaction SMILES: [C@@H:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].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>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C@@H:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)[C@H]1CCCc2ccccc21
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: CCOC(=O)C1(NC(=O)[C@H]2CCCc3ccccc32)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of (S)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (300 mg, 1.7 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (349 mg, 1.7 mmol), HATU (760 mg, 2 mmol) in anhydrous DMF (8 mL) is added DIPEA (330 μL, 2 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (69) as white solid (615 mg, 100%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][OH:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1.C(N(CC)CC)C>[C:24](=[O:25])([O:16][CH2:15][CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCC1c2ccccc2Oc2ccccc21
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)OCC1c2ccccc2Oc2ccccc21
Temperature: 80 °C
Yield: 95.2 %

Procedure:
To a mixture of 1.0 g of 9-xanthenemethanol and 0.51 mL of phenyl isocyanate in 5.0 mL of dry benzene was added two drops of triethylamine. The mixture was heated in an oil bath at 80° C. for 20 hours and cooled in an ice bath for 2 hours. The precipitated crystals were filtered and rinsed with Skelly B to give 1.48 g (95.2%) of the crude urethane as white crystals. Recrystallization from EtOAc--Skelly B (5:1) gave 1.37 g (88.1%) of the pure Xmoc-aniline as white needles, m.p. 180°-181° C.; IR (KBr): 3350 (NH), 1705 (C=O) cm-1 ; 1H NMR (CDCl3): δ 4.30 (m, 3H, CHCH2O), 6.55 (b, 1H, NH , 6.90-7.40 (m, 13H, aryl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]([C:27]1([NH:38][CH2:39][CH3:40])[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)=[O:26].C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:24][C:25]([C:27]1([N:38]([CH2:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][C:15]=2[O:21][CH3:22])[N:12]=[CH:11][N:10]=[C:9]3[NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:23])[CH2:39][CH3:40])[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:28]1)=[O:26]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CCNC1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Yield: 19.2 %

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (360 mg, 0.93 mmol, prepared as described in Example 62) was added portionwise over 2 hours to a solution of tert-butyl 3-(aminocarbonyl)-3-(ethylamino)azetidine-1-carboxylate (294 mg, 1.21 mmol) and diisopropylethylamine (0.5 ml, 2.79 mmol) in DMF (1 ml) at 120° C. The resulting product was purified on preparative HPLC (standard basic conditions) to give tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-1-carboxylate as a solid (100 mg, 19%); Mass Spectrum: (M+H)+ 559. This was dissolved in 1,4-dioxan (3 ml) and a solution of concentrated hydrochloric acid (5 ml) in 1,4-dioxan (25 ml) was added dropwise. The reaction mixture was stirred overnight and concentrated under reduced pressure. The residues were triturated with a mixture of methanol/dichloromethane/diethylether to give a hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-3-carboxamide as a solid (89 mg, 100%); 1H NMR Spectrum: (CDCl3) 1.16 (t, 3H), 2.59 (q, 2H), 3.41 (d, 2H), 3.76 (d, 2H), 3.89 (s, 2H), 3.98 (s, 3H), 5.47 (brs, 1H), 7.15 (m, 2H), 7.24 (s, 1H), 7.77 (s, 1H), 7.90 (s, 1H), 8.44 (m, 1H), 8.72 (s, 1H); Mass Spectrum: (M+H)+ 459.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[Cl:17][C:18]([Cl:25])([Cl:24])[CH2:19]C(=N)OC>C(O)(=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:19]([C:18]([Cl:25])([Cl:24])[Cl:17])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: COC(=N)CC(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Yield: 81.2 %

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (16.5 g, 58.90 mmol) in acetic acid (55 mL) was added methyl 2,2,2-trichloroethanecarboximidate (11 g, 62.35 mmol) dropwise with stirring. The reaction mixture was stirred at room temperature for 3 hr and then at 45° C. overnight. The resulting solution was diluted with 100 mL of water and the precipitate was collected by filtration. The solid was dried in a vacuum oven to give 19.5 g (81%) of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a light brown solid: 1H NMR (300 MHz, DMSO) delta 8.58 (d, J=4.8 Hz, 1H), 7.68 (t, J=4.5 Hz, 1H), 7.61-7.58 (m, 2H), 7.21 (s, 2H), 7.01 (d, J=5.1 Hz, 3H); LC-MS: m/z=+408 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH:25]=O)=[C:13]3[C:17]4=[C:18]([CH2:20][NH:21][CH2:22][C:23](=[O:24])[N:16]4[CH:15]=[CH:14]3)[CH:19]=2)=[CH:7][CH:6]=1>N1C=CC=CC=1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH:25]=[N:2][OH:3])=[C:13]3[C:17]4=[C:18]([CH2:20][NH:21][CH2:22][C:23](=[O:24])[N:16]4[CH:15]=[CH:14]3)[CH:19]=2)=[CH:9][CH:10]=1
Reactant: NO
Reactant: O=Cc1c(-c2ccc(F)cc2)cc2c3c1ccn3C(=O)CNC2
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CNCc2cc(-c3ccc(F)cc3)c(C=NO)c3ccn1c23
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
Hydroxylamine hydrochloride (0.10 g, 0.325 mmol) was added to a solution of 6-(4-fluoro-phenyl)-1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-7-carbaldehyde (56.0 mg, 0.813 mmol) in pyridine (10 mL) and stirred at rt for 20 h. Upon consumption of the aldehyde as indicated by TLC, the solvent was removed in vacuo. The residue was taken up in 2N HCl and extracted with EtOAc several times. The combined organic extracts were dried over anhydrous MgSO4 and concentrated to give 97 mg (92%) of a pale-yellow solid: mp 277-279° C.; 1H NMR (DMSO-d6) δ 3.50 (br s, 2H), 4.12-4.14 (m, 2H), 7.30 (t, 1H, J=6.0 Hz), 7.43 (t, 2H, J=9.0 Hz), 7.57-7.62 (m, 2H), 7.89 (s, 1H), 7.94 (d, 1H, J=9.0 Hz), 8.33 (d, 1H, J=6.0 Hz), 8.41 (t, 1H, J=6.0 Hz), 10.80 (s, 1H). HRMS calcd. for C18H14N3O2F 323.1070 (M+), found 323.1066.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([OH:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2nnc(CC(O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nnc(CC(=O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 47.4 %

Procedure:
The title compound was prepared from 36 (22 mg, 0.052 mmol) following general procedure B. Flash chromatography (SiO2, 5% MeOH—CH2Cl2) afforded the title compound (10.2 mg, 47%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.39 (d, 1H, J=7.8 Hz), 8.25 (d, 1H, J=7.8 Hz), 8.02 (t, 1H, J=7.8 Hz), 7.59-7.54 (m, 4H), 7.44 (t, 2H, J=7.8 Hz), 7.36-7.30 (m, 2H), 4.19 (s, 2H), 4.02 (s, 3H), 3.93 (s, 2H); 13C NMR (CDCl3, 150 MHz) δ 199.1, 164.7, 164.1, 162.1, 148.5, 143.5, 140.5, 140.4, 138.4, 131.4, 129.9, 128.7, 127.7, 127.4 (2C), 127.1, 127.0 (2C), 126.1, 53.2, 49.4, 38.9; HRMS-ESI-TOF m/z 414.1460 ([M+H]+, C24H19N3O4 requires 414.1448).