Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)=[C:17]([NH:20][C:21](=[O:31])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Br[CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH:34]4[CH2:35][CH2:36]4)=[C:17]([NH:20][C:21](=[O:31])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[O:47])[CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(C=CCN1CCNCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(C=CCN1CCN(CC(=O)OCc2ccccc2)CC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
500 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(piperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline are dissolved in 5 ml of acetonitrile, and 0.35 ml of triethylamine followed by 0.17 ml of benzyl bromo-acetate are added dropwise at room temperature. The reaction mixture is stirred for approximately 45 minutes at room temperature and then concentrated in vacuo. The solid residue is triturated with water and filtered off. The crude product is purified by column chromatography on silica gel with methylene chloride/methanol (20:1) followed by recrystallization from ethyl acetate. Yield: 380 mg (59% of theory), Melting point: 174° C. Mass spectrum (ESI−): m/z=657, 659 [M−H]−
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=O>C1(C)C=CC=CC=1.N1CCCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=[C:7]([C:6](=[O:11])[CH3:5])[C:8](=[O:10])[CH3:9]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(C)=O
Yield: 88.4 %

Procedure:
Glacial acetic acid (0.49 ml, 8.6 mmol) and piperidine (57 μL, 0.6 mmol) were added to a stirred solution of 2,4-pentanedione (2.86 g, 28.6 mmol) and 3,5-dichlorobenzaldehyde (5.00 g, 28.6 mmol) in toluene (25 ml) and the mixture was heated under reflux using a Dean-Stark trap for 18 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (10:1, by volume) to give the title compound (6.5 g) as a red/brown solid, m.p. 85–87° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH2:3]1.[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)#[N:17]>C(O)C>[CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]3[NH:12][C:22]([C:21]4[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=4)=[N:13][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(C#N)cc4)[nH]c3cc21

Procedure:
4.1 g. 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one and 2.6 g. 4-cyanobenzaldehyde were stirred in 100 ml. ethanol for 7 days at 25° C. with the action of air. Subsequently, the reaction mixture was evaporated to 10 ml., mixed with 10 ml. water, filtered off with suction and recrystallized from ethanol/water (1:1 v/v) to give 5 g. of the title compound; m.p. 228°-233° C.
Reaction SMILES: [CH2:1]([N:4](C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][N:17]([CH2:25][CH3:26])C(OC(C)(C)C)=O)[CH:2]=[CH2:3].[ClH:48]>C(OCC)C>[ClH:48].[ClH:48].[ClH:48].[ClH:48].[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:25][CH3:26])[CH:2]=[CH2:3]
Reactant: C=CCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C=CCNCCCNC/C=C/CNCCCNCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.28 g (0.418 mmol) of (E)-1-allyl-14-ethyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 6 ml of 3N methanolic hydrochloric acid is stirred for 6 h at room temperature, and then 10 ml of diethyl ether are added. Working up analogously to Example 1 yields the title compound, m.p. >260° C. 1H-NMR (D2O): δ1.28(t,3H); 2.05-2.17(m,4H); 3.07-3.19(m,10H); 3.69(d,2H); 3.77(d,4H); 5.49-5.55(m,2H); 5.84-5.98(m,1H); 6.04-6.07(m,2H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([OH:8])[CH3:7])[CH2:2][CH3:3].[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:13]([O:8][CH:6]([CH3:7])[CH2:5][NH:4][CH2:1][CH2:2][CH3:3])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCNCC(C)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCNCC(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(propylamino)propan-2-ol (8.00 g, 68.3 mmol), tert-butylchlorodimethylsilane (10.9 g, 72.4 mmol), and catalytic amount of DMAP in CH2Cl2 (68 mL) at 0° C. was added dropwise TEA (9.61 ml, 68.3 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h. Additional 1 mL of TEA was added and stirred for additional 20 h. Water (60 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was filtered again to afford quantitatively 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine that was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH2:23]([C:25]1[S:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=1)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[N:12][CH:11]=[C:10]([CH:9]=2)[C:20]([NH:31][CH2:30][C:28]2[N:29]=[C:25]([CH2:23][CH3:24])[S:26][CH:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: CCc1nc(CN)cs1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CCc1nc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-82-5) and 2-ethyl-4-thiazolemethanamine as starting materials; LC-MS (UV peak area/ESI) 98%, 456.074 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[N:4]=[CH:3][CH:2]=1.[NH2:17]/[C:18](/[C:23]#[N:24])=[C:19](\[NH2:22])/[C:20]#[N:21].C(O)C.O>C1C=CC=CC=1>[N:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]1[N:17]=[C:18]([C:23]#[N:24])[C:19]([C:20]#[N:21])=[N:22][C:9]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Reactant: N#C/C(N)=C(/N)C#N
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1nc(-c2ccccn2)c(-c2ccccn2)nc1C#N
Yield: 45.7 %

Procedure:
Into a 250 mL round bottomed flask are placed, 2,2'-pyridil (8.48 g, 40 mmol), diaminomaleonitrile (4.32 g, 40 mmol) and 125 mL of ethanol. The flask is fitted with a magnetic stirrer and a condenser, and refluxed for 30 minutes. The mixture is allowed to cool, and 10 mL of water is added. Filtration yielded 8.9 g of crude product as a beige solid. The solid is boiled in benzene (400 mL) and filtered hot. The red filtrate is discarded giving 5.2 g of the title compound as a pale beige solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:19]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=2)[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])C>C1COCC1.[OH-].[Na+]>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]([C:19]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=2)([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1(c2cncc(Cl)n2)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)O)(c2cncc(Cl)n2)C1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A solution of 3-(6-chloro-pyrazin-2-yl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (350.1 mmol) in THF (360 mL) and 1.5 N aqueous NaOH (360 mL) was heated at 80° C. for 5 hr. After it was cooled to room temperature, the aqueous layer was separated and then carefully acidified to pH=5 by the addition of 1 N aqueous HCl solution. The resulting mixture was extracted with DCM (300 mL×3) and the combined organic layers were dried over anhy. Na2SO4, filtered and concentrated under reduced pressure to give a crude tile compound (46 g), which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[F:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: Nc1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 1 (1.0 g, 4.4 mmol), 2-fluoroaniline (463 μl, 4.8 mmol) in CH2Cl2 (25 ml) at 0° C. was added DCC (0.99 g, 4.8 mmol) in several portions. The mixture was stirred at room temperature overnight. The white precipitate was removed by filtration. After removal of solvent, the residue was purified by column chromatography (silica gel, hexane/ethyl acetate, 4:1) to give 3-(2-fluorophenylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (2) as a colorless oil (1.13 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]([CH2:15][CH3:16])(O)[C:11](O)=[O:12])[CH:5]=[CH:6][CH:7]=1.[NH2:18][NH2:19]>CCCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][CH3:16])[C:11](=[O:12])[NH:18][N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCC(O)(CC(=O)c1cccc(Cl)c1)C(=O)O
Solvent: CCCCO
Product: CCc1cc(-c2cccc(Cl)c2)n[nH]c1=O
Temperature: 130 °C

Procedure:
A RBF was charged with 4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid (2.78 g, 10.8 mmol), hydrazine (0.510 ml, 16.2 mmol) and 11 mL of n-BuOH. A Dean-Stark apparatus fitted with a reflux condenser was attached, and the mixture was heated under nitrogen at 130° C. for 15 h. Upon cooling a precipitate formed, which was filtered, washed with cold EtOH, and dried. 6-(3-chlorophenyl)-4-ethylpyridazin-3(2H)-one was isolated as a white solid. MS m/z=235 [M+H]+. Calc'd for C12H11ClN2O: 234.68.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([OH:20])[CH:7]=1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][C:32](=[O:33])[N:31]([CH3:35])[CH3:30])[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OC(C)(C)C
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OC(=O)N(C)C)c1)NC(=O)OC(C)(C)C

Procedure:
(S)-3-(4-Benzyloxy-3-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (401 mg) was dissolved in dichloromethane (8 ml) and N,N-dimethylcarbamoyl chloride (0.092 ml, leg) added. Triethylamine (0.14 ml, 1 eq) was added and the mixture was stirred and heated under reflux. The reaction was monitored by HPLC/MS and further portions of N,N-dimethylcarbamoyl chloride and triethylamine were added in order to complete the reaction. After a total of 8 hours reflux the reaction mixture was evaporated to dryness and absorbed onto silica gel. Chromatography, eluting with mixtures of ethyl acetate-hexane afforded (S)-3-(4-Benzyloxy-3-dimethylcarbamoyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester as an oil, 315 mg; Rf 0.14 (ethyl acetate-hexane 1:3); HPLC/MS retention time 3.89 min, m/z 473 (MH+). Crystallisation from ethyl acetate-hexane gave (S)-3-(4-benzyloxy-3-dimethylcarbamoyloxy-phenyl)-2-tert-butoxycarbonyl-amino-propionic acid methyl ester as a white solid, 126 mg; NMR (500 MHz, CDCl3) 1.42 (9H, s), 2.95 (3H, s), 2.98-3.04 (5H, m), 3.70 (3H, s), 4.52-4.54 (ca 1H, m), 4.97-5.00 (ca 1H, br d), 5.05 (2H, s), 6.88-6.92 (3H, m), 7.28-7.40 (5H, m).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)[CH3:2].C([Li])CCC.CN(C)[CH:19]=[O:20]>O1CCCC1>[Cl:10][C:8]1[CH:9]=[C:4]([S:3][CH2:1][CH3:2])[CH:5]=[C:6]([Cl:11])[C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: CCSc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCSc1cc(Cl)c(C=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 97.5 %

Procedure:
A solution of 3,5-dichlorophenyl ethyl sulfide (1.0 g, 4.8 mmol) in tetrahydrofuran (4 mL) was cooled to −78° C. A solution of n-butyllithium (4.5 mL, 1.6 M in hexane) was added dropwise and the mixture was stirred at −78° C. for 45 minutes. N,N-dimethylformamide (4.47 mL, 57.7 mmol) was added and the mixture was stirred at −78° C. for 1 hour. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice water and extracted three times with ethyl acetate. The combined extracts were dried with sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel to give the desired product (1.1 g, 97%). 1H NMR (CDCl3) δ 10.40 (s, 1H), 7.20 (s, 2H), 3.00 (m, 2H), 1.4 (m, 3H). LC/MS: 235 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:22]([F:25])([F:24])[F:23].ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([C:22]([F:25])([F:23])[F:24])=[O:34]
Reactant: Cn1c(-c2ccccc2SC(F)(F)F)nc2cc(C(F)(F)F)cnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2S(=O)C(F)(F)F)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
To a mixture of 3-methyl-6-trifluoromethyl-2-(2-trifluoromethylsulfanylphenyl)-3H-imidazo[4,5-b]pyridine (0.80 g) and chloroform (7 ml), 3-chloroperbenzoic acid (purity: not less than 65%) (0.49 g) was added under ice-cooling. The mixture was heated to room temperature, stirred for 20 minutes, and then heated to 62° C., and stirred under reflux for 2 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.44 g of 3-methyl-6-trifluoromethyl-2-(2-trifluoromethylsulfinylphenyl)-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 19).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([C:39]1([C:47](Cl)=[O:48])[CH2:45][CH:44]2[O:46][CH:41]([CH2:42][CH2:43]2)[CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:50])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:47](=[O:48])[NH:2][OH:3])[CH2:45][CH:44]2[O:46][CH:41]([CH2:42][CH2:43]2)[CH2:40]1)[CH3:16]
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCN(C1(C(=O)NO)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight. This mixture is then cooled to 0° C. and treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of the title compound in dichloromethane is used in the next step.
Reaction SMILES: [Cl:1]C(Cl)(Cl)CO[C:5](=[O:17])[NH:6][C:7]1[N:8]([CH3:16])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[NH2:20][C@@H:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]([O:31][C:32]2[CH:33]=[CH:34][C:35]3[N:36]([C:38]([C@H:41]4[N:45]([CH3:46])[CH2:44][C@@H:43]([N:47]([CH3:49])[CH3:48])[CH2:42]4)=[N:39][N:40]=3)[CH:37]=2)[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.Cl>O1CCOCC1.CC#N>[ClH:1].[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([C@@H:41]5[CH2:42][C@H:43]([N:47]([CH3:49])[CH3:48])[CH2:44][N:45]5[CH3:46])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:17])[N:8]([CH3:16])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CN(C)[C@H]1C[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)N(C)C1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1COCCO1
Product: CN(C)[C@H]1C[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5C)c5ccccc54)cn23)N(C)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(5-Tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (US2004/0192653, which is incorporated herein by reference in its entirety; 242 mg, 0.74 mmol) was treated with a solution of Intermediate 38d (300 mg, 0.74 mmol) in 1,4-dioxane (5 mL) then DIPEA (185 μL, 1.1 mmol) was added. The mixture was stirred at 50° C. overnight. The mixture was evaporated in vacuo and the residue purified by HPLC (Method 6, 20-40% MeCN in H2O, 0.1% HCO2H over 30 min) to give a colourless glass that was dissolved in MeCN and treated with 1N HCl (550 μL, 1 eq.). The volatiles were evaporated to drieness under reduced pressure affording a colourless glass that upon trituration with ether gave a solid. The solid was collected by filtration, washed with ether and dried at 50° C. in vacuo to give the title compound as an off white solid (346 mg, 74%). LCMS (Method 5): Rt 3.01 min, m/z 586.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.81-2.15 (5H, m), 2.16-2.24 (2H, bs), 2.42-2.52 (4H, br s, partially obscured by DMSO), 2.74-2.80 (6H, s), 3.45-3.53 (2H, m), 3.56 (3H, s), 3.97-4.06 (1H, m), 4.79-4.88 (1H, m), 5.54 (1H, t, J 4.3 Hz), 6.00 (1H, s), 7.08 (1H, d, J 8.4 Hz), 7.22-7.27 (1H, m), 7.33-7.39 (4H, m), 7.77 (1H, d, J 9.3 Hz), 8.45 (1H, bs), 8.60 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14](OC3C=CC([N+]([O-])=O)=CC=3)=[O:15])[C:12]([O:26][CH3:27])=[N:11][C:10]([CH3:28])=[C:9]2[C:29]([O:31][CH3:32])=[O:30])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CO.C(Cl)Cl>[C:46]([O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][NH:39][C:14]([N:13]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:29]([O:31][CH3:32])=[O:30])=[C:10]([CH3:28])[N:11]=[C:12]1[O:26][CH3:27])=[O:15])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)NCCCC(=O)OC(C)(C)C)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99460.8 %

Procedure:
To a solution of 5-methyl 1-(4-nitrophenyl) 6-(4-fluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate (88.7 mg, 0.200 mmol) and K2CO3 (41.5 mg, 0.300 mmol) in CH3OH/CH2Cl2 (0.1/2.0 mL) was added tert-butyl 4-aminobutanoate (31.8 mg, 0.200 mmol). After stirring at rt for 1 h, the mixture was washed with saturated Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (5%-10% 2 M NH3/MeOH in 50% EtOAc/Hexanes) to afford the product (92.2 g, 99%). mp 135-138° C.; 1H NMR (CD3OD) δ 7.29-7.23 (m, 2H), 6.97-6.88 (m, 2H), 6.65 (s, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 3.38-3.30 (m, 2H), 2.43 (s, 3H), 2.28 (t, 2H, J=7.2 Hz), 1.89-1.78 (m, 2H), 1.43 (s, 9H); ESMS m/e: 464.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[I-].[Na+].[NH2:14][CH2:15][CH2:16][O:17][CH:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:49])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[CH:33][C:32]=2[O:47][CH3:48])[CH2:21][CH2:20][CH2:19]1>CN(C)C=O.O>[C:3]([CH2:2][NH:14][CH2:15][CH2:16][O:17][CH:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:49])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[CH:33][C:32]=2[O:47][CH3:48])[CH2:21][CH2:20][CH2:19]1)#[N:4]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCN)c2cc(Cl)ccc21
Reactant: N#CCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCNCC#N)c2cc(Cl)ccc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
0.01 ml of chloroacetonitrile, 0.22 ml of triethylamine and 0.24 ml of sodium iodide were added to 50 ml of a solution of 0.7 g of 5-(2-aminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in dimethylformamide. The mixture was stirred at 60° C. for 2 hours. The reaction mixture was mixed with water, followed by extraction with ethyl acetate-n-hexane (10:1). The organic layer was water-washed, dried and subjected to vacuum distilation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=50/1) and crystallized from acetone-n-hexane to obtain 0.5 g of 5-(2-cyanomethylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine.