Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)=[O:18])C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][CH:19]2[C:17]([OH:18])=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCC3)n2)c(Cl)c1
Yield: 76 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (52 mg, 0.26 mmol) obtained in Step C of Preparation Example 37 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (70 mg, 0.29 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 84%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][N:11]([C:19]([C:21]2[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:22]=2)=[O:20])[CH2:10][CH2:9]1.Br[CH2:31][C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][OH:40])[CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>C(#N)C>[OH:40][CH2:39][CH2:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][N:16]1[CH2:17][CH2:18][C:13]2([O:8][CH2:9][CH2:10][N:11]([C:19]([C:21]3[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:22]=3)=[O:20])[CH2:12]2)[CH2:14][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: OCCc1cccc(CBr)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of methyl 5-(1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)thiophene-2-carboxylate trifluoroacetate (example 30, step b) (0.46 g) and 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.226 g) in acetonitrile (10 mL) was treated with triethylamine (0.44 mL) and the mixture stirred at 20° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% triethylamine and 3% methanol in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.41 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:13])[CH3:12].[O:14]1[CH2:16][C@H:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CN(C=O)C.O.C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:10][C:11](=[O:13])[CH3:12])=[C:2]([O:1][CH2:17][C@@H:15]2[CH2:16][O:14]2)[CH:7]=1
Reactant: COc1ccc(NC(C)=O)c(O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(C)=O)c(OC[C@@H]2CO2)c1
Yield: 122.2 %

Procedure:
N-(2-Hydroxy-4-methoxyphenyl)acetamide (18.12 g, 0.1 mol) and (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (25.92 g, 0.1 mol) were dissolved in dry DMF (75 mL) and stirred under nitrogen (N2) on an ice-bath. Cesium carbonate (35.8 g, 0.1 mol) was added and the stirring under N2 was continued at ambient temperature overnight. The mixture was poured into ethyl acetate (1 L) and water (250 mL). The organic phase was washed with water (3×250 mL), dried over Na2SO4, filtered and concentrated in vacuo to give an orange solid crude product (29 g), which was recrystallized from ethanol (100 mL) and washed with ether to give white crystals. More white crystals were obtained from the mother liquor, after evaporation and recrystillazition from 2-propanol. Total yield 15 g is (63%).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35]C)=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>CO>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:42])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 87 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 87% of theory, Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1) C27H28N6O3 (484.6) ##EQU31##
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)[CH:40]=[CH:41][CH:42]=1>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(OC)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Product: COc1cccc(NC(=S)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c1
Yield: 87 %

Procedure:
The compound of example 60 was prepared analogous to compound of example 52 by hydrolysis of compound of example 59.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][N:8]([C:12]([O:14][CH2:15]Cl)=[O:13])[C:7]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].[I-:25].[Na+]>CC(C)=O>[CH2:1]([N:5]1[C:10](=[O:11])[CH2:9][N:8]([C:12]([O:14][CH2:15][I:25])=[O:13])[C:7]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [I-]
Reactant: CCCCN1N=C(c2cc(Cl)cc(Cl)c2)N(C(=O)OCCl)CC1=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCN1N=C(c2cc(Cl)cc(Cl)c2)N(C(=O)OCI)CC1=O

Procedure:
1-(n-Butyl)-3-(3,5-dichlorophenyl)-4-(chloromethyloxycarbonyl)-4,5-dihydro-1,2,4-triazin-6-one was treated with sodium iodide in acetone as described in Folkmann, M.; Lund, F. J. Synthesis 1990, 1159 to give 1-(n-butyl)-3-(3,5-dichlorophenyl)-4-(iodomethyloxycarbonyl)-4,5-dihydro-1,2,4-triazin-6-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1F)[CH3:2].[CH2:13]([O:15][CH2:16][CH2:17][NH2:18])[CH3:14].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:18][CH2:17][CH2:16][O:15][CH2:13][CH3:14])[CH3:2]
Reactant: CCOCCN
Reactant: CCOC(=O)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCNc1ccccc1C(=O)OCC
Temperature: 120 °C

Procedure:
To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 2-Ethoxy-ethylamine (0.500 g, 2.97 mmole) in dry N,N′dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (1.1 eq, 0.223 g, 3.27 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(2-Ethoxy-ethylamino)-benzoic acid ethyl ester as a clear liquid (0.493 g, 70%, LCMS calc M+H 238, obs M+H 238).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[F:11][C:6]1[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=[CH:2][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Reaction time: 2 h

Procedure:
To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (115, 0.69 g, 2.3 mmol) in methanol (10 mL) was added 20% palladium hydroxide on carbon (200 mg). The reaction was stirred under hydrogen at 50 psi for 2 hours. The reaction was filtered and concentrated to give white solid 50 that was used in the next step. MS (ESI) [M−H+]−=260.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:27])[CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:27])[CH2:17][CH2:18][NH2:19])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1
Reactant: C=C(CCNC(=O)OC(C)(C)C)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(CCN)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
To a solution of [4-(3-tert-butoxycarbonylamino-1-methylene-propyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.79 g, 2.0 mmol) in methylene chloride (28.5 mL) was added trifluoroacetic acid (7.5 mL, 98 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum and the resulting brown residue was dissolved in toluene. The solvent was again removed under vacuum, then dissolved in methylene chloride (−5 mL) with heating. The mixture was diluted with hexanes (˜10 mL). As a result, some oil precipitated. The mixture was diluted with dichloromethane and the dark brown solution was stored in the refrigerator for 15 hours; however, further precipitation of the product was not successful. The solvent was removed and the crude mixture (1.1 g) was purified using flash chromatography (80 g ISCO column, 0-100% methylene chloride in hexanes followed by 0-20% methanol in methylene chloride) to afford [4-(3-amino-1-methylene-propyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.502 g, 75%) as a white, amorphous, and hygroscopic solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.64-7.71 (m, 1H), 7.55-7.59 (m, 1H), 7.32-7.38 (m, 1H), 7.16 (td, J=8.5, 2.3 Hz, 1H), 5.53 (s, 1H), 5.09 (s, 1H), 3.77-3.81 (m, 2H), 3.67-3.71 (m, 4H), 2.99 (d, J=6.0 Hz, 2H), 2.65 (t, J=7.4 Hz, 2H), 2.28 (s, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:3]1.FC(F)(F)S(O[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=2)[N:27]=[CH:26][CH:25]=1)(=O)=O.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:35][O:34][C:31]1[N:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[C:24]2[N:7]1[CH2:6][CH2:5][N:4]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NCCN1CCNC(=O)C1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2nccc(N3CCN(CCNC(=O)OC(C)(C)C)CC3=O)c2n1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
In a sealed tube 1,1-dimethylethyl [2-(3-oxo-1-piperazinyl)ethyl]carbamate (1.7 g, 7.02 mmol), 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate (2.17 g, 7.02 mmol), Pd2dba3 (436 mg, 0.421 mmol), rac-Binap (262 mg, 0.421 mmol), Cs2CO3 (4.81 g, 14.75 mmol) and 18-C-6 (186 mg, 0.702 mmol) in dioxane (35 mL) were combined and flushed with N2. After 15 min, the tube was sealed and heated to 100° C. while stirring rapidly. After 12 h, the solution was filtered, concentrated and the residue purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (1.5 g, 53%) as a burgundy foam: LCMS (ES) m/e 402 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[NH2:17])[C:8]1=[O:19])(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[NH:17][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[C:22]([C:31]([F:32])([F:34])[F:33])[CH:23]=2)[C:8]1=[O:19])(=[O:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC(=O)OCCn1ccc2c(N)c(Cl)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCn1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Temperature: 45 °C
Reaction time: 96 h

Procedure:
A reaction vial was charged with 2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (60.0 mg, 0.000214 mol), 2-(4-fluoro-3-(trifluoromethyl)phenyl)acetic acid (57.0 mg, 0.000256 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (203 mg, 0.000534 mol), N,N-diisopropylethylamine (0.093 mL, 0.00053 mol) and methylene chloride (3 mL, 0.05 mol) and the reaction stirred at 45° C. for 4 days. The reaction did not go to completion and a polar by product started increasing and so the reaction was stopped and solvent removed and the residue purified by flash chromatography to obtain the product as a light yellow solid. MS m/z=485.2 (M+H)
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Cl:22].C([O-])([O-])=O.[K+].[K+].CO>O>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Cl:22]
Reactant: COc1nc2c(c(Cl)c1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1nc2c(c(Cl)c1Br)C(C)CNCC2
Temperature: 57.5 °C
Yield: 98.2 %

Procedure:
To a solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (303 mg, 1.00 mmol) in MeCN (6 ml) was added a solution of NCS (134 mg, 1.00 mmol) in MeCN (6 ml). The resulting mixture was stirred for 2 h at 50° C. and then quenched with excess of sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 165 mg (49%) of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 4.28 (0.5H), 3.95 (2.5H), 3.88 (3H), 3.71 (2H), 3.61 (1H), 3.34 (1H), 3.16 (1H), 2.99 (1H), 1.13 (3H) ppm. To a solution of CuBr2 (43.0 mg, 0.19 mmol) and nBuNO2 (28.0 μl, 0.24 mmol) in MeCN (2.7 ml) was added a solution of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (54.0 mg, 0.16 mmol) in MeCN (2 ml) at room temperature. After leaving the mixture for 16 h at room temperature, it was heated at 50° C. for 4 h. After removal of MeCN under reduced pressure, the reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 45 mg (70%) of 3-bromo-4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H NMR (CDCl3) δ 4.29 (0.5H), 4.00 (0.5H), 3.90 (3H), 3.85 (1H), 3.75 (1H), 3.40 (1H), 3.30 (1H), 3.20 (1H), 3.10 (1H), 1.16 (3H) ppm. A mixture of 3-bromo-4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (60 mg, 0.15 mmol), K2CO3 (62 mg, 0.45 mmol), MeOH (2.4 ml) and H2O (0.5 ml) was heated at 55-60° C. for 1 h. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to give 45 mg (98%) of 3-bromo-4-chloro-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 3.89 (s, 3H), 3.58 (m, 1H), 3.22 (m, 2H), 3.09 (dd, 1H), 2.93 (m, 2H), 2.71 (dd, 1H), 1.24 (d, 3H) ppm.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:14]([NH:16][C@@H:17]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C@@H:2]([C:14]([NH:16][C@@H:17]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CCCC[C@@H](NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@@H](NC(=O)[C@H](N)Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 98.4 %

Procedure:
To a solution of Boc-DNal-DNle-OBzl (233 mg) in dichloromethane (2 ml) was added TFA (5 ml) and the mixture was stirred at room temperature for 13 h. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with sat. aq. NaHCO3, water and brine successively, dried over MgSO4 and evaporated in vacuo to give the product (185 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[O:20]1[CH2:23][CH:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([CH:22]4[CH2:23][O:20][CH2:21]4)[CH2:25][CH2:26]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: C1CC(C2COC2)CCN1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)ccc2n1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.199 g) was reacted with 4-(oxetan-3-yl)piperidine via General Procedure B to afford 0.11 g 4-(2-chloro-6-((4-(oxetan-3-yl)piperidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8].C([O-])(O)=O.[Na+].O.C([O-])(O)=O.[Na+]>O>[ClH:2].[NH:5]1[CH2:4][CH2:3][S:8][CH2:7][C@H:6]1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)[C@H](CS)NCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1CSCCN1

Procedure:
20 g of 2-chloroethyl cysteine hydrochloride was dissolved in water, added dropwise of NaHCO3 water solution containing 7.2 g of NaHCO3 in an ice bath, after the addition, the mixture was fully stirred for neutralization, extracted with ethyl acetate for three times, the organic phases were combined and dried with Na2SO4.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[OH-].[Na+].Br[CH:20]([CH3:22])[CH3:21]>CC(C)=O>[CH3:13][C:12]([C:7]1[CH:8]=[C:9]([S:11][CH:20]([CH3:22])[CH3:21])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)Br
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.0 g, 8.4 mmole) in acetone (20 ml) was added sodium hydroxide (0.71 g, 17.6 mmole). After the sodium hydroxide had reacted, 2-bromopropane (1.08 g, 8.8 mmole) was added, and the reaction mixture was stirred for two hours. The mixture was concentrated in vacuo to an oil that was dissolved in diethyl ether (50 ml), washed with water (30 ml in two portions), dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. Chromatography on silica gel and recrystallization from aqueous methanol gave the title compound, m.p. 80°-82°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][NH:15][CH2:14][C:13]3[S:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.Cl.[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1.Cl.CN(C)CCCN=C=NCC>C(N(CC)CC)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][N:15]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH3:40])[CH3:26])=[CH:39][CH:38]=3)=[O:36])[CH2:14][C:13]3[S:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CNCc3sccc32)cc1OC
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(C(=O)c3ccc(OCCN(C)C)cc3)Cc3sccc32)cc1OC

Procedure:
Similarly as described in example 22 using a solution of 4-(3,4-Dimethoxyphenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 pi), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 9 in 8.3 ml) affords the title compound.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Br:14][CH:15]([CH3:19])[C:16](Cl)=[O:17]>ClCCl>[CH:1]1([O:7][C:16](=[O:17])[CH:15]([Br:14])[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: CC(Br)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Br)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of cyclohexanol (10.9 g, 10.9 mmol), pyridine (8.62 g, 10.9 mmol) in dichloromethane was added 2-bromopropionyl chloride (18.53 g, 10.9 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hr. The product was partitioned between hexane and 10% citric acid. The organic phase was separated, dried over MgSO4 and concentrated to yield 2-bromo-propionic acid cyclohexyl ester, which was used in the following reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[C:20]1([CH:26]2[CH2:31][NH:30][CH2:29][CH2:28][NH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N12CCN(CC1)CC2>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:30]4[CH2:29][CH2:28][NH:27][CH:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:31]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: c1ccc(C2CNCCN2)cc1
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccccc4)C3)c(F)cc2c1=O
Temperature: 140 °C
Yield: 31.9 %

Procedure:
A mixture of 2.8 g (0.01 mols) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.8 g (0.011 mole) of 2-phenylpiperazine and 2.2 g (0.02 mole) of 1,4-diazabicyclo[2.2.2]octane in 6 ml of dimethyl sulphoxide is heated at 140° C. for 4 hours. The solution is concentrated under high vacuum, and the residue is stirred with 20 ml of water and the pH is adjusted to 7 with 2N hydrochloric acid. The precipitate is filtered off with suction, washed with water and methanol, and boiled in 30 ml of methanol. 1.3 g (32% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylic acid of melting point 218°-220° (with decomposition) is obtained (recrystallized from glycol monomethyl ether).