Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([C:38]3([C:42]#[N:43])[CH2:41][CH2:40][CH2:39]3)[CH:35]=[N:36][CH:37]=2)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:34]([C:38]6([C:42]#[N:43])[CH2:41][CH2:40][CH2:39]6)[CH:35]=[N:36][CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cncc(C3(C#N)CCC3)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C5(C#N)CCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-cyclobutanecarbonitrile (Stage 221.1.1) to give the title compound as an off-white foam. (HPLC: tR 2.43 min (Method A); M+H=450 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.74-8.73 (m, 1H), 8.70-8.68 (m, 1H), 8.17-8.12 (m, 2H), 8.06-8.03 (m, 1H), 7.90-7.88 (m, 1H), 7.63-7.61 (m, 1H), 3.89 (s, 3H), 3.59 (s, 3H), 2.86-2.71 (m, 4H), 2.13-2.01 (m, 2H), 1.97 (s, 3H))
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].Br[CH2:40][CH2:41][CH2:42][Cl:43].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:40][CH2:41][CH2:42][Cl:43])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCCl)c2)c2cccnc21
Reaction time: 6 h
Yield: 88.7 %

Procedure:
To a solution of N-{1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl}-N'-(2,6-diisopropylphenyl)urea (1000 mg, 1.95 mmol) and 1-bromo-3-chloropropane (460 mg, 2.93 mmol) in DMF (10 ml) was added potassium carbonate (673 mg, 4.88 mmol), and the mixture was stirred at 50°-60° C. for 6 hours. After allowed to stand for cooling, the mixture was poured into water, extracted with ethyl acetate, washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate:hexane=50:50), and crystallized from hexane to give the title compound (1020 mg, 1.73 mmol) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[N:11]([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[N:11]([CH2:21][C:22]([OH:24])=[O:23])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CN2CCOC2=O)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Product: C[C@@H]1CN(CC(=O)O)[C@@H](CN2CCOC2=O)CN1C(=O)OC(C)(C)C
Yield: 89.3 %

Procedure:
Following similar methods to those described in Preparation 12, starting from (2R,5S)-4-benzyloxycarbonylmethyl-2-methyl-5-(2-oxo-oxazolidin-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (265 mg), and Pd/C (65 mg) gave the title compound (189 mg) as a white solid. MS: [M+H]+=358.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]([NH2:35])=[NH:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:34]=[C:33]([NH:32][C:26]4[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([OH:23])[CH:25]=4)[N:35]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(NC(=N)N)cc1O
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1O

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-hydroxy-4-methoxy-phenyl)-guanidine nitrate were converted to I-65 (69%): HRMS Calcd. for C19H11ClN4O3: 383.091, Found 383.0913.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: COc1ccccc1C1(O)CCC(=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1ccccc1C1(O)CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(2-methoxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:25]=[C:26]4[CH2:37][CH2:36][N:35]([C:47]([N:46]([CH3:50])[CH3:45])=[O:48])[CH2:34][C:27]4=[N:28][C:29]=3[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]2)=[C:9]([F:8])[CH:10]=1)#[N:13]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCN(C(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (32.5 mg, 0.062 mmol) in DCM (620 μL) at 0° C. was treated with triethylamine (25.9 μL, 0.186 mmol) and dimethylcarbamic chloride (11.4 μL, 0.124 mmol). The reaction mixture was allowed to gradually warm to room temperature and stir for 1 h. The reaction mixture was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 40% to 70% ACN gradient to give the title compound in (about 90% purity), as a TFA salt, as a yellow solid (6.8 mg, 18%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (m, 6H), 2.02 (m, 2H), 2.19 (m, 2H), 2.81 (t, J=5.3 Hz, 2H), 2.91 (s, 5H), 3.17 (m, 3H), 3.43 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 4.13 (m, 1H), 4.32 (s, 2H), 4.80 (m, 1H), 7.34 (m, 1H), 7.54 (t, J=10.9 Hz, 2H); ESI-MS m/z [M+H]+ 482.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH2:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1([CH2:30][CH2:31][CH:32]=O)[CH:29]=[CH:28][N:27]=[CH:26]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:24][CH2:32][CH2:31][CH2:30][N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)([CH3:22])[CH3:23])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=CCCn1ccnc1
Product: CC(C)(NCCCn1ccnc1)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
In a similar manner to Example 24, 1-(4'-benzyloxybiphenyl-4-yl)-1-methylethylamine (Al5) (1.4 g) and 3-(imidazol-1-yl)propionaldehyde (0.72 g) were reacted to give N-[1-(4'-benzyloxybiphenyl-4-yl)-1-methylethyl)-3-(imidazol-1-yl)propylamine, m.p. 93°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32]C)=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([OH:32])=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(OC)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (80 mg, 0.18 mmol) in water (1 mL) and MeOH (15 mL) was added sodium hydroxide (29 mg, 0.72 mmol) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(4-fluorophenyl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (50 mg, 64.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Br[C:12]1[CH:21]=[N:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:18]1[CH:19]=[N:20][CH:21]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccncc1Br
Product: COC(=O)c1ccncc1NCc1ccc(Cl)c(Cl)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 3,4-dichlorobenzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.95 (d, 1H, J=5.1 Hz), 7.87 (br s, 1H), 7.65 (d, 1H, J=5.1 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.39 (s, 1H), 7.18 (dd, 1H, J=8.2 Hz), 4.48 (d, 2H, J=6.0 Hz), 3.91 (s, 3H). [M+H] calc'd for C14H12Cl2N2O2, 311, 313. Found 311, 313.
Reaction SMILES: [F:1][CH:2]([F:12])[CH:3]([NH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:4]C=C.[Mn]([O-])(=O)(=O)=O.[K+].[C:19]([OH:22])(=[O:21])[CH3:20]>O>[F:1][CH:2]([F:12])[CH:3]([NH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:20][C:19]([OH:22])=[O:21]
Reactant: CC(=O)O
Reactant: C=CCC(NC(=O)OC)C(F)F
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)NC(CCC(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1,1-Difluoro-2-methoxycarbonylamino-4-pentene prepared as in Step F (4.00 g, 20.7 mM), dissolved in glacial acetic acid (60 ml), is added to potassium permanganate (9.80 g, 62 mM) in water (300 ml) at 0° C. After stirring for 15 hours at room temperature, the excess of potassium permanganate is destroyed with a 10% sodium bisulfite solution and the mixture saturated with sodium chloride. Extraction with diethyl ether and evaporation of the solvent in vacuo affords 1,1-difluoro-2-methoxycarbonylamino-5-pentanoic acid as a colorless oil. Crystallization from ether/petroleum ether gives 3.200 g of pure acid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:1]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:17]2=[O:22])[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1ccnc(N2CCCCC2=O)c1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1ccnc(N2CCCC(Cc3ccccc3)C2=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
To a solution of N-benzyl-2-(2-oxopiperidin-1-yl)isonicotinamide (0.14 g, 0.45 mmol) in anhydrous tetrahydrofuran (15 mL) was added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.52 mL, 0.45 mmol) at −78° C. under nitrogen atmosphere. The resulting solution was stirred for 30 minutes at −78° C., followed by the addition of a solution of benzyl bromide (0.15 g, 0.90 mmol) in anhydrous tetrahydrofuran (5 mL) dropwise at −78° C. The reaction mixture was warmed to ambient temperature, stirred for 2 hours, quenched with aqueous saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 50-65% ethyl acetate in hexanes to give N-benzyl-2-(3-benzyl-2-oxopiperidin-1-yl)isonicotinamide as a colorless solid (0.06 g, 32%): 1H NMR (300 MHz, CD3OD) δ 8.61 (d, J=6.1 Hz, 1H), 7.98 (s, 1H), 7.58 (d, J=6.2 Hz, 1H), 7.42-7.12 (m, 10H), 4.58 (d, J=4.1 Hz, 2H), 2.88-2.81 (m, 2H), 2.1-1.91 (m, 4H), 1.81-1.58 (m, 3H); MS (ES+) m/z 400.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][OH:36])[CH:24]=[C:23]1[CH2:37][CH2:38][N+:39]([O-:41])=[O:40])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:45]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]([OH:45])=[O:36])[CH:24]=[C:23]1[CH2:37][CH2:38][N+:39]([O-:41])=[O:40])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1CO
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1C(=O)O

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-4-(2-nitroethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 221, 4.1 g, 6.92 mmol) according to the procedure described for Intermediate 19. The desired product was obtained as an off-white foam (4.0 g, 98%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][C:18]([C:7]1[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:6]=1)=[O:20]
Reactant: NCc1ccc(F)cc1F
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(OC)c(=O)c(C(=O)NCc2ccc(F)cc2F)cn1CC(OC)OC
Reaction time: 0.17 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.300 g, 0.95 mmol), prepared as described in WO2011/119566 A1, was evaporated once from dry toluene, suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.329 mL, 1.90 mmol), 2,4-difluorobenzylamine (0.125 mL, 1.05 mmol) and HATU (0.433 g, 1.14 mmol). The reaction mixture was stirred for 10 minutes and concentrated. The residue was purified by flash chromatography on silica gel (10 to 60% ethyl acetate:dichloromethane) to afford the compound methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate, 1-B. 1H-NMR (400 MHz, DMSO-d6) δ 10.28 (t, J=6.0 Hz, 1H), 8.46 (s, 1H), 7.42 (dd, J=15.4, 8.6 Hz, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 4.52 (m, 3H), 4.22 (d, J=4.4 Hz, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.29 (d, 6H). LCMS-ESI+ (m/z): [M+H]+ calculated for C20H23F2N2O7: 441.15; found: 441.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[CH3:10][N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:16]([C:12]2[N:11]([CH3:10])[CH:15]=[CH:14][CH:13]=2)=[O:17])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: Cn1cccc1C(=O)Cl
Reactant: C#Cc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2cccn2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a 0° C. solution of 3-ethynylaniline (10.35 g, 0.088 mol) in anhydrous THF (700 mL) under N2 was added dropwise 1-methylpyrrole-2-carboyl chloride (12.69 g, 0.088 mol). Triethylamine (15.0 mL, 0.108 mol) was added and the mixture was allowed to warm to rt and stirred for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered and concentrated to give a brownish solid that was triturated with diethyl ether to give 13.4 g (68%) of product. LCMS (AP)+ 225.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:17]=CC2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[O:15][CH3:16])[N:6]=1.O.NN.O>C(O)COCCO>[NH2:17][N:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[O:15][CH3:16])[N:6]=[C:2]1[NH2:1]
Reactant: COc1ccc(OC)c(-c2cn(N=Cc3ccccc3)c(N)n2)c1
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(OC)c(-c2cn(N)c(N)n2)c1

Procedure:
A solution of 26.1 g of 2-amino-1-benzylideneamino-4-(2,5-dimethoxyphenyl)-imidazole and 16.2 ml of hydrazine hydrate in 80 ml of diethylene glycol is stirred at 170° C. for 6 hours. After cooling, 400 ml of water are added to the reaction mixture. The product that has separated out is filtered off with suction, washed with water and recrystallized from 150 ml of ethanol. In that manner there is obtained the title compound, m.p. 159°-160° C., 1H-NMR (DMSO): δ=7.47 (d, 1H); 7.07 (s, 1H); 6.87 (d, 1H); 6.63 (q, 1H); 5.52 (s, 2H); 5.34 (s, 2H); 3.79 (s, 3H); 3.69 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([F:8])=[C:6]([CH:7]=1)[CH:11]=[O:12]
Reactant: COC(Cl)Cl
Reactant: COc1cc(F)ccc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)c(C=O)cc1Br
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
8.4 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was dissolved in 200 ml of dichloromethane. 21 ml of titanium tetrachloride and 5.6 ml of dichloromethyl methyl ether were added at 0° C. in nitrogen atmosphere, followed by stirring at room temperature for 4.5 hours. Then, the reaction mixture was gradually poured onto ice-water, and extracted with diethyl ether for two times. The organic layer was sequentially washed with each one portion of water, saturated aqueous sodium hydrogencarbonate solution and water, dried over magnesium sulfate and the solvent was evaporated, to give 9.44 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([C:10](Cl)=[O:11])=[N:8][N:7]([CH3:13])[N:6]=1)=[O:4].C(N(C(C)C)C(C)C)C>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]=[O:11])=[N:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(C)nc1C(=O)Cl
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1nn(C)nc1C=O

Procedure:
To a solution of freshly prepared 5-Chlorocarbonyl-2-methyl-2H-1,2,3-triazole-4-carboxylic acid methyl ester (2.7 g; ca. 13 mmol) in THF (270 ml) was added ethyl-diisopropyl-amine (1.88 g; 1.1 eq.). The mixture was hydrogenated in the presence of 2.7 g 10% Pd/C at 0-5° C. at normal pressure for 2½ hours and subsequently filtered from the catalyst. The clear solution was evaporated to give the crude as a solid which was dissolved again in ethyl acetate and stirred for a couple of minutes with silica gel. After filtration and evaporation 1.77 g (84%) of pure product as off-white crystals were obtained [m.p. 107-108° C.; 1H-NMR (300 MHz, CDCl3), δ (ppm): 10.43(s,1H), 4.33(s,3H), 4.01(s,3H)].
Reaction SMILES: [ClH:1].C(OC([NH:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:25])=[C:21]([OH:24])[CH:22]=2)[CH2:17][CH2:16][NH:15]1)=O)C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:1].[ClH:1].[NH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:25])=[C:21]([OH:24])[CH:22]=2)[CH2:17][CH2:16][NH:15]1
Reactant: O=C(NCC1NCCc2cc(O)c(O)cc21)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NCC1NCCc2cc(O)c(O)cc21
Yield: 61.8 %

Procedure:
A mixture of 1-(N-benzyloxycarbonylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.3 g), conc. hydrochloric acid (6 ml) and acetic acid (6 ml) was refluxed for 1 hour and 20 minutes. The reaction mixture was cooled and concentrated under reduced pressure. The residue was crystallized by adding methanol and acetone. The crystals were collected by filtration, washed with a mixture of methanol and acetone and recrystallized twice from a mixture of water, methanol and acetone to give 1-aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (1.2 g), mp 142° to 147° C. (dec).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:11]=2[CH:24]=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[CH2:16]1[C:10]2[CH:9]=[CH:8][C:7]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:11]=2[CH2:12][CH2:13][CH2:14][N:15]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)ccc2C1
Reactant: COC(=O)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCCN(C(=O)OC(C)(C)C)C2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
To a 50-mL round-bottom flask charged with THF (15 mL) cooled to −78° C. under an N2 atmosphere was slowly added tert-butyllithium (0.922 mL, 1.474 mmol, 1.6 M in pentane). At this temperature, tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (0.37 g, 1.134 mmol) in THF (4 mL) was added. The resulting solution was stirred at −78° C. for 10 min. To the reaction flask was quickly added methyl chloroformate (1.75 mL, 22.68 mmol), and the resulting mixture was stirred at −78° C. for 30 min then warmed to room temperature for 10 min. The solvent was evaporated under reduced pressure and the residue was partitioned between water (10 mL) and EtOAc (50 mL). After separation, the aqueous phase was extracted with EtOAc (2×15 mL), the combined organic phases were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated. Flash column chromatography (EtOAc:hexanes, 0-10%) provided 2-tert-butyl 7-methyl 1,3,4,5-tetrahydro-2H-2-benzazepine-2,7-dicarboxylate (0.142 g, 41%) as a slightly yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.83-7.80 (m, 2H), 7.24 (d, J=7.6 Hz, 1H), 4.45 (br, 0.7H), 4.40 (br, 1.3H), 3.90 (s, 3H), 3.68 (br, 2H), 3.00 (br, 2H), 1.78 (m, 2H), 1.37 (s, 9H).