Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[CH3:31]C1C=C(C=CC=1)C=O>>[CH3:31][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:3]=1)[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: Cc1cccc(C=O)c1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: Cc1cccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-methylbenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (1H, br. s.) 10.26 (1H, s) 7.96-8.06 (1H, m) 7.75 (1H, d, J=5.47 Hz) 7.44 (1H, d, J=5.27 Hz) 7.25-7.32 (1H, m) 6.93-7.17 (2H, m) 6.78 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.51, 1.76 Hz) 3.61 (2H, s) 3.31-3.36 (2H, m) 2.60 (2H, t, J=6.54 Hz) 2.22 (3H, s)
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]#[C:26][C:27](O)=[O:28]>ClCCl.CO>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:27](=[O:28])[C:26]#[C:25][C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][C:15]=2[Cl:14])=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)Cc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 4-diethylaminomethylphenylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 72 mg (59% of theory); C21H20ClF3N2O (M=408.85); calc.: molecular ion peak (M+H)+: 409/411; found: molecular ion peak (M+H)+: 409/411; Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:41]1[CH:46]=[C:45]([C:47]([OH:49])=O)[N:44]=[CH:43][C:42]=1[C:50]([OH:52])=O.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:32][C:28]1[CH:27]=[C:26]2[C:31](=[CH:30][CH:29]=1)[C:22]([CH2:21][N:18]1[C:17]3[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=3[N:15]([C:47]([C:45]3[CH:46]=[N:41][C:42]([C:50]([N:15]4[C:16]5[CH:38]=[CH:37][CH:36]=[CH:35][C:17]=5[N:18]([CH2:21][C:22]5[C:31]6[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=6)[CH:25]=[CH:24][C:23]=5[O:33][CH3:34])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:40])[CH3:8])[CH3:10])[CH2:14]4)=[O:52])=[CH:43][N:44]=3)=[O:49])[CH2:14][C@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:40])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[C:19]1=[O:20])=[C:23]([O:33][CH3:34])[CH:24]=[CH:25]2
Reactant: O=C(O)c1cnc(C(=O)O)cn1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2cnc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)cn2)c2ccccc21
Reaction time: 5 h
Yield: 16 %

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 11) (300 mg, 0.49 mmol) and pyrazine-2,5-dicarboxylic acid (41.2 mg, 0.24 mmol) in pyridine (5 mL) at 0° C. was added POCl3 (46 μL, 0.49 mmol) and the cooling bath removed. After 5 h, the mixture was diluted with dichloromethane, washed with water, dried (Na2SO4) and concentrated. The residue was purified by preparative reverse phase HPLC to afford tert-butyl N-[(1S)-2-[[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[5-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]pyrazine-2-carbonyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (52 mg, 7.82%) as an off white solid. LC-MS: 1355.0 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:11][CH2:10]3)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14]C=3F)[N:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].ClC1C=CC([N+]([O-])=O)=C[N:30]=1>CS(C)=O>[CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:10][CH2:11]3)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:30]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(-n2nc(C3CC3)cc2C2CC2)c(F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2nc(C3CC3)cc2C2CC2)nc1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
A solution of intermediate 3 (8.0 g, 54.05 mmol) and K2CO3 (27.96 g, 202.6 mmol) in DMSO (60 mL) was heated at 110° C. under nitrogen for 0.5 h. To the mixture, 2-chloro-5-nitro pyridine (12.8 g, 80.75 mmol) was added and stirred at the same temperature for 2 h. Work-up (H2O/AcOEt) and purification afforded the title compound (3.03 g). 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.24 (d, J 2.6, 1H), 8.51 (dd, J 2.6, 9.9, 1H), 8.10 (d, J 9.2, 1H), 5.72 (s, 1H), 2.90-2.75 (m, 1H), 1.99-1.90 (m, 1H), 1.06-0.93 (m, 4H), 0.82-0.64 (m, 4H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[C:17]([Cl:20])(=[O:19])[CH3:18]>C(#N)C.C(OCC)C>[ClH:20].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:17](=[O:19])[CH3:18])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)Nc1ccc(NC2=NCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 1.0 g (3.8 mmole) of the product compound of Example 9 and 30.5 mmole of acetyl chloride in 40 ml of acetonitrile was stirred at room temperature for 18 to 20 hours. The reaction mixture was then diluted eight-fold with diethyl ether. The resultant solid was collected and washed with three portions of ether, then dried in a high vacuum over 5A molecular sieves, giving the title compound as the hydrochloride salt. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 59.1 using 6-bromopicolinic acid and 4-(trifluoromethoxy)aniline to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.27 min, m/z=361.0/363.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=O)[O:5][C:6](=[O:8])[CH:7]=1.Cl.Cl.[NH2:14][NH2:15]>O>[F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:5])[NH:14][NH:15][C:6](=[O:8])[CH:7]=1
Reactant: O=C1C=C(C(F)(F)F)C(=O)O1
Reactant: NN
Agent: Cl
Solvent: O
Product: O=c1cc(C(F)(F)F)c(=O)[nH][nH]1
Reaction time: 4 h
Yield: 4.6 %

Procedure:
3-Trifluoromethylfuran-2,5-dione (5 g) was introduced in portions into an already boiling solution of hydrazine dihydrochloride (3.2 g) in water (50 ml). After stirring for 4 h, the mixture was left to stand overnight; the next day, the mixture was refluxed for a further 8 h and left to stand overnight. Then it was dried and the residue was purified by means of preparative chromatography (met. C). The clean fractions were combined, the ACN was drawn off and the residue was freeze-dried. 250 mg of the title compound were obtained. LC-MS rt: 0.23 min
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.C([N:23](C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.N>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH2:23])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
Suspend Boc-(L)-Pal-OH (1.34 g, 5 mmol) in methylene chloride (50 mL) and cool to -15° C. Add diisopropylethylamine (963 μl, 5.5 mmol) and isobutylchloroformate (715 μL, 5.5 mmol). Stir the mixture 15 minutes at -15° C. Pass through the solution a vigorous stream of anhydrous ammonia (over solid sodium hydroxide) for about 3 minutes. Stir the mixture 10 minutes at -15° C. and 20 minutes at room temperature. Evaporate methylene chloride, add ethyl acetate (70 mL) and wash with saturated aqueous solution of sodium bicarbonate. Dry over magnesium sulfate and evaporate. Crystallize from ethyl acetate/hexane to give Boc-(L)-Pal-NH2 (0.98 g, 75%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=[O:10].[CH3:12][C:13](=[CH2:16])[CH2:14][OH:15]>CC1C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>[CH3:3][C:2](=[CH2:1])[CH2:6][O:10][CH:9]([O:15][CH2:14][C:13]([CH3:12])=[CH2:16])[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]1([CH3:11])[CH3:1]
Reactant: C=C(C)CO
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: C=C(C)COC(CC1CC=C(C)C1(C)C)OCC(=C)C
Yield: 186.9 %

Procedure:
A 2 liter 3 neck flask equipped with a Dean-Stark trap, condenser, thermometer, mechanical agitator, and nitrogen inlet and outlet was charged with 392.5 g of 2,2,3-trimethylcyclopent-3-en-1-yl acetaldehyde at a purity of 88.9% (2.30 moles), 415 g of 2-methyl-2-propen-1-ol (5.64 moles), 0.2 g of p-TSA and 1 liter of heptane. The contents were brought to reflux and 43 ml of water were collected. The batch was cooled and washed with 2×250 ml of 10% sodium hydroxide. The batch was dried (MgSO4), filtered and concentrated in vacuo to yield 671 g of crude 2,2,3-trimethylcyclopent-3-en-1-yl acetaldehyde bis-(2-methyl-2-propenyl) acetal. BP 88° C./1.0 mmHg; 1H-NMR (300 MHz), δ 0.76 (3H, s), 0.98 (3H, s), 1.58 (1H, m), 1.61 (3H, s), 1.76 (6H, s), 1.86-2.0 (3H, m), 2.31 (1H, br s), 3.88-4.04 (4H, m), 4.65 (1H, m), 4.87 (2H, s), 4.89 (2H, s), 5.22 (1H, s); 13C-NMR (75 MHz), δ 12.74, 19.87, 19.91, 25.71, 33.98, 35.88, 46.20, 47.10, 69.00, 69.72, 102.28, 112.27, 112.35, 122.36, 142.84, 148.98; IR (Neat), 1130, 1000 cm-1 ; MS (m/e), 206 (M+ -72), 108 (Base); The crude acetal, with 3 g of citric acid added, was distilled through a 10" saddle packed column at a pressure of 115 mmHg. A total of 185.6 g of lights was distilled out between 68°-115° C. The batch was now heated under nitrogen at 160° C. for 3 hours. The batch was now distilled to afford 320.1 g of purified product (74% yield). BP 81° C./0.4 mmHg; 1H-NMR (300 MHz), δ 0.88 (3H, s), 0.96 (3H, s), 1.59 (3H, s), 1.71 (3H, s), 1.9-2.4 (5H, m), 2.65 (1H, m), 4.71 (1H, s), 4.76 (1H, s), 5.24 (1H, s), 9.49 (1H, d, J=5.43 Hz); 13C-NMR (75 MHz), δ 12.64, 20.26, 22.67, 26.34, 34.19, 37.57, 47.24, 50.47, 52.29, 113.20, 121.39, 143.01, 149.47, 205.82; IR (Neat), 3080, 3050, 2950, 2715, 1730, 1655 cm-1 ; MS (m/e), 206 (M+), 108 (Base);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH:6]([NH:21]C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH:6]([NH2:21])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-butyric acid ethyl ester (300 mg, 0.718 mmol) in THF (10 ml) at −78° C. is added LiHMDS/THF (1M) (1.579 ml, 1.579 mmol). The reaction mixture is stirred at −78° C. for 50 min and then to this mixture is added methyl iodine (0.054 ml, 0.861 mmol) and the reaction is slowly warmed up to room temperature and stirred over night. The reaction is quenched by sat. NH4Cl and is extracted with EtOAc. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. Reverse phase HPLC [20 to 90% ACN—H2O (0.1% TFA) over 10 min by Sunfire C18] give (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester. LCMS (condition B): 432 (M+1); retention time=1.55 min. To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester (240 mg, 0.556 mmol) in DCM (2 ml) at room temperature was added TFA (1.070 ml, 13.89 mmol) and the mixture is stirred at room temperature. 1 hr the reaction is done so the mixture is concentrated to give (R)-3-amino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester trifluoroacetate. LCMS (condition B): 332 (M+1); retention time=1.00 min.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])C.[H-].[Na+].C(O)C.Cl>C1(C)C=CC=CC=1>[O:5]=[C:4]1[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2
Reactant: CCOC(=O)CCCOc1ccccc1C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2ccccc2C1=O
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of ethyl 4-(2-ethoxycarbonylphenyloxy)-butyrate (13.0 g, 46.4 mmol), 60% sodium hydride (5.56 g, 139 mmol), ethanol (2.5 ml) and toluene (250 ml) was stirred at 80-85° C. for 2 hours. The reaction mixture was poured into cold 1N hydrochloric acid and extracted twice with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; ethyl acetate:n-hexane=3:97) to obtain 9.05 g of ethyl 1,2,3,4-tetrahydro-5-oxo-benz[b]oxepine-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][NH:30][CH:31]3[CH3:34])=[CH:26][CH:25]=2)=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][C:24]([C:19]5[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=5)=[CH:25][CH:26]=4)[CH:31]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ncc(-c2ccc3c(c2)C(C)NCC3)c(OC)n1
Product: COc1ncc(-c2ccc3c(c2)C(C)N(C(=O)c2cc4ncc(Cl)cn4n2)CC3)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:20]=1)(OC(C)(C)C)=O.[ClH:26]>C(Cl)Cl.CCOCC>[ClH:26].[ClH:26].[CH3:25][O:24][CH2:23][CH2:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:16]=[N:17][CH:18]=1
Reactant: COCCOc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOc1cncc(OC[C@@H]2CCCN2)c1
Reaction time: 2 h

Procedure:
To 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-methoxyethoxypyridine from step 197e (480 mg, 1.36 mmol) in CH2Cl2 at 0° C. was added a solution of HCl in Et2O, and the solution was stirred for 2 h. The solvent was removed and the residue was recrystallized from EtOH/Et2O to afford the title compound (215 mg): mp 182-184° C.; [α]25D +22.8° (c 0.56, MeOH); 1H NMR (D2O, 300 MHz) δ 1.98 (m, 1H), 2.00-2.06 (m, 2H), 2.25 (m, 1H), 3.00 (m, 1H), 3.05 (s, 3H), 3.65 (t, 2H, J=6.0 Hz), 3.85 (t, 2H, J=6.0 Hz), 4.15 (m, 1H), 4.30-4.35 (m, 2H), 4.52 (m, 1H), 7.15 (t, 1H, J=3.0 Hz), 8.02 (br s, 2H); MS (CI/NH3) m/z 253 (M+H)+, 279 (M+NH4)+ ; Anal. Calcd for C13H20N2O3.2.1 HCl: C, 47.48; H, 6.77; N, 8.52. Found: C, 47.56; H, 6.83; N, 8.51.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[OH:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32]>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]3[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=3)=[CH:18][C:17]=2[O:23][CH2:27][C:28]2[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(O)cc2O)CC1
Reactant: N#Cc1cccc(CBr)c1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(OCc3cccc(C#N)c3)cc2OCc2cccc(C#N)c2)CC1
Yield: 53.4 %

Procedure:
[4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester (0.85 g, 2.42 mmol) and 3-bromomethyl-benzonitrile (1.89 g, 9.68 mmol) and other reagents as described in Example 75(a) were used to afford 0.75 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 1.75 (4H, m), 3.15 (1H, m), 3.65 (2H, m), 4.55 (1H, m), 5.25 (4H, s), 6.72 (2H, m), 6.9 (1H, s), 7.7 (6H, m), 7.85 (4H, m), 7.94 (1H, s), 8.04 (1H, s).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH:49]([CH3:51])[CH3:50])[C:42](Cl)=O>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]3[N:19]=[C:42]([C:41]4[CH:45]=[CH:46][C:47]([O:48][CH:49]([CH3:50])[CH3:51])=[C:39]([Cl:38])[CH:40]=4)[O:21][N:20]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCOC(=O)CC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.3 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 19; 264 mg, 0.629 mmol) in dioxane (4 ml) was added triethylamine (0.263 ml, 1.89 mmol) followed by dropwise addition of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 33; 176 mg, 0.755 mmol) in dioxane (2 ml). The resulting mixture was stirred at room temperature for 90 min, followed by heating at 100° C. for 24 h. The mixture was cooled to room temperature, most of the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography, eluting with 5-25% ethyl acetate in cyclohexane, gave the title compound as a pale yellow oil (80 mg).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:17][CH2:16]1.C([O-])(=O)C.[Na+]>O>[CH3:11][O:10][C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:19][CH2:20]1)=[O:9]
Reactant: COC(=O)c1ccccc1N
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccccc1NCCN1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A mixture of 0.93 g of methyl anthranilate, 2 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine, 0.88 g of sodium acetate and 5 mL of H2O was stirred for 24 h at reflux. After cooling at room temperature, the mixture was extracted with EtOAc, the organic phase dried on Na2SO4, evaporated to dryness and the residue purified via flash chromatography (CH2Cl2-MeOH 98:2) giving 0.41 g (18%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10](=O)[CH2:11][C:12]([O:14]CC)=O)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:29][C:30]1[NH:34][N:33]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[N:31]=1>CCCCO>[NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[NH:29][C:30]4[N:34]([N:33]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[N:31]=4)[C:12](=[O:14])[CH:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CCOC(=O)CC(=O)c1ccc2nn[nH]c2c1
Reactant: COC(=O)c1n[nH]c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: COC(=O)c1nc2[nH]c(-c3ccc4nn[nH]c4c3)cc(=O)n2n1
Temperature: 130 °C
Reaction time: 20 h
Yield: 36.5 %

Procedure:
To a solution of ethyl 3-(1H-benzo[d][1,2,3]triazol-6-yl)-3-oxopropanoate (246 mg, 1.5eq) in n-BuOH (5 ml) was added TsOH (10 mg, 0.1eq) and methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (100 mg, 1.0 eq), and the reaction mixture was stirred for 20 h at 130° C. The solids were collected by filtration and washed with methanol (10 ml) to afford methyl 5-(1H-benzo[d][1,2,3]triazol-6-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-α]pyrimidine-2-carboxylate (80 mg, 60%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19].[C:20](OCC)(OCC)(OCC)[CH3:21].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=[C:20]1[CH3:21]
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCCCCCCl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2cnc3ccccc3c2n1CCCCCCCl
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
N4-(6-Chlorohexyl)quinoline-3,4-diamine (5 g, 18 mmol), triethyl orthoacetate (2.92 g, 18 mmol), toluene (75 mL), and a catalytic amount of pyridine hydrochloride were combined in a pressure vessel and heated to 140° C. After about 1.5 hours the reaction mixture was allowed to cool and then it was concentrated under reduced pressure to provide 3.8 g of 1-(6-chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinoline as a dark orange oil.