Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 51 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-hexyl chloroformate. Yield: 51% of theory, C34H41N7O5 (627.8); Rf value: 0.53 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=628; (M+H+Na)++=325.7; (M+2H)++=314.7.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[N:12]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:11]=2)=[CH:6][CH:5]=1
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
At 0° C., NaH (60 percent, 0.48 g, 12.0 mmol) was added to a THF solution (15 mL) containing 6-(4-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.1 g, 9.7 mmol). Then SEM-Cl (90 percent, 2.4 mL, 12 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.0 g, 6.7 mmol) as brown solid in 69% yield.
Reaction SMILES: [H-].[K+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH2:18](Br)[CH:19]=[CH2:20].C(O)(=O)C>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH2:20][CH:19]=[CH2:18])[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(C(=O)OC)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 35% potassium hydride oil suspension (6.04 g, 35% w/w/, 53 mmols of potassium hydride) in 240 mL of sieve dried tetrahydrofuran was cooled to 0° C. The cold mixture was treated with homoterephthalic acid dimethyl ester (10.0 g, 48 mmols). The mixture was stirred at 0° C. for one hour. Allyl bromide (6.41 g, 53 mmols) was added and the mixture was stirred at 0° C. for 30 minutes, then at room temperature for 16 hours. The resulting mixture was treated with 4.8 mL of 50% acetic acid, then poured into 480 mL of water. The mixture was extracted with ether (2 ×250 mL). The ether extracts were combined, dried over magnesium sulfate, and concentrated to a brown oil. Chromatography on 250 g of flash silica gel (10% ether in hexane eluent) gave the product IV-1a as a pale yellow oil, 10.5 g (89% yield).
Reaction SMILES: [CH:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1(=O)CCCCC1>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[CH:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)C=CC=Cc1ccccc1
Solvent: O=C1CCCCC1
Product: C=CC(=O)O
Product: C=Cc1ccccc1

Procedure:
styrene-acrylic acid copolymer resin (Mw=3,100, solid acid value=108, manufactured by Johnson Polymers Ltd.) dissolved in cyclohexanone; solid content=60%, solid equivalent=519 g/eq, refractive index=1.55
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]1[C:18]([NH2:20])=[O:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]1[C:18]([NH2:20])=[O:19]
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](CN=[N+]=[N-])[C@H]1C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CC[C@@H](CN)[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A mixture of (2S,3S)-3-azidomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Stage 36.3) (0.723 mmol) and triphenylphosphine (0.867 mmol) in THF (3 mL) was stirred at rt for 25 h. The reaction mixture was concentrated to afford the crude title compound as a light brown solid. HPLC: tR 3.53 min (method H); ESI-MS: [M+H]+ 248.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:22][Si](C)(C)C)([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.CO.Cl>O>[OH2:22].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[Si](C)(C)OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: O
Product: OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
Yield: 186.9 %

Procedure:
A mixture of 7.50 g (0.02 mol) of 2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazole-1-yl)-2-(trimethylsilyloxy)propane, 25 ml of methanol, 2 ml of water and 1.0 ml of concd. hydrochloric acid was stirred at 30° C. for 1 h. The reaction mixture was concentrated to a volume of 10 ml and after adding 50 ml of water the pH of the hot solution was adjusted to 8 with 10% aqueous sodium hydroxide. After cooling the precipitated crystals were filtered off, and dried at 40° C. until the weight was constant to yield 6.06 g (93.5%) of the title compound. M.p.: 139–140° C.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[N:10]=2)=[CH:7][C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]1=2.[Cl:30]C1N=C(C2SC3C(Cl)=CC=CC=3C=2)C=CN=1.NCCCN1CCN(C)CC1>>[Cl:30][C:29]1[C:5]2[S:4][C:8]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[N:10]=3)=[CH:7][C:6]=2[CH:26]=[CH:27][CH:28]=1
Reactant: Clc1nccc(-c2cc3cccc(Cl)c3s2)n1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: CN1CCN(CCCNc2nccc(-c3cc4cccc(Cl)c4s3)n2)CC1

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 2-chloro-4-(7-chlorobenzo[b]thiophen-2-yl)pyrimidine and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a solid. ES+(m/z) 402 (35Cl) and 404 (37Cl) [M+H].
Reaction SMILES: [Cl-].[Cl-].[CH:3]1([Zr+2:12]C2C3C(CC=CC=3)CC2)[C:11]2[CH:6]([CH2:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[C:22]([OH:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[CH:3]1([Zr+3:12])[C:11]2[CH:6]([CH2:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)O
Reactant: C1=CCC2CCC([Zr+2]C3CCC4CC=CC=C43)C2=C1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)[O-]
Product: [Zr+3]C1CCC2CC=CC=C12
Yield: 75 %

Procedure:
To a solution of bis(tetrahydroindenyl)zirconium dichloride (1.182 g, 2.950 mmol) and pivalic acid (0.900 g,8.810 mmol) in toluene (45 ml) at 25° C. was added triethylamine (0.871 g, 8.610 mmol) with stirring. A white precipaitate formed immediately which was removed by filtration. The title compound was isolated as a pale-yellow powder in 75% yield by evaporating the solvent under vacuum. The title compound such prepared exhibit purity above 98% based on NMR results. 1H NMR (toluene-d8)δ 6.24 (t, J=3.1 Hz, 1H), 5.85 (d, J-3.1 Hz, 2H), 2.72 (m, 2H), 2.48 (m, 2H), 1.91 (m, 2H), 1.49 (m, 2H), 1.14 (s, 27H0. 13C NMR (toluene-d8) δ 200 and 197 (CO2), 114.4 and 114.1 (Cp), 39.2 (CMe3), 26.48 (CH3), 23.8 and 22.7 (CH2).
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].O>CCCCCC.C1(C)C=CC=CC=1>[CH3:18][C:8]1[CH:9]=[C:10]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]2=[N:12][C:7]=1[CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=1)[OH:25]
Reactant: COc1cccc(C=O)c1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cccc(C(O)c2nc3c(cc2C)CCCCC3)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 m,) in toluene (20 ml) at -20°, under nitrogen, was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl 5-H-cyclohepta[b]pyridine (6 g, 0.025 m) in toluene (30 ml). The reaction mixture was kept at -20° C. for 0.25 hours and then blown over into a cooled solution (-20° C.) of 3-methoxybenzaldehyde (3.7 g) in toluene (30 ml) and allowed to warm up to room temperature. Water was added and the organic phase separated and treated with 2N hydrochloric acid. A precipitate formed and this was collected by filtration and treated with sodium carbonate solution, then chloroform. The organic phase was washed with water, dried (MgO4) and evaporated. Trituration with diethyl ether gave 1-(6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyrid-2-yl)-1-(3-methoxyphenyl)methanol (4.42 g, 59%) m.p. 104°-6° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][NH2:33]>>[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([NH:33][CH2:32][C:28]1[O:27][CH:31]=[CH:30][CH:29]=1)=[O:17])(=[O:7])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NCc1ccco1)[C@@H]1CC(=CCl)CN1C(=O)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 2-furylmethylamine the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=345.6.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.CCCCCC>CCO>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:7]2[CH2:8][CH2:9][C:4]([S:3][CH3:2])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:6]2)=[N:29][CH:30]=1
Reactant: CCOC(=O)C1(SC)CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(SC)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
To a solution of ethyl 4-(methylthio)piperidine-4-carboxylate hydrochloride (0.17 g, 0.75 mmol) in EtOH (10.0 mL) was added DIPEA (0.60 mL, 3.75 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.18 g, 0.90 mmol). The reaction was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 3.0% EtOAc:hexane to obtain the desired product as a white solid (0.16 g, 60% yield). 1H NMR (DMSO-d6): δ 1.18 (t, J=7.20 Hz, 3H), 1.70 (m, 2H), 2.04 (s, 3H), 2.14 (m, 2H), 3.50 (m, 2H), 4.00 (m, 2H), 4.20 (q, J=7.20 Hz, 2H), and 8.46 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 84 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4-fluoroaniline (1 M in DMF) instead of methylamine, to the title compound (109 mg, 84%) which was obtained as a white solid. MS: m/e=404.4 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([C:32]([F:35])([F:34])[F:33])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[C:14]4[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17][C:15]=4[N:16]=[C:10]3[C@H:9]2[CH:29]([CH3:31])[CH3:30])=[N:6][CH:7]=1.[C:36]([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH:29]([C@H:9]1[N:8]([C:5]2[N:4]=[C:3]([C:32]([F:35])([F:33])[F:34])[C:2]([CH3:36])=[CH:7][N:6]=2)[CH2:13][CH2:12][N:11]2[C:14]3[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17][C:15]=3[N:16]=[C:10]12)([CH3:31])[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(Br)c(C(F)(F)F)n1)[C@@H]3C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C)c(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 120 °C
Yield: 56 %

Procedure:
A mixture of (R)-methyl 2-(5-bromo-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (7 mg, 0.012 mmol), Pd(PPh3)4 (1 mg, cat. Amount), 2M aq. K2CO3 solution (100 μL, excess), and dry 1,4-Dioxane (700 μL) was degassed and refilled with nitrogen gas for 3 times. A solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5 mg, excess) in dry 1,4-Dioxane (100 μL) was added. The mixture was heated in a microwave oven for 30 minutes at 120° C. After concentration, the residue was filtered and purified by Gilson to afford 3.5 mg (R)-methyl 1-isopropyl-2-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (56% yield). LC-MS: m/z 512.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=2)[N:3]=1.[CH2:19]([NH2:22])[CH:20]=[CH2:21]>O>[ClH:1].[CH2:19]([NH:22][C:2]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=2)[N:3]=1)[CH:20]=[CH2:21]
Reactant: CC(C)Nc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NC(C)C)c2cc([N+](=O)[O-])ccc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 870 mg (3.26 mmol) of 2-chloro-4-isopropylamino-6-nitroquinazoline was added 3.81 g (66.64 mmol) of allylamine, followed by stirring at room temperature for 4 hours. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 895 mg (yield: 95.7%) of a free base compound of the title compound.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].Cl.N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:28][CH:27]=[CH:26][CH:25]=2>N1C=CC=CC=1>[CH2:2]([C:3]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:20]=1)[CH3:1]
Reactant: Nc1cnc2ccccc2c1NCCCCO
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCO

Procedure:
Triethyl orthopropionate (15.1 mL of 97%, 1.1 eq.) and a catalytic amount of pyridine hydrochloride were added to a solution of 4-[(3-aminoquinolin-4-yl)amino]butan-1-ol (16 g, 69 mmol, 1 eq.) in pyridine (150 mL). The reaction mixture was refluxed for 1 hour at which time analysis by TLC indicated that all of the starting material had been consumed. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water (300 mL). The resulting solid was isolated by filtration and then recrystallized from ethyl acetate to provide 8.2 g of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol. A second crop (1.9 g) was obtained by reducing the volume of the mother liquor.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-:12].[Na+].C1(OCC[O:27][C:28]2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1>>[OH:11][C:2]1[C:3]([C:28]([OH:27])=[O:12])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: [OH-]
Reactant: c1ccc2c(OCCOc3cccc4ccccc34)cccc2c1
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 260 °C
Yield: 72 %

Procedure:
A stirred autoclave is charged with 1210 parts of β-naphthol, 620 parts of caustic soda solution (50% by weight strength) and 300 parts of 1,2-dinaphthoxyethane. As described in Example 4 the mixture is heated to an internal temperature of 260° C. while stirring and kept at this temperature for ten minutes. During this period the residual moisture is removed from the autoclave by applying 100 mm pressure. Dehydration is practically complete. Carbon dioxide is then introduced at the internal temperature of 260° C. up to a pressure of 7 atmospheres. After the absorption of carbon dioxide is completed the β-naphthol formed in the reaction is distilled off in vacuo. Further processing is carried out as in Example 5. 525 parts (72% of theory based on reacted β-naphthol) of 2-hydroxy-naphthalene-3-carboxylic acid is obtained with a melting point of 212° to 215° C.
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:10][CH2:9][CH2:8][C@H:7]([OH:11])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC[C@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H](O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of (S)-1-phenylpropane-1,3-diol (500 mg, 3.28 mmol) and triethylamine (399 mg, 3.94 mmol) in CH2Cl2 (5 mL) was added 4-methylbenzene-1-sulfonyl chloride (626 mg, 3.28 mol) slowly at 0° C., and the reaction mixture was stirred at rt for 2 h. The reaction solution was dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (576 mg, 57%). 1H NMR (400 MHz, CDCl3): δ=1.91-2.00 (m, 3H), 2.48 (s, 2H), 4.00 (m; 1H), 4.22 (m, 1H), 4.75 (m, 2H), 7.25-7.30 (m, 7H), 7.75 (d, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:5][CH:4]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28](O)=[O:29])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28](=[O:29])[NH:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Nc1cccc(-c2ccc(Cl)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(Cl)cc2)c1
Reaction time: 16 h
Yield: 99.5 %

Procedure:
4′-Chloro-biphenyl-3-ylamine hydrochloride (1 g, 4.16 mmol), Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.08 g, 5.00 mmol) and HATU (2.06 g, 5.41 mmol) were suspended in DMF (20 mL) and DIPEA (2.20 mL, 12.5 mmol) was added. The mixture was stirred for 16 hours before being diluted with ethyl acetate (250 mL) and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (25% to 45% EtOAc/hexanes) to provide 2-(4′-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.66 g, 99%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[N:8]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6]1)C.C[NH:29]N>CO>[CH3:1][N:2]1[CH:4]=[C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:27])[C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]2=[N:29]1
Reactant: CNN
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Solvent: CO
Product: Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2

Procedure:
A solution of 0.150 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one and 44 μl of methylhydrazine in 5 ml of methyl alcohol is heated at reflux for 18 hours. A precipitate forms on standing. The volaties are evaporated to a residue which is purified by column chromatography on silica gel by elution with 5% ethyl acetate-methylene chloride. The product fractions are combined and the volatiles evaporated to a residue which is dissolved in chloroform-methanol, filtered through glass wool and the filtrate evaporated in vacuo to give 0.110 g of the desired product as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH:17]=C1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
4-Nitrobenzaldehyde (1 g) was dissolved in methylene chloride (20 ml), and the reaction system was cooled to 0° C. The solution was added with carboethoxymethylenetriphenylphospholan (2.56 g) and stirred at 0° C. for 1 hour. The reaction system was concentrated-under reduced pressure without any treatment, and the residue was purified by silica gel column chromatography (50 g, hexane:ethyl acetate 4:1) to obtain ethyl 3-(4-nitrophenyl)acrylate(1.27 g, 86%).