Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][C:23]([OH:25])=O)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN=C=NCCCN(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][C:23]([N:30]3[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]3)=[O:25])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1CCNCC1
Reactant: O=C(O)CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC(=O)N2CCC(O)CC2)CC1
Reaction time: 4 h

Procedure:
A solution of 0.100 g (0.26 mmol) of 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionic acid (intermediate 5) and 0.032 g (0.31 mmol) of 4-hydroxypiperidine in 5 ml of dichloromethane was treated at 0° C. with 0.060 g (0.31 mmol) of EDCI. The cooling bath was allowed to come to RT and after 4 h the reaction was extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield after evaporation of the solvent 0.108 g (89%) of the titled compound as white solid. MS: 468.3 (MH+, 1Cl).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=4[F:37])[CH:24]=[C:23]([C:38]([F:41])([F:40])[F:39])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:37][C:28]1[CH:29]=[C:30]([C:33]([F:34])([F:36])[F:35])[CH:31]=[CH:32][C:27]=1[C:25]1[CH:24]=[C:23]([C:38]([F:39])([F:40])[F:41])[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.7 %

Procedure:
To a cooled and stirred solution of 3′-[4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.54 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.39 g, 72%). MS (ISP) 542.1 [(M+H)+]; mp 224.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.C1CCCCC=1.[ClH:25]>C(O)C.[Pd]>[ClH:25].[ClH:25].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]2=[O:13])=[CH:8][CH:9]=1
Reactant: O=C1NCCCCC1Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1ccc(NC2CCCCNC2=O)cc1
Yield: 81 %

Procedure:
2 g (8 mmol) of α-N-(4-nitrophenyl)amino-ε-caprolactam are partially dissolved in 40 ml of 95° ethanol in a 150 ml three-necked flask equipped with a thermometer and a reflux condenser. 2 g of palladium-on-charcoal (10% active and 50% moisture) are then introduced, followed by 20 ml of cyclohexene. The mixture is brought to reflux for 3 hours and is then cooled, before being filtered through celite. After having run approximately 6 ml (˜3.5 eq) of 5N hydrochloric acid onto the filtrate, the latter is evaporated to dryness and the residue is taken up in ethanol and precipitated from acetone. After filtration, 1.9 g of a white product are obtained, i.e. a final yield of 81%.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].N1C=CC=C(C=O)C=1.O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:28]=O)=O)=[CH:22][CH:21]=1.N.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[NH:38]C=C[N:41]=2)[CH:32]=1>CO.O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:41]=[C:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[NH:38][CH:28]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)C=O)cc1
Reactant: c1cncc(-c2ncc[nH]2)c1
Agent: CC(=O)[O-]
Agent: N
Agent: O=Cc1cccnc1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2c[nH]c(-c3cccnc3)n2)cc1
Reaction time: 8 h

Procedure:
A solution of sodium acetate trihydrate (5.8 g, 0.04 m), 3-pyridinecarboxaldehyde (2.3 g., 0.02 m), p-methoxyphenylglyoxal monohydrate (3.92 g., 0.02 m), water (20 ml.), concentrated aqueous ammonia (25 ml.), and methanol (75 ml.) is allowed to stand at room temperature overnight. The solution is concentrated to dryness under reduced pressure (20 mm) over steam, treated with saturated Na2CO3 (100 ml.) and extracted with chloroform (3 × 100 ml.). The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel (300 ml.) and the product eluted with 3-5% MeOH/CHCl3. The material is crystallized from acetonitrile to give 2.3 g. of 4-p-methoxyphenyl)-2-(3-pyridyl)imidazole of m.p. 184-186.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]1([N:6]2[C:10]3[C:11]([Br:16])=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrBr
Reactant: Nc1ccc2ncn(C3CCCC3)c2c1
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc2ncn(C3CCCC3)c2c1Br
Yield: 50 %

Procedure:
To a solution of 3-cyclopentyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.70 g (2.5 mmol, 50%) of the product.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:12]=2[N:11]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]>>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:3](=[O:28])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[N:14]([CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[C:13]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:12]=3[N:11]=2)=[C:31]([F:38])[CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: COC(=O)c1ccccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: N#Cc1ccc(NC(=O)c2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 85, from 2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-benzoic acid methyl ester and 4-amino-3-fluoro-benzonitrile (CAS Reg. No. 63069-50-1). Off-white powder (65%). MS (Turbo Spray): m/z=489.6 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](=[N:18]/[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])/[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:2]=1.[OH-].[Na+].Cl>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](=[N:18]/[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])/[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:2]=1
Reactant: CCOC(=O)CCCCO/N=C(/c1cccnc1)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCO/N=C(/c1cccnc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.2 %

Procedure:
A mixture of 4.3 parts of ethyl (E)-5-[[[(3-pyridinyl) [3-(trifluoromethyl)phenyl]methylen]amino]oxy]pentanoate, 25 parts of a sodium hydroxide solution 1N and 20 parts of ethanol was stirred for 2.5 hours at room temperature. 25 Parts of a hydrochloric acid solution 1N were added and the ethanol layer was evaporated. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and hexane (2:1 by volume). The product was filtered off and dried, yielding 1.7 parts (42.2%) of (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylen]amino]oxy]pentanoic acid; mp. 70.3° C. (compound 63).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH2:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1.C(OCC)(=O)C.CCCCCC>ClC(Cl)C.CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.CC(O)=O.CC(O)=O.[Ru]>[Cl:1][C:2]1[CH:10]=[C:9]([C@H:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])[N:7]=2)[CH:3]=1
Reactant: C=C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [Ru]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CCCCCC
Product: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 8 h

Procedure:
tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)vinyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (1 g, 1.62 mmol) was transferred to a parr bottle (pre-purged with nitrogen) and dissolved in dichloroethane (40 mL). The resulting solution was purged by bubbling nitrogen through it for 45 min. To the bottle was quickly added diacetato[(S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl]ruthenium(II) (233 mg, 0.259 mmol). The bottle was purged for 10 additional min, and quickly affixed to the parr shaker. After 3 vaccuum/pressurize cycles, the shaker was pressurized to 65 psi and shaken overnight. The crude reaction mixture was loaded onto a pre-conditioned column of 12% ethyl acetate/n-hexane. After several volumes, the polarity was increased to 25% ethyl acetate/n-hexane to give 850 mg (85%) as a viscous amber oil. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.5, 5.2 Hz, 2H), 7.03 (dd, J=8.9, 8.6 Hz, 2H), 6.77 (s, 1H), 5.67 (d, J=10.7 Hz, 1H), 5.64 (d, J=10.7 Hz, 1H), 4.93 (q, J=6.4 Hz, 1H), 3.72 (m, 2H), 3.59 (t, J=8.4 Hz, 2H), 3.37 (d, J=9.2 Hz, 1H), 3.34 (d, J=9.2 Hz, 1H), 3.05 (m, 2H), 2.19 (m, 1H), 2.08 (m, 1H), 1.94 (m, 1H), 1.87 (m, 1H), 1.44 (s, 9H), 1.43 (d, J=6.4 Hz, 3H), 0.91 (dd, J=9.2, 7.3 Hz, 2H), −0.06 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=245 Hz), 155.1, 145.6, 138.9, 135.8, 128.9 (d, J=7.7 Hz), 128.3, 122.82, 122.76, 122.2, 117.6, 115.2 (d, J=21 Hz), 81.9, 79.4, 77.9, 73.9, 67.6, 41.3, 40.3, 32.3, 32.0, 28.6, 22.8, 17.9, −1.4. Mass spec.: 618.39 (MH)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2([NH2:13])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([CH2:22][C:23](O)=[O:24])[CH2:15]2>>[N:14]12[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21]1)[CH:16]([CH2:22][C:23]([NH:13][C:10]1([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[CH2:12][CH2:11]1)=[O:24])[CH2:15]2
Reactant: CC(C)c1cccc(C2(N)CC2)c1
Reactant: O=C(O)CC1CN2CCC1CC2
Product: CC(C)c1cccc(C2(NC(=O)CC3CN4CCC3CC4)CC2)c1
Yield: 13.6 %

Procedure:
Using general procedure I, 1-(3-isopropyl-phenyl)-cyclopropylamine (278 mg, 1.58 mmol) and (1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (267 mg, 1.58 mmol) gave the title compound as a white solid (70 mg, 14%). 1H NMR (400 MHz, CD3OD) δ 7.16 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.97 (dd, J=19.2, 7.6 Hz, 2H), 3.16-3.23 (m, 1H), 2.79-2.97 (m, 5H), 2.51-2.58 (m, 1H), 2.23-2.41 (m, 3H), 1.83-1.92 (m, 1H), 1.68-1.81 (m, 3H), 1.54-1.62 (m, 1H), 1.15-1.25 (m, 10H) ppm. 13C NMR (400 MHz, CD3OD) δ 173.6, 148.5, 142.4, 127.8, 123.6, 123.1, 122.0, 73.0, 53.1, 46.6, 45.9, 39.3, 34.1, 32.3, 28.1, 26.4, 24.4, 19.7, 16.8 ppm. Purity: 96.9% HPLCMS (210 nm); retention time 2.55 min; (M+1) 327.
Reaction SMILES: [OH-].[K+].[CH3:3]S(C)=O.[OH:7][C:8]1[C:18]([OH:19])=[CH:17][C:11]2[S:12][C:13]([C:15]#[N:16])=[CH:14][C:10]=2[CH:9]=1.ICI>ClCCl.O>[O:7]1[C:8]2[CH:9]=[C:10]3[CH:14]=[C:13]([C:15]#[N:16])[S:12][C:11]3=[CH:17][C:18]=2[O:19][CH2:3]1
Reactant: CS(C)=O
Reactant: N#Cc1cc2cc(O)c(O)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ICI
Solvent: O
Product: N#Cc1cc2cc3c(cc2s1)OCO3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of powdered potassium hydroxide (12.36 g) and dimethylsulphoxide (100 ml) was stirred at room temperature for 5 min. then treated with 5,6-dihydroxy-benzo[b]thiophene-2-carbonitrile (5.26 g). After 1 minute di-iodomethane (4.4 ml) was added and the suspension was stirred at room temperature for 75 minutes, then more di-iodomethane (2.2 ml) was added. After a further 30 minutes the reaction was poured into water (500 ml) and extracted with ethyl acetate (2×100 ml). The organic extracts were combined, washed with 2M HCl and saturated brine, then dried and evaporated to give a brown crystalline residue. The crude product was suspended in hot dichloromethane (200 ml), filtered, and the filtrate was passed through a column of silica gel (0.2-0.5 mm, Merck, 25 g). The appropriate fractions were combined and evaporated to dryness to give a white solid (3.4 g). Crystallisation from acetone/ether afforded pure thieno[2,3-f]-1,3-benzodioxole-6-carbonitrile, m.p. 179°-180° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)(=[O:10])[CH3:9].[CH3:25][O:26][C:27](Cl)=[O:28]>O1CCCC1>[C:8]([C:11]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([O:24][C:27]([O:26][CH3:25])=[O:28])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)(=[O:10])[CH3:9]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c2ncccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1c([N+](=O)[O-])cc(C(C)=O)c2cccnc12

Procedure:
10.5 g of triethylamine are added to a solution of 23 g of 5-acetyl-7-nitro-8-hydroxyquinoline in 150 ml of tetrahydrofurane and 9.5 g of chloroformic acid methyl ester are slowly added dropwise to this mixture.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[OH-].[Na+].O.Cl>C(O)C>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:7])=[O:5])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc(Cl)c2ccccc2c1O
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 9.23 g of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (33 mmol), 90 ml of 2.5 N aqueous sodium hydroxide solution, water (20 ml) and ethanol (110 ml) was refluxed with stirring for 2 h. Then the pH of the mixture was adjusted to 2 by the addition of concentrated aqueous hydrochloric acid. During the addition the temperature of the mixture was kept at 20° C. by cooling with an ice bath. Stirring was then continued for 1 h before the solid component was separated by vacuum filtration. The filter cake was washed with water and dried in vacuo at 85° C. to give a white powder. 6.64 g of the title compound were obtained; MS-(+)-ion: M+1=224.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]#[N:16]>>[N:7]1([CH:4]2[CH2:5][CH2:6][N:1]([CH2:14][C:15]#[N:16])[CH2:2][CH2:3]2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: N#CCBr
Product: N#CCN1CCC(N2CCOCC2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Piperidin-4-yl-morpholine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=210.1: 1HNMR(DMSO-d6) 3.65 (s, 2H), 3.55 (t, 4H), 2.80-2.75 (m, 2H), 2.40 (t, 4H), 2.15-2.00 (m, 3H), 1.80-1.70 (m, 2H), 1.40-1.30 (m, 2H).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCc1ccccc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.250 g (1.566 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.33 g (1.7 mmol) of 6-phenylhexanoic acid and 0.87 ml (6.3 mmol) of triethylamine in 30 ml of dichloromethane, 0.36 ml (2.4 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([CH:13]=1)[C:8](=[NH:12])[O:9][CH2:10][CH3:11].O.OP([O-])(O)=O.[Na+].O.O.O.O.O.O.O.OP([O-])([O-])=O.[Na+].[Na+].[N:37]#[C:38]N>CC#N.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([CH:13]=1)[C:8](=[N:12][C:38]#[N:37])[O:9][CH2:10][CH3:11]
Reactant: CCOC(=N)c1cc(Cl)ccc1OC
Reactant: N#CN
Agent: Cl
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: CCOC(=NC#N)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of ethyl 5-chloro-2-methoxybenzimidate (1.3 g, 6.2 mmol, obtained after aqueous bicarbonate wash of Example 128C) in MeCN (2 mL) was added to a solution of sodium phosphate monobasic monohydrate (3.4 g, 24.7 mmol), sodium phosphate dibasic heptahydrate (3.3 g, 12.4 mmol) and cyanamide (0.52 g, 12.4 mmol) in water (20 mL). The reaction mixture was stirred at room temperature overnight and then extracted with dichloromethane (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue contained about 30% of starting material. The residue was reprocessed with half the amounts of the reagents to drive the reaction to completion and that yielded 1.32 g (90%) of the title compound. MS (ESI+) m/z 239 (M+H)+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)(C(C)(C)C)(C)C.[H-].[K+].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.ClCCl>CO>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[C:12]([CH:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)=[CH:13]2)=[CH:30][CH:29]=1
Reactant: CN1CCC(c2c[nH]c3ccc(O[Si](C)(C)C(C)(C)C)cc23)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2cn(Cc3ccc(F)cc3)c3ccc(O)cc23)CC1
Yield: 89.9 %

Procedure:
By a method similar to Preparation 32, using 5-(t-butyldimethylsilanyloxy)-3-(1-methylpiperidin-4-yl)-1H-indol (400 mg, 1.16 mmol), potassium hydride (139 mg of a 35% dispersion oil, 1.21 mmol) and 4-fluorobenzyl bromide (148 μL, 1.21 mmol), and chromatographic purification with a 9:1 mixture of dichloromethane and methanol provided 353 mg (90%) of the desired compound as an orange foam: 1H NMR (dmso-d6): 8.61 (s, 1H), 7.25-7.00 (m, 6H), 6.82 (d, 1H, J=2.0 Hz), 6.54 (dd, 1H, J=8.8, 1.6 Hz), 5.20 (s, 2H), 2.84 (br d, 2H, J=11.6 Hz), 2.62-2.50 (m, 1H), 2.19 (s, 3H), 2.01 (br t, 2H, J=11.0 Hz), 1.85 (br d, 2H, J=13.2 Hz), 1.62 (qd, 2H, J=12.0, 2.4 Hz). MS (APCI): m/e 339.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:4].S(Cl)(Cl)=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:40][CH3:41])=[C:24]([S:26]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=3)[CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:25]=1.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:4])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:12])[NH:39][C:36]2[CH:37]=[C:38]3[C:33]([CH2:32][CH2:31][CH2:30][N:29]3[S:26]([C:24]3[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[O:40][CH3:41])(=[O:28])=[O:27])=[CH:34][CH:35]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(N)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(=O)Nc2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-Methoxycarbonylmethyl-benzoic acid (52.00 mg, 0.27 mmol) was suspended in dichloromethane (2.00 mL) and treated with thionyl chloride (95.57 mg, 0.80 mmol). The mixture was stirred at 50° C. for 18 hours, and the volatiles were evaporated. The residue was redissolved in tetrahydrofuran (2.00 mL) and treated with 1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylamine (94.48 mg, 0.27 mmol) and 4-dimethylaminopyridine (66.76 mg, 0.54 mmol). The mixture was warmed to 75° C. and stirred for 2.5 hours. The mixture was treated with HCl 1 N and the slurry extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (dichloromethane/methanol gradient) to yield {4-[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylcarbamoyl]-phenyl}-acetic acid methyl ester as an off-white solid, 134.20 mg (95%), MS (ISP): m/e=529.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.Br[CH2:27][CH2:28][Cl:29]>>[CH3:1][C:2]1([CH3:25])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH:9]2[CH2:27][CH2:28][Cl:29])[CH:4]=[N:3]1
Reactant: ClCCBr
Reactant: CC1(C)N=CC2=C3N=C(CCc4ccccc4)N=C3C(=O)CC2C1=O
Product: CC1(C)N=CC2=C3N=C(CCc4ccccc4)N=C3C(=O)C(CCCl)C2C1=O

Procedure:
Prepared analogous to Example 23 at room temperature from 4.3 gm of 7,7-dimethyl-2-phenethyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 2.2 gm of 2-bromo-1-chloro-ethane. The viscous oily crude product was directly further processed.