Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:22][CH3:23])[C:13]([CH2:27][CH2:28][OH:29])([CH2:24][CH2:25][OH:26])[C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][O:22][C:18]1[C:19]2[S:20][C:21]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][CH3:6])[C:13]([CH2:24][CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:27][CH2:28][O:29][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1Sc1c(OC)cccc1C2(CCO)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1Sc1c(OC)cccc1C2(CCOS(C)(=O)=O)CCOS(C)(=O)=O

Procedure:
Methanesulphonyl chloride (1.71 ml.) is added dropwise over 5 minutes at 5° C. to a solution of 4,5-dimethoxy-9,9-bis(2'-hydroxyethyl)thioxanthene (3.46 g.), and triethylamine (4.18 ml.) in dry methylene chloride (70 ml.) with stirring. The mixture is stirred for 15 minutes, diluted with methylene chloride (70 ml.) and washed successively with water, 10% aqueous HCl, a saturated solution of NaHCO3 and brine. The solution is dried over MgSO4 and evaporated to dryness. The solid residue is recrystallised from ethanol to give 4,5-dimethoxy-9,9-bis(2'-methanesulphonyloxyethyl)thioxanthene, m.p. 176°-178° C.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:6]([C:7]([O:9]C)=O)[CH:5]=1.[CH2:18]([CH2:20][NH2:21])[OH:19]>CO>[OH:19][CH2:18][CH2:20][NH:21][C:7]([C:6]1[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:4]([C:3]([NH:21][CH2:20][CH2:18][OH:19])=[O:17])[CH:5]=1)=[O:9]
Reactant: NCCO
Reactant: COC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Solvent: CO
Product: O=C(NCCO)c1cc(C(=O)NCCO)cc([N+](=O)[O-])c1
Yield: 67.3 %

Procedure:
A solution containing dimethyl-5-nitroisophthalate (23.9 g, 100 mmol) and ethanolamine (13.4 g, 220 mmol) in methanol (300 mL) was refluxed for 48 hours. The solvent was removed by evaporation under reduced pressure. The crude product was purified by crystallization from EtOAC:MeOH 1 ml v/v) to afford 20.0 g of pure N,N′-bis(2-hydroxyethyl)-5-nitro-1,3-benzenedicarboxamide as white crystals. m.p.=151.3-151.4° C., uncorrected
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:33])=[C:26]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)[CH:27]=2)OC1>>[F:33][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[N:28]1[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: CC1(C)COB(c2ccc(F)c(-n3cccn3)c2)OC1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-n1cccn1
Yield: 39 %

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b)(1,2,4]triazine was coupled with 1-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]-1H-pyrazole as described in Example 3, step f, final paragraph, to give 41 mg (39%) of the title compound: 1H NMR (360 MHz, DMSO-d6) δ 6.63 (1H, t, J 2.1 Hz), 7.74 (1H, dd, J 8.7, 11.2 Hz), 8.23 (1H, ddd, J 2.1, 4.2, 8.7 Hz), 8.31 (1H, t, J 2.8 Hz), 8.71 (1H, dd, J 2.5, 7.7 Hz), 9.00 (1H, s), 9.41 (1H, s); MS (ES+) m/z 349 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([CH3:25])[N:9]3[C:14](=[O:15])[NH:13][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH3:24])=[N:11][C:10]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][S:27](O)(=[O:29])=[O:28]>ClCCl>[CH2:23]([O:22][C:17]1[CH:18]=[CH:19][C:20]([S:27]([Cl:26])(=[O:29])=[O:28])=[CH:21][C:16]=1[C:12]1[NH:13][C:14](=[O:15])[N:9]2[C:8]([CH3:25])=[N:7][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:10]2[N:11]=1)[CH3:24]
Reactant: CCOc1ccccc1-c1nc2c(C3CCCC3)nc(C)n2c(=O)[nH]1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(C3CCCC3)nc(C)n2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
372.3 mg (1.1 mmol) of 8-cyclopentyl-2-(2-ethoxy-phenyl)-6-methyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one (example IX) are added in portions to 0.66 ml (9.9 mmol) of ice-cooled chlorosulfonic acid. The mixture is subsequently stirred overnight at room temperature before being diluted with dichloromethane and poured onto ice water. The organic phase is separated off. The aqueous phase is extracted once again with dichloromethane and the organic phases are combined, dried and evaporated.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:14][C:5]1[C:4]2[C:9](=[CH:10][N:11]=[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cnc2cnc(Cl)cc2c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc2c(O)c(C#N)cnc2cn1
Temperature: 120 °C

Procedure:
To 1 g of 6-chloro-4-hydroxy-[1,7]naphthyridine-3-carbonitrile in 5 mL each dimethyl formamide and triethyl amine was added 1 g triphenyl phosphine, 7 mL of trimethylsilanylethyne, and 225 mg of palladium (II) acetate. The reaction was heated at 120° C. for 18 hours, stripped of solvent, and purified by flash chromatography on silica gel with a methanol/chloroform gradient. Recrystallization from ethanol containing a small amount of water yielded 690 mg of 4-hydroxy-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile: melting point 307° C. (decomposed); mass spectrum (m/e): M+H 268.0.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH3:29])[S:5][C:6]=1[CH:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)[OH:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:28]([CH3:29])[C:4]2[S:5][C:6]([C:7]([C:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)=[O:8])=[CH:2][N:3]=2)=[CH:32][CH:33]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(C)Cc3ccc(Cl)cc3)nc2Cl)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(Cc1ccc(Cl)cc1)c1ncc(C(=O)c2c[nH]c3ncccc23)s1
Temperature: 40 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
A mixture of {4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (552, 1 g, 2 mmol), triethylsilane (2 mL, 12 mmol), and trifluoroacetic acid (1 mL, 13 mmol) in acetonitrile (10 mL) was stirred at 40° C. for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate and brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid (P-0178, 0.17 g, 30%). MS (ESI) [M+H+]+=383.09.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.O[CH2:52][C:53]([N:55]([CH3:57])[CH3:56])=[O:54]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:52][C:53](=[O:54])[N:55]([CH3:57])[CH3:56])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: CN(C)C(=O)CO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 3c from 100 mg (0.15 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 16 mg (0.16 mmol) 2-hydroxy-N,N-dimethyl-acetamide. After purification by HPLC the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(OCC)C)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]=[O:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:45](O)[CH2:46][OH:47].C([O-])(O)=O.[Na+].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]3[O:20][CH2:45][CH2:46][O:47]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCO
Reactant: CCCCc1nc2cc(-c3ccccc3)c(C=O)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCc1nc2cc(-c3ccccc3)c(C3OCCO3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 84.9 %

Procedure:
0.1 g(0.000169 mole) of the aldehyde compound obtained in step 11 of Example 1 and 0.032 g(0.000507 mole) of ethylene glycol were dissolved in 5 ml of benzene and to the resulting solution was added 0.01 mg of p-toluenesulfonic acid. The resultant was refluxed for 6 hours and thereto were added 1 ml of aqueous saturated NaHCO3 solution and 5 ml of water. The reaction solution was extracted with ethyl acetate(5 ml×3) and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resultant was recrystallized from hexane-methylene chloride to obtain 80 mg of the title compound(yield 85%).
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH2:7])=O)[CH2:4][CH2:3]1.C1([C:11]2[N:15](C)[C:14]([CH:17]=[O:18])=[CH:13]N=2)CC1>>[CH3:11][N:15]1[C:14]([CH:17]=[O:18])=[CH:13][N:7]=[C:5]1[C:2]1([CH3:1])[CH2:4][CH2:3]1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: CC1(C(N)=O)CC1
Product: Cn1c(C=O)cnc1C1(C)CC1

Procedure:
3-Methyl-2-(1-methyl-cyclopropyl)-3H-imidazole-4-carbaldehyde was prepared from 1-methyl-cyclopropyl carboxamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6]([CH2:9]Br)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6]([CH2:9][NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(CO)CO
Reactant: BrCc1noc2cc(Br)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCC(CO)NCc1noc2cc(Br)ccc12
Yield: 24.5 %

Procedure:
A solution of 6-bromo-3-bromomethyl-1,2-benzisoxazole (Intermediate 1, 130 mg), serinol (50 mg) and DIPEA (0.05 ml) in DMF (0.2 ml) was stirred at 60° under nitrogen for 3 h. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried through a hydrophobic filter and concentrated. The residue was purified on a Varian Bond Elut SPE cartridge (silica, 2 g) eluting with dichloromethane followed by dichloromethane-methanol (9:1) to give the title compound as a yellow gum (33 mg).
Reaction SMILES: CSC.[Cl-].[Al+3].[Cl-].[Cl-].C[O:9][C:10]([CH2:12][CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14]1)=[O:11].Cl>ClCCl>[C:10]([CH2:12][CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:42])[C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:30]=2)[CH2:16][CH2:15][CH2:14]1)([OH:11])=[O:9]
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)COc3ccccc3)cc2)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CSC
Solvent: ClCCl
Product: O=C(O)CC1CCCN(C(=O)c2ccc(NC(=O)COc3ccccc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To dimethylsulfide (170 ml) is added dropwise with stirring aluminum chloride (23.6 g) under ice-cooling, and further thereto is added dropwise a solution of 5-methoxycarbonylmethyl-1-[4-(2-phenoxyacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (16.76 g) in dichloromethane (150 ml), and the mixture is stirred at room temperature for two hours. The reaction mixture is poured into a mixture of conc. hydrochloric acid and crashed ice, and the mixture is extracted with dichloromethane. The organic layer is washed with water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=30:1) to give 5-carboxymethyl-1-[4-(2-phenoxyacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (13.67 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 53 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (s, 1H), 7.49 (br s, 1H), 7.28–7.21 (m, 10H), 6.91 (m, 1H), 4.77 (s, 1H), 3.38 (dd, 2H, J=6.0, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.46 (m, 1H), 2.41 (t, 2H, J=6.0 Hz), 2.31 (t, 2H, J=7.2 Hz), 1.96 (dt, 2H, J=1.6, 12.0 Hz); 1.82–1.66 (m, 6H), 1.58–1.54 (m, 2H), 0.98 (t, 3H, J=7.6 Hz); ESMS m/e: 566.3 (M+H)+.
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:11]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=C(CF)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CN1CCOCC1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 2-fluoroacetophenone (19.9 g), morpholine (21 cc) and potassium carbonate (27.6 g) in dimethyl sulphoxide (32 cc) is heated at 110° C. for 30 hours. The reaction mixture is diluted with water (100 cc) and extracted with ethyl acetate (4×100 cc); the organic solution is washed with distilled water (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 9 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 250 cc fractions. Fraction 24 to 44 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2-(4-Morpholinyl)acetophenone (4.72 g) is obtained which is used as such for the subsequent syntheses.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]=[C:11]=[O:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.ClCCl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:12]
Reactant: O=C=Nc1c(F)cc(Cl)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2c(F)cc(Cl)cc2Br)CC1

Procedure:
1-Bromo-5-chloro-3-fluoro-2-isocyanatobenzene (D6) (4.4 mmol, 1.1 g) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 4.4 mmol, 0.88 g) were mixed together. Dichloromethane (5 ml) was added to the mixture at room temperature for 1 hour. THF (5 ul) was added at room temperature for one hour. Solvent was subsequently evaporated and the crude obtained was purified by chromatography to afford the title compound, 0.6 g, 30%.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)=[N:4][CH:5]=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Product: N#Cc1ccc(-c2cc(C(=O)N[C@@H]3CCCC[C@H]3O)cnc2OCC2CC2)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31, using 5-bromo-6-cyclopropylmethoxy-N-(trans-2-hydroxy-cyclohexyl)-nicotinamide and 4-cyanophenylboronic acid (commercially available) as starting materials. MS (ISP): 392.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[NH:27][CH:26]=1>>[NH:22]1[C:21]2[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]3[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[CH:5][C:4]=2[N:1]=[C:34]1[C:32]1[CH:31]=[CH:30][C:29]2[NH:25][CH:26]=[N:27][C:28]=2[CH:33]=1
Reactant: O=Cc1ccc2nc[nH]c2c1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5[nH]cnc5c4)nc3c2)cc1

Procedure:
Compound 187 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and benzimidazole-5-carboxaldehyde. [M+H]+ calcd for C23H20N6O: 397.17; found: 397.52.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH3:11].C(OCC)C>O>[C:2]([O:6][N:7]=[C:10]([CH2:9][Cl:8])[CH3:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(CCl)=NOC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.51 g of O-tert-butylhydroxylamine hydrochloride, 0.93 g of chloroacetone, and 10 ml of diethyl ether is stirred at room temperature for 3 hours, poured into water, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which affords chloroacetone O-tert-butyloxime.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of compound 99 (0.35 g, 0.776 mmol) was treated with 20% TFA in CH2Cl2 (20 mL) at 0° C. and stirring was continued for 1 h at the same temperature. The solvent was evaporated and crude was diluted with 10% aq. NH3 (15 mL) and product was extracted into CH2Cl2 (3 20 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 100 (0.2 g, 74%) as a solid. mp 167-169° C.: 1H NMR (DMSO-d6) δ: 1.39-1.47 (m, 2H), 1.88-1.96 (m, 3H), 2.33 (s, 3H), 2.40-2.46 (m, 1H), 2.57-2.61 (m, 1H), 6.01 (s, 1H), 6.19 (brs, 2H), 6.65 (dd, 1H, J=1.5, 8.2 Hz), 7.09 (dd, 1H, J=4.2, 4.9 Hz), 7.20 (s, 1H), 7.28-7.31 (m, 2H), 7.59 (d, 1H, J==4.2 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.87 (s, 1H); ESI-MS m/z (%): 351 (MH+, 66), 320 (54), 160 (63), 119 (100); ESI-HRMS calculated for C20H23N4S (MH+), Calculated: 351.1654. Observed: 351.1637.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1CCCCC1.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:15]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:16]([CH3:17])[C:18](=[O:25])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]2[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n(C)c1=O
Yield: 73.1 %

Procedure:
A mixture of 5-chloro-2-methylaminobenzophenone (1.23 g), diethyl malonate (1.6 g) and piperidine (0.1 ml) was heated for 3 hours at 170°-180° C. After cooling, the mixture was treated with isopropyl ether to give crystals, which were recrystallized from ethanol to afford ethyl 6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylate (1.25 g, 73.1%). mp 124°-125° C. The product was identical with the compound obtained in Reference Example 12.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:29])([F:28])[F:1])[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4C(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:33][CH2:32][CH2:30][OH:31])=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: NCCO
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(NCCO)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(2-hydroxy-ethyl-amino)-nicotinamide was prepared starting from intermediate E and ethanolamine. MS calcd. for C24H21ClN4O3 [(M+H)+] 449.1, obsd. 449.0.