Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(O[C:9](=[O:20])[NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([CH2:18][CH3:19])[CH:12]=2)=C(F)C(F)=C(F)C=1F.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]([CH2:45][CH2:46][CH3:47])[S:35]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:30][CH2:29]1>>[CH2:18]([C:13]1[CH:12]=[C:11]([NH:10][C:9](=[O:20])[NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([N:34]([CH2:45][CH2:46][CH3:47])[S:35]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])[CH2:30][CH2:29]2)[CH:16]=[C:15]([CH3:17])[N:14]=1)[CH3:19]
Reactant: CCCN(C1CCN(CCN)CC1)S(=O)(=O)c1ccc(F)cc1
Reactant: CCc1cc(NC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc(C)n1
Product: CCCN(C1CCN(CCNC(=O)Nc2cc(C)nc(CC)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (2-ethyl-6-methyl-pyridin-4-yl)-carbamic acid pentafluorophenyl ester (Example C13., 0.2M, 3 mL, 0.6 mmol) is added a solution of N-[1-(2-amino-ethyl)-piperidin-4-yl]-4-fluoro-N-propyl-benzenesulfonamide (Example B6., 182 mg, 0.53 mmol). The mixture is stirred at r.t. for 15 h. The mixture is evaporated and the residue purified by HPLC to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].F[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[OH:6][CH2:5][CH2:4][CH2:3][O:7][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: OCCCO
Reactant: Oc1ncnc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCOc1ccc2c(O)ncnc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Sodium hydride (14.6 g, 365 mmol) was added at 0° C. to a solution of 1,3-propanediol (27.8 g, 365 mmol) in dimethylformamide (70 ml). 7-Fluoroquinazolin-4-ol (10 g, 60.9 mmol) was added portion wise and the reaction mixture heated at 60° C., then at 110° C. for 3 hours. The reaction was cooled to 0° C., quenched with water (280 ml) and adjusted to pH 5.9. The resulting suspension was filtered, washed with water then diethyl ether and dried over phosphorus pentoxide to yield 7-(3-hydroxypropoxy)quinazolin-4-ol as a white powder (12.41 g, 92% yield):
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](F)=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH:26]([CH3:28])[CH3:27])[N:18]=1)[CH:14]=[C:13]([C:29]([OH:31])=[O:30])[C:12]2=[O:32].Cl.Cl.[NH2:37][CH:38]1[CH2:41][NH:40][CH2:39]1.CN1CCCC1>C(O)C>[NH2:37][CH:38]1[CH2:41][N:40]([C:8]2[C:7]([Cl:6])=[C:16]3[C:11]([C:12](=[O:32])[C:13]([C:29]([OH:31])=[O:30])=[CH:14][N:15]3[C:17]3[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH:26]([CH3:27])[CH3:28])[N:18]=3)=[CH:10][C:9]=2[F:33])[CH2:39]1
Reactant: NC1CNC1
Reactant: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To 160 mg of N,N-dimethylformamide were added 55 mg of 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 35 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 80° C. for 30 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 51 mg of the title compound as a colorless powder.
Reaction SMILES: Cl[B:2]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)C>[CH:12]1([B:2]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:11]=[CH:10][CH:9]=[CH:17]1
Reactant: ClB(c1ccccc1)C1C=Cc2ccccc21
Solvent: CCOCC
Product: C1=CC(B(c2ccccc2)C2C=Cc3ccccc32)C=C1
Temperature: 0 °C
Yield: 182.4 %

Procedure:
To 2.40 g (10.1 mmol) of (chloro) (indenyl) (phenyl)borane in 20 ml of diethyl ether is slowly added a suspension of 725 mg (10.1 mmol) of lithium cyclopentadienyl in 30 ml of diethyl ether at -78° C. The mixture is allowed to warm to 0° C. in the cooling bath, insolubles are filtered off, and concentrating the filtrate in vacuo yields 2.47 g (91%) of (cyclopentadienyl)(indenyl)(phenyl)borane as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][C:26]#[N:27])=[CH:14][CH:13]=2)(C)(C)C.C(OC(=O)C)C.[ClH:40]>C(OCC)(=O)C>[ClH:40].[NH2:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][C:26]#[N:27])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC#N)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(CC#N)ccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
To a solution of tert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.13 g, 0.29 mmol) in ethyl acetate (4 mL) was added a 4N hydrogen chloride ethyl acetate solution (1 mL), and the mixture was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether and washed with diisopropyl ether (5 mL×2) to give [3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]acetonitrile hydrochloride (0.096 g, 88%) as a pale yellow powder.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[OH:36])(=[O:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]1([CH3:71])[CH:61]=[CH:60][C:59]([S:62]([O:65][CH2:66][CH2:67][CH:68]([CH3:70])O)(=[O:64])=[O:63])=[CH:58][CH:57]=1>O1CCCC1>[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH:68]([CH3:70])[CH2:67][CH2:66][O:65][S:62]([C:59]1[CH:58]=[CH:57][C:56]([CH3:71])=[CH:61][CH:60]=1)(=[O:63])=[O:64])(=[O:17])[CH3:16]
Reactant: COc1ccc(O)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC(C)CCOS(=O)(=O)c2ccc(C)cc2)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reaction time: 4 h
Yield: 36.9 %

Procedure:
A solution of diisopropyl azodicarboxylate (1.54 g, 7.61 mmol) in anhydrous tetrahydrofuran (10 ml) was added to a solution of 3-acetyl-6-chloro-2-(2-hydroxy-5-methoxyphenyl)benzothiazoline (2.56 g, 7.62 mmol), triphenylphosphine (2.00 g, 7.61 mmol) and 3-p-toluenesulfonyloxy-1-methylpropanol (1.86 g, 7.61 mmol) in anhydrous tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for four hours. The reaction mixture was concentrated, and the obtained oily matter was purified by silica gel column chromatography (mobile phase:hexane/ethyl acetate=4/1) to give 1.58 g (37%) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:17]=3)([OH:12])[CH:9]([CH3:10])[CH3:11])=[CH:4][CH:3]=2)=[CH:40][CH:39]=1
Reactant: CC(C)C(O)(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)C(O)(c1ccc(-c2ccc(Cl)cc2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 79.7 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.60 g), 4-chlorophenylboronic acid (1.68 g), 2M aqueous sodium carbonate solution (26.8 ml) and tetrakis(triphenylphosphine)palladium(0) (387 mg), the title compound (3.04 g) was obtained as colorless needle crystals.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A solution of acryloyl chloride (0.042 mL, 0.51 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 18, 245 mg, 0.51 mmol) and DIPEA (0.097 mL, 0.56 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 2 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave a foam after concentration in vacuo. This foam was triturated using CH2Cl2 and diethyl ether, and the resulting solid was collected by filtration and dried to give the title compound (157 mg, 58%) as a yellow solid; 1H NMR: 1.68-1.83 (1H, m), 2.05-2.16 (1H, m), 2.18 (6H, s), 2.64-2.76 (1H, m), 3.18-3.29 (3H, m), 3.36-3.47 (1H, m), 3.77 (3H, s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H, dd), 6.54 (1H, s), 7.12 (1H, t), 7.37 (1H, t), 7.43 (1H, s), 8.28-8.46 (2H, m), 8.55 (1H, s), 8.83 (1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z: ES+ MH+ 533.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH:16]=O)=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH2:16][N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CCC(CN2CCN(C(=O)OC(C)(C)C)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
To a 2 L three neck RB flask provided with a mechanical stirrer were charged a solution of 4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbaldehyde (50.0 g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20° C. for 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the internal temperature rose to ˜29.5° C. in 15 min cooling may be needed). The yellow mixture was stirred at ˜25° C. for NLT 4 hrs. A conversion of starting material to product of 99.5% was observed by HPLC after a 3 hour reaction time.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[NH:19][C:17]3[C:18]4[C:9](=[N:10][NH:11][C:12](=[O:20])[C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH:8]2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:3][CH:2]=1>[Pt](=O)=O>[NH:24]1[CH2:25][CH2:26][CH:21]([CH:8]2[C:9]3=[N:10][NH:11][C:12](=[O:20])[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([C:18]=43)[NH:19][CH:7]2[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:22][CH2:23]1
Reactant: O=c1[nH]nc2c3c(cccc13)NC(c1ccncc1)C2c1ccncc1
Agent: O=[Pt]=O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccncc1)C2C1CCNCC1
Temperature: 50 °C
Yield: 14.5 %

Procedure:
A mixture of 8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.35 mmol), platinum (IV) oxide (60 mg) and concentrate hydrochloric acid (0.3 mL) in methanol (20 mL) was stirred at 50° C. under 20 atm of hydrogen. The mixture was filtered out and the filtrate was concentrated to give crude product. The crude product was purified by prep-HPLC to give 9-(piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7 H)-one (17.6 mg, yield: 16%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) 1.25-1.39 (m, 1H), 1.40-1.52 (m, 1H), 1.60-1.70 (m, 1H), 1.75-1.84 (m, 1 H), 1.89-1.98 (m, 1H), 2.50-2.57 (m, 1H), 2.60-2.66 (m, 1H), 3.09-3.21 (m, 2H), 3.34-3.37 (dd, J1=8 Hz, J2=2.4 Hz, 1H), 4.24 (d, J=2 Hz, 1H), 7.02-7.04 (dd, J1=8 Hz, J2=0.8 Hz, 1H), 7.09-7.11 (dd, J1=4.8 Hz, J2=1.2 Hz, 2H), 7.41-7.43 (dd, J1=7.6 Hz, J2=0.8 Hz, 1H), 7.50-7.54 (t, J=8 Hz, 1H), 8.30-8.32 (dd, J1=4.4 Hz, J2=1.6 Hz, 2H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.Cl[C:16]1C=C(N2N=NC(C(O)C)=N2)C=CC=1>>[Br:1][CH:2]([C:3]1[N:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1)[CH3:16]
Reactant: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: Clc1cccc(-n2nnc(CBr)n2)c1
Product: CC(Br)c1nnn(-c2cccc(Cl)c2)n1

Procedure:
The title compound is prepared according to the procedure for 5-bromomethyl-2-(3-chloro-phenyl)-2H-tetrazole (example 7a) using 1-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl-ethanol as starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:39])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:22]2[CH:32]=[C:33]([Br:36])[CH:34]=[CH:35][C:21]=2[N:20]([CH3:37])[C:19]1=[O:38])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:39])[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:22]3[CH:32]=[C:33]([Br:36])[CH:34]=[CH:35][C:21]=3[N:20]([CH3:37])[C:19]2=[O:38])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2F)c2cc(Br)ccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2F)c2cc(Br)ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-D), the title compound was prepared as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:27][C:23]2[CH:24]=[CH:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][N:17]=3)[N:22]=2)[C:9](=[O:11])[N:10]=1
Reactant: Cc1cccc(Cl)c1CNC1=NC(=O)CS1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1CNC1=NC(=O)C(=Cc2ccc3ncccc3n2)S1
Temperature: 130 °C
Yield: 52.1 %

Procedure:
To a suspension of 2-(2-chloro-6-methyl-benzylamino)-thiazol-4-one (40.8 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 15 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-(2-chloro-6-methyl-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (32.9 mg, 52.1%). HR-ES (+) m/e calcd. for C20H15ClN4OS: (M+H)+ 395.0728. Found: 395.0728.
Reaction SMILES: [CH2:1]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[S:14])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:13](=[S:14])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4])[CH3:28]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/Cc1ccccc1C(O)=S
Product: CCN1CCCC1CNC(=S)c1ccccc1C/C=C(\C)CCC=C(C)C
Yield: 54 %

Procedure:
In a manner identical to Example 15, 2-geranylthiobenzoic acid (2.03 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (1.0 ml), thereby yielding 1.52 g (54%) of the aimed compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[O:8][C:7](=[O:12])[CH:6]=2)[CH2:15][CH2:16]1
Reactant: Cc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Reactant: O=Cc1cccc(O)c1
Product: Cc1ccc2oc(=O)cc(NC3CCN(Cc4cccc(O)c4)CC3)c2c1

Procedure:
According to Procedure A above, 6-methyl-4-(piperidin-4-ylamino)-chromen-2-one and 3-hydroxybenzaldehyde were processed to give the title compound. MS (DCI/NH3) m/z 465 [M+H]+; 1H NMR (500 MHz, DMSO) δ ppm 9.41-9.63 (m, 1H), 7.94 (m, 1H), 7.40 (m, 1H), 7.29 (m, 2H), 7.20 (m, 1H), 6.90 (m, 3H), 5.36 (m, 1H), 4.22 (m, 2H), 3.74 (m, 1H), 3.48 (m, 2H), 3.09 (m, 2H), 2.37 (m, 3H), 2.18 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16](=[N:19][OH:20])[C:17]#[N:18]>N1C=CC=CC=1>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16](=[N:19][O:20][C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:17]#[N:18]
Reactant: N#CC(=NO)c1nc2ccccc2o1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)ON=C(C#N)c1nc2ccccc2o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
12 g (0.11 mol) of ethyl chloroformate are added dropwise to a solution of 18.7 g (0.1 mol) of α-[benzoxazol-2-yl]-α-oximino-acetonitrile in 120 ml of pyridine, with ice-cooling. After stirring for 3 hours, the mixture is poured into 1 liter of ice-water and the residue is filtered off and washed with water: 23 g (89% of theory) of end product, which is recrystallised from acetonitrile; melting point 187° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=2)[CH2:4][CH2:3]1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[C:16]([C:6]1[CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:15])[CH3:1])(=[O:18])[CH3:17]
Reactant: CC(C)(C)c1ccc2c(c1)C(C)(C)CC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: CC(=O)c1cc(C(C)(C)C)cc2c1CCC2(C)C
Temperature: 0 °C
Yield: 121.2 %

Procedure:
A solution of 1,1-dimethyl-6-t-butylindane (600 grams) and acetyl chloride (314 grams) is added over a 4 hour period at -10° C. to a slurry of aluminum chloride (534 grams), 1,1-dimethyl-6-t-butylindane (1420 grams) and n-hexane (400 grams). The resulting reaction mass is poured into 5 liters of ice water with vigorous stirring thereby forming 2 liquid layers. The bottom (aqueous) layer is discarded and the organic layer is washed twice with 2 liters of water. Distillation affords recovered 1,1-dimethyl-6-t-butylindane (1252 grams, 62% recovery) and 878 grams of 4-acetyl-6-t-butyl-1,1-dimethylindane (90% yield based on acetyl chloride, 95% yield based on consumed 1,1-dimethyl-6-t-butylindane.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[CH2:50]([O:49][C:47]([C:16]1([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:15]2[C:11](=[N:12][N:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:14]=2[CH:24]([CH3:26])[CH3:25])[C:10](=[O:35])[N:9]1[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:48])[CH3:51]
Reactant: CCOC(=O)Cl
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCOC(=O)C1(c2ccc(Cl)cc2)c2c(nn(-c3ccccc3OC)c2C(C)C)C(=O)N1c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to the procedure described for example 74 but using the compound prepared in example 88, 1 equivalent of KHMDS and 5 equivalents of ethyl chloroformate. No purification was performed. tR: 1.42 min (LC-MS 1); ESI-MS: 582.2 [M+H]+ (LC-MS 1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2].C(OC(=O)C)(=[O:19])C.S(=O)(=O)(O)O.O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([NH:4][C:5]1[C:14]([CH:15]=[O:19])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C)c(NC(C)=O)c(Cl)c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c(C=O)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a cooled solution (ice bath) of 10.8 g of methyl 4-acetamido-3-chloro-5-methylbenzoate in 73.8 ml of glacial acetic acid; and 73.8 ml of acetic anhydride were added dropwise 11 mL of concentrated sulfuric acid followed by the portion wise addition of 12.96 g (0.1295 mole) of chromium trioxide over a 25 minute period. The reaction mixture was stirred at 0° C. for 2.5 hours and then poured into a mixture of 612 g of ice and 162 ml of water. The resulting aqueous mixture was extracted with methylene chloride (4×250 ml). The combined organic layers were washed sequentially with water (3×250 ml), 5% aqueous sodium bicarbonate (2×250 ml) and then brine (1×250 ml) and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator. The resulting residue was purified by chromatographic column (silica gel, ethyl acetate:hexane 30:70 followed by ethyl acetate:hexane 50:50), yielding 2.5 g methyl 4-acetamido-3-chloro-5-formylbenzoate.