Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[C:7]([C:9]([NH2:11])=O)[N:8]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl.C(O)(C(F)(F)F)=O.[OH-].[Na+]>O.C(#N)C.C(Cl)CCl>[CH:1]([C:4]1[S:5][C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[C:7]([C:9]#[N:11])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(N)=O)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Yield: 65.8 %

Procedure:
Combine 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid amide (47.5 g, 155 mmol) and 2-dichloroethane (475 mL) and stir at rt under N2 as a dark solution. Pour POCl3 (14.5 mL, 155 mmol) into the solution, and heat the reaction to reflux (80–83° C.) for 2–3 h until complete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 L/min). Coolthe reaction to rt, cool further to 0–5° C. Adjust the pH to 8–9 by adding aqueous 2N NaOH (275 mL) at such a rate to maintain the temperature below 20° C. Separate the layers, extract the aqueous layer with CH2Cl2 (2×100 mL). Combine the organic layer, wash with brine (2×100 mL), dry (MgSO4), filter, and concentrate the filtrate in vacuo to a dark oil/solid residue (40 g). Purify the crude product by silica gel chromatography (1200 g silica gel 60, CH2Cl2) to afford 29.4 g (66%) of the title compound as a red solid: 1H NMR (300 MHz, DMSO-d6) δ 9.78 (bs, 1h), 8.15 (dd, 1H, J=6.95 Hz, 1.46 Hz), 7.67 (dt, 1H, J=7.32 Hz, 1.46 Hz), 7.26 (dd, 1H, J=7.32 Hz, 1.10 Hz), 7.15 (dt, 1H, J=6.95 Hz, 1.10 Hz), 3.26 (dq, 1H, J=6.95 Hz), 1.33 (d, 6H, J=6.95 Hz). 13C NMR (75 MHz, DMSO-d6) δ 171.85, 150.83, 139.10, 136.22, 136.00, 126.05, 121.41, 118.64, 116.09, 113.73, 33.01, 22.07(2). IR (CHCl3) 3311, 3021, 2970, 2928, 2868, 2223, 1613, 1583, 1518, 1492, 1448, 1403, 1341 cm−1. HRMS (ES) M/z calculated for C13H12N4O2S 289.0759, found 289.0744.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([O:36]C(=O)C)[C:8]2[CH2:19][S:18][CH2:17][C@@H:16]([C:20]([O:22][CH3:23])=[O:21])[NH:15][C:14](=[O:24])[C@@H:13]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:12][O:11][C:10](=[O:33])[C:9]=2[C:34]=1[CH3:35])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[OH:4][C:5]1[CH:6]=[C:7]([OH:36])[C:8]2[CH2:19][S:18][CH2:17][C@@H:16]([C:20]([O:22][CH3:23])=[O:21])[NH:15][C:14](=[O:24])[C@@H:13]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:12][O:11][C:10](=[O:33])[C:9]=2[C:34]=1[CH3:35]
Reactant: COC(=O)[C@@H]1CSCc2c(OC(C)=O)cc(OC(C)=O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 32 mg of t-butyl (4R,7S)-12,14-diacetoxy-1,3,4,5,6,7,8,10-octahydro-4-methoxycarbonyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate in 3 ml of methanol were added 15 mg of potassium carbonate. After stirring for 30 minutes at room temperature the reaction mixture was diluted with ethyl acetate and washed consecutively with 0.1M pH 7 aqueous sodium phosphate buffer and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel using acetone/n-hexane 1:2 (v/v) as eluent. The purified product was dissolved in methylene chloride and precipitated by slow addition of n-hexane to yield t-butyl (4R,7S)-1,3,4,5,6,7, 8,10-octahydro-12,14-dihydroxy-4-methoxycarbonyl-11-methyl-6,10-dioxo -9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white, amorphous material.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[CH:42]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:44]3[C:45]4[C:41](=[CH:40][C:39]([Cl:38])=[CH:47][CH:46]=4)[CH:42]=[N:43]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Clc1ccc2[nH]ncc2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(Cl)ccc43)nc12
Temperature: 110 °C
Yield: 85.6 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol) in toluene (1 mL) was added copper (I) iodide (3.52 mg, 39.3 μmol), sodium iodide (105 mg, 702 μmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (12.7 mg, 89.5 μmol). The reaction mixture was sealed under nitrogen and the mixture heated at 110° C. for 15 h then 5-chloro-1H-indazole (53.5 mg, 351 μmol) and potassium phosphate tribasic (156 mg, 737 μmol) were added. The mixture was degassed, filled with nitrogen, and the mixture heated at in sealed tube at 110° C. for 15 h. The mixture was filtered, the cake washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-chloro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 86%). 1H NMR (CDCl3) δ: 9.17 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.68 (s, 1H), 7.46 (dd, J=8.9, 1.6 Hz, 1H), 5.72 (s, 2H), 3.51-3.65 (m, 2H), 1.61 (s, 9H), 0.87-1.03 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in general procedure A. Purification by column chromatography yielded 5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-2-yl]-pyrimidin-2-ylamine.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[OH-].[NH4+:15]>C(O)(C)C>[NH2:15][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: N#Cc1ccc(OCC(O)CN)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
4-(Oxiranylmethoxy)benzonitrile (from step (i) above; 100 g, 0.57 mol) was added to a mixture of concentrated aqueous ammonium hydroxide (500 mL) and iso-propanol (300 mL). The resulting slurry was stirred at room temperature for 3 days. The reaction mixture was filtered to remove the insoluble by-product, and the filtrate was concentrated in vacuo to give a crude product, which was crystallised from acetonitrile to yield 50 g (46%) of the sub-title compound.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[S:33]>>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:33]1
Reactant: CC(C)C[C@H](N)CO
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: CC(C)C[C@H]1CSC(=Nc2cccc(Cl)c2Cl)N1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2,3-Dichlorophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2,3-dichlorophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 3-bromopentane according to Method D2a to afford (4S)-2-(N-(3-pentyl)-2-methyl-4-nitrophenylamino)-4-isobutyl-1,3-thiazoline.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[CH2:10][C:5]=2[O:4][CH:3]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl>C(O)C>[ClH:27].[NH:25](/[N:26]=[C:7]1\[CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:10][C:5]2[O:4][CH:3]=[C:2]([CH3:1])[C:6]\1=2)[C:22]([NH2:24])=[NH:23]
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1C(F)(F)F)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1C(F)(F)F)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
To a mixture of 3-methyl-6-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.28 g) and aminoguanidine hydrochloride (105 mg) were added ethanol (20 ml) and 6N hydrochloric acid (0.082 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-4-guanidinoimino-3-methyl-6-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 39) (0.21 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:6]2=O)[CH3:2].O.[NH2:27][NH2:28]>C(O)C>[CH2:1]([C:3]1[C:12]([OH:13])=[CH:11][C:10]([OH:9])=[C:5]([C:6]2[C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[C:8]([C:14]([OH:16])=[O:15])[NH:27][N:28]=2)[CH:4]=1)[CH3:2]
Reactant: NN
Reactant: CCc1cc2c(=O)c(-c3ccc(OC)cc3)c(C(=O)O)oc2cc1O
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2n[nH]c(C(=O)O)c2-c2ccc(OC)cc2)c(O)cc1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
6-Ethyl-7-hydroxy-3-(4-methoxyphenyl)-4-oxo-chromene-2-carboxylic acid (13.6 g, 41.73 mmol) and hydrazine monohydrate (6.1 ml, 125.19 mmol) were suspended in ethanol (200 ml) at room temperature. The mixture was then heated slowly to 70° C. and stirred at this temperature for 4 hours. The mixture was cooled to room temperature and all volatile components were removed in vacuum. The residue was partitioned between water (11) and Ethyl acetate (1.41). Then the aqueous phase was separated. The organic phase yielded some product. The remainder of the product was extracted from the aqueous phase with Ethyl acetate (4×500 ml). The combined organic extracts were dried over Magnesium sulfate and evaporated to dryness under vacuum resulting in a further quantity of the desired product. The combined isolated product portions yielded 6.99 g (51%) of a light brown solid. 1H NMR Spectrum: δH (400 MHz, DMSO-6d) 0.84 (3H t, J=7.5 Hz), 2.23 (2H q, J=7.5 Hz), 3.38 (1H s, br), 3.74 (3H, s), 6.36 (1H, s), 6.56 (1H, s), 6.85 (2H d, J=8.7 Hz), 7.13 (2H d, J=8.7 Hz), 9.3 (1H s, br), 9.4 (1H s, br), 12.8 (1H s, br); Mass Spectrum: (M+H+) 355.04, (M+H−) 353.09.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([CH3:20])=[CH:14][C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:28][CH3:29]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:20])=[N:16][C:17]=3[O:19][CH2:28][CH3:29])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1C1C(C#N)=C(C)Nc2cc(C)[nH]c(=O)c21
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C#N)=C(C)N2
Temperature: 130 °C

Procedure:
1920 mg (5.77 mmol) of 4-(4-cyano-2-methoxyphenyl)-2,7-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile are suspended in 40 ml (240 mmol) of anhydrous triethyl orthoformate. The reaction mixture is heated to 130° C. Then 10 drops of concentrated sulfuric acid are added each hour. After complete reaction has been detected (analytical HPLC; reaction time about 36 h), the reaction mixture is cooled to room temperature, and the volatile components are removed in a rotary evaporator. The crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). The product obtained in this way is crystallized from ethyl acetate. 451 mg (22% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][C:16]3=[CH:18][N:19]=[C:20]([CH3:21])[N:15]3[C:14]2=[O:22])[CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[C:39]([CH3:46])[CH:38]=1>C(#N)C>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:3][CH:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][C:16]4=[CH:18][N:19]=[C:20]([CH3:21])[N:15]4[C:14]3=[O:22])[CH2:9][CH2:8]2)=[O:6])=[O:45])=[C:39]([CH3:46])[CH:38]=1
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Reactant: Cc1cc(Cl)ccc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Cl)ccc1NC(=O)NC(C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1)c1ccccc1
Yield: 64.3 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.21 g) obtained in Example 115a) was dissolved in acetonitrile (5.0 ml). Triethylamine (0.14 ml) and 4-chloro-2-methylphenyl isocyanate (80 mg) were added thereto, and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate). The product was crystallized from ethyl acetate-diethyl ether to obtain the title compound as colorless powder (0.16 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=[O:11])[CH:3]=1.C[Si](C)(C)[O-].[K+].Cl.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(N)c(Cl)c(Cl)n1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(C(=O)O)nc(Cl)c1Cl
Yield: 98.5 %

Procedure:
The compound prepared in Example 405 (2.438 g) and potassium trimethylsilanolate (2.971 g) were suspended in tetrahydrofuran (100 mL) and stirred at reflux for 4 hours. The reaction mixture was dissolved in water and added to 1 N hydrochloric acid. Ethyl acetate was added and the system stirred at room temperature. The organics were dried, magnesium sulfate and concentrated under reduced pressure to furnish the title compound (2.250 g), which was used without further purification, possessing the following physical data.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[OH:31])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[C:5]([C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:31])=[C:21]([CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:30]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cc2ccccc2)c(O)c2ccccc12
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of aluminum chloride (1.25 g, 9.4 mmole) in methylene chloride (25 mL) was stirred at 0° and treated dropwise with benzoyl chloride (1.1 mL, 9.4 mmole) and stirred for 5 minutes. A solution of 2-(phenylmethyl)-1-naphthol (2.0 g, 8.5 mmole) in methylene chloride (6 mL) was added dropwise over 15 minutes, and stirring was continued at 0° for 3 hours. The mixture was poured into 1.0N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride. Recrystallization from toluene provided the title compound (1.15 g, 40%) as pale yelow crystals, mp 152°-155°.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8][C:7]=3[N:6](COCC[Si](C)(C)C)[C:5]=2[C:30]2[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([CH3:45])([CH3:44])[O:35]3)[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([C:4]2[C:12]3[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:30]2[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([CH3:45])([CH3:44])[O:35]3)[CH2:3][CH2:2]1
Reactant: CC1(C)C=Cc2c(-c3c(C4CC4)c4c(=O)n(COCC[Si](C)(C)C)ncc4n3COCC[Si](C)(C)C)ccc(OC(F)F)c2O1
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CC1(C)C=Cc2c(-c3[nH]c4cnn(COCC[Si](C)(C)C)c(=O)c4c3C3CC3)ccc(OC(F)F)c2O1
Yield: 84 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 1.35 g (containing an amount corresponding to 2.00 mmol) of 3-cyclopropyl-2-(8-difluoromethoxy-2,2-dimethyl-2H-chromen-5-yl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 55-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 907 mg of the title compound was obtained as a pale yellowish solid. (Yield: 84%)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:29]=[C:26]([CH:27]=[O:28])[C:25]([OH:30])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([CH:29]=1)[CH:27]=[O:28]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Temperature: 100 °C
Yield: 84.5 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (2.87 g, 9.6 mmol) in dimethylformamide (20 mL) was added 5-chlorosalicylaldehyde (1.65 g, 10.5 mmol), potassium carbonate (2.64 g, 19.2 mmol) and potassium iodide (1.59 g, 9.6 mmol). The resulting mixture was heated to 100° C. for 12 hours. The reaction was cooled, diluted with saturated aqueous brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give crude product. Purification via chromatography on silica gel gave the title compound (3.40 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([C:27](OCC)=[O:28])[CH2:12][N:13]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][C:15]([CH3:17])([CH3:16])[C:5]=3[C:4]=2[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:44]([NH2:47])([CH3:46])[CH3:45]>>[CH:44]([NH:47][C:27]([C:11]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[C:5]=2[C:15]([CH3:17])([CH3:16])[CH2:14][N:13]([C:18](=[O:26])[C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:12]=1)=[O:28])([CH3:46])[CH3:45]
Reactant: CC(C)N
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(F)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(F)cc21

Procedure:
In a similar manner, ethyl 9-fluoro-3-(4-fluorobenzoyl)-1,1-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate was saponified, converted to the corresponding carboxamide using CDI and isopropylamine, and then oxidized to give 9-fluoro-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino-[4,5-b]indole-5-carboxylic acid isopropylamide MS (ESI): 438 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20][N:21]([CH2:32][C:33]([O:35][CH3:36])=[O:34])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO.[Cl-].[Na+].O>[CH3:36][O:35][C:33]([C:32]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:20][N:21]=1)[N:7]([CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:34]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1CC1CCOCC1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2CC2CCOCC2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
5-Bromo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1-(tetrahydro-pyran-4-ylmethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (411 mg, 0.70 mmol) was dissolved in 15 mL of MeOH and placed in ice bath. NaOMe solution (0.5 mL, 2.11 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, and brine was added until precipitate appeared. The resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-4% MeOH/CH2Cl2) to give 200 mg of the title compound as a light yellow solid. MS: (+) m/z 397.21, 399.16 (M+1, 79/81Br).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=O)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:19][NH2:20]>C(O)C>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]1[N:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:20][N:19]=1
Reactant: O=c1nc(-c2ccccc2)oc2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1ccccc1-c1n[nH]c(-c2ccccc2)n1

Procedure:
1.9 g of 2-phenyl-benzo[e][1,3]oxazin-4-one are refluxed in 75 ml of ethanol with 1.0 g of hydrazine hydrate. After about 1 hour the solvent is distilled off in vacuo and the residue remaining is stirred into water. The solid formed (3-(2-hydroxyphenyl)-5-phenyl-1,2,4-triazole) is used in the next step without further purification. Yield: 0.5 g (25%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[CH:16]=[CH2:17])C=C>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[O:4]1[C:5]2[C:6](=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=2)[CH:16]=[CH:17][CH2:1]1
Reactant: C=CCOc1ccc(C(=O)OCC)cc1C=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Product: CCOC(=O)c1ccc2c(c1)C=CCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.7 %

Procedure:
To a stirred solution of ethyl 4-(allyloxy)-3-vinylbenzoate (1.8 g, 7.7 mmol) in CH2Ci2 (40 mL) at rt is added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (127 mg, 0.15 mmol). The mixture is stirred at rt for 2.5 h. The reaction mixture is concentrated in vacuo to a dark residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 1.3 g (80%) of ethyl 2H-chromene-6-carboxylate as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.8, 7.7, 6.8, 6.4, 5.8, 4.9, 4.4, 1.4.