Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH3:13])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)CCC.[OH-].[Na+].C(O[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(C)(C)C>O>[CH3:31][C:28]([O:27][C:26]([N:1]([C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:13])=[O:32])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.6 g of H-MePhe-OH are dissolved in a mixture of ter.-butanol, 25 ml of 10% aqueous KHCO3 solution and 5 ml of 4 N sodium hydroxide. 8 ml of di-tert.-butylcarbonate are added and the mixture stirred for 2 days at room temperature. The reaction mixture is diluted with ca. 100 ml of water and extracted with ether. The aqueous phase is acidified, with stirring to pH 2. The precipitated product is extracted with acetic acid, the extract washed with water and dried over Na2SO4. The liquid is evaporated and the product crystallised from ether/petroleum ether to yield Boc-MePHe-OH. M.P. 87°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[Cu][C:15]#[N:16]>CN(C=O)C.O.Cl.C1(C)C=CC=CC=1>[C:15]([C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13])#[N:16]
Reactant: N#C[Cu]
Reactant: Cc1cc(Br)c2c(c1C)C(=O)CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)c2c(c1C)C(=O)CC2
Reaction time: 6 h

Procedure:
A mixture of 17.8 g (74.5 mmol) of 4-bromo-6,7-dimethyl-1-indanone [J. Het. Chem. 24, 677 (1987)] and 7.3 g (82 mmol) of copper(I) cyanide in 18 ml of DMF is stirred for 6 hours at 170°. The reaction mixture is then cooled to 100° and 200 ml of toluene and a solution of 31.2 g of iron(HI) chloride hexahydrate in 47 ml of water and 8.2 ml of concentrated hydrochloric acid are added in succession thereto. The reaction mixture is stirred for 20 minutes at 70°, cooled and diluted with toluene and water. The organic phase is separated off, washed with water, a semi-saturated sodium hydrogen carbonate solution and again with water, dried and concentrated by evaporation. The residue is crystallised from ethyl acetate and ether and corresponds to starting compound (a). Beige crystals having a melting point of 160°-163° are obtained; IR (CH2C12): 2220, 1710 cm-1.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].O.CCCCCC.CC(C)=O>CN(C=O)C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of methyl pheophorbide-a (100 mg, 0.17 mmol) in DMF (25 mL) was added distilled water (48 μL, 2.7 mmol, 16 equiv.) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexane-acetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). After 60 min the reaction was shown to have reached 99.6% completion by HPLC peak area. The solution was cooled to room temperature after 100 min of reflux and solvent removed under reduced pressure. The residue was precipitated from methylene chloride-methanol to give methyl pyropheophorbide-a (50 mg, 56%).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH2:4][OH:5].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]>>[CH2:14]([CH:15]1[S:1][CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH2:4][O:5]1)[CH2:13][CH2:12][CH2:11][C:10]#[CH:9]
Reactant: CC(C)C(CO)CS
Reactant: C#CCCCCC=O
Product: C#CCCCCC1OCC(C(C)C)CS1

Procedure:
Using the method described in Example 4(ii), and starting from 2-mercaptomethyl-3-methylbutan-1-ol and hept-6-ynal, 2-(hex-5-ynyl)-5-isopropyl-1,3-oxathiane was obtained as a mixture of isomers. Column chromatography on silica, eluting with hexane/ether gradients, gave a mixture of trans-and cis-isomers (50:50) followed by an enriched mixture of the trans-compound (95:5).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22]CC)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1.O>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([OH:22])=[O:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A solution of potassium trimethylsilanoate (0.141 g) in dry THF (5 ml) was added to a cooled solution of ethyl 2-benzenesulphonylamino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylate (Intermediate 1, 0.076 g) in dry THF (5 ml). The resultant cloudy solution was stirred at room temperature for 2 hours. Further potassium trimethylsilanoate (0.076 g) was added and the resultant mixture was stirred for a total of 72 hours. The mixture was then stirred and heated at 60° C. for a total of 48 hours. The resultant mixture was diluted with water and acidified to pH1 by addition of concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether. The solid was collected by filtration and air dried to give 2-benzenesulphonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.034 g) as an off white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=[O:15])[CH3:14].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:2]1([CH2:14][C:13]([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccs1
Reactant: Brc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)c1cccs1
Temperature: 90 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
1-Bromobenzene (2 g, 12 mmol) in toluene (30 mL) was treated 1-(thiophen-2-yl)ethanone (1.8 g, 14.4 mmol), potassium bis(trimethylsilyl)amide (28.8 mL of 0.5 M solution in toluene, 14.4 mmol), 2,2′-bis(diphenyl)phosphino-1,1′-binaphthyl (racemic BINAP, 1.86 g, 3 mmol). The reaction was heated to 90° C. in an oil bath under a nitrogen atmosphere. After 4 h, the reaction was allowed to cool to room temperature and diluted with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 10 to 40% ethyl acetate in hexanes to yield a yellow oil (1 g). MS (M+H)+ 203.
Reaction SMILES: [C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1(O)CC1)CC>>[CH2:6]([C:1]1([O:7][S:8](=[O:10])(=[O:11])[NH2:9])[CH2:2][CH2:3]1)[CH2:5][CH3:4]
Reactant: NS(=O)(=O)Oc1ccccc1
Agent: CCCC1(O)CC1
Product: CCCC1(OS(N)(=O)=O)CC1

Procedure:
Sulfamic acid 1-propyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-propylcyclopropanol (synthesized by methods reported in Synthesis 1991, 234) to obtain sulfamic acid 1-propyl-cyclopropyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:12]NC(NC1C=CC(C([O-])=O)=CC=1)=O>>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH3:12])(=[O:3])[CH3:2]
Reactant: CNC(=O)Nc1ccc(C(=O)[O-])cc1
Reactant: CC(=O)Nc1ccc(I)cc1
Product: CC(=O)N(C)c1ccc(I)cc1

Procedure:
The desired compound is prepared according to the method of Example 3, step2, except substituting, 4-(N-acetylamino)iodobenzene, prepared as in step 1, for 4-(N-methylaminocarbonyl)aminobenzoate
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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>[O:9]1[CH2:10][CH:11]=[C:12]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[N:4][CH:5]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Nc1cncc(Br)c1
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+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cncc(C2=CCOCC2)c1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 3-amino-5-bromopyridine (0.25 g, 1.4 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.33 g, 1.6 mmol), tetrakis(triphenylphosphine)palladium (83.3 mg, 0.072 mmol), and 2.0M sodium carbonate (3.6 mL, 7.2 mmol) in toluene (3.0 mL) and EtOH (1.0 mL) was heated to 70° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a white solid as 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.05 (1H, d, J=2.0 Hz), 7.96 (1H, d, J=2.7 Hz), 6.95 (1H, m), 6.10 (1H, tt, J=2.9, 1.5 Hz), 4.28 (2H, q, J=2.9 Hz), 3.90 (2H, t, J=5.5 Hz), 3.81 (1H, br. s.), 2.48 (2H, m). Mass Spectrum (pos.) m/e: 177.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=1>[C].[Pd].C(OCC)(=O)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)cn1
Yield: 93.7 %

Procedure:
A mixture of 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine (13.4 g), palladium carbon (5%, 1.5 g) and ethyl acetate (200 ml) methanol (150 ml) was subjected to catalytic hydrogenation at room temperature under 1 atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to leave crystals. The crystals were collected by filtration to obtain 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (11.4 g, 93%), which was recrystallized from ethyl acetate--hexane to give brown crystals, m.p.107°-108° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: Cc1ccc(Oc2ccc(C[C@H](N)C(=O)O)cc2)nc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C[C@H](Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)cc2)nc1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-methyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27]CC4C=CC=CC=4)[CH:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.CO.Cl>[Pd]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc1O
Reaction time: 4 h
Yield: 40.7 %

Procedure:
Into a Parr pressure reactor 1-Benzenesulfonyl-3-(3-benzyloxy-4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (92 mg, 0.00020 mol) was placed with Palladium (50 mg, 0.00005 mol) 10%, tetrahydrofuran (15 mL, 0.18 mol) and Methanol (1 mL, 0.02 mol) and HCl solution (3 mL, 0.04 mol). The reaction was shaken under an atmosphere of hydrogen at 50 psi for 4 hours. The mixture reaction was filtered through Celite™ and concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate/hexanes 1:1) to give 31 mg of the titled product. MS(ESI) [M+H+]+=381.11.
Reaction SMILES: [C:1](C(O)(CC=C)C(C)(C)C)(C)([CH3:3])[CH3:2].C([Li])CCC.[CH2:19]([N:26]=[CH:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)C>CCCCC.[Cl-].[Cl-].[Zn+2]>[CH2:3]([CH:27]([NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:28]=[C:29]([CH3:31])[CH3:30])[CH:1]=[CH2:2]
Reactant: CC(C)=CC=NCc1ccccc1
Reactant: C=CCC(O)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCC
Solvent: CCOCC
Product: C=CCC(C=C(C)C)NCc1ccccc1

Procedure:
The reaction was performed analogous to Example 1 with 500 mg (2.71 mmol) 3-tert-butyl-2,2-dimethylhex-5-en-3-ol, 1.93 ml (2.71 mmol) of a 1.4-molar n-butyllithium solution in pentane, 468 mg (2.71 mmol) benzyl-(3-methyl-but-2-enylidene)amine and 370 mg (2.71 mmol) ZnCl2. The raw product obtained was cleaned by means of a silica column with 25-100% diethyl ether/light gasoline. There was obtained the amine as a colorless oil.
Reaction SMILES: [ClH:1].[CH:2]([SiH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7])([CH3:4])[CH3:3]>>[CH:2]([Si:5]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[Cl:1])([CH3:4])[CH3:3]
Reactant: CC(C)[SiH](C(C)C)C(C)C
Reactant: Cl
Product: CC(C)[Si](Cl)(C(C)C)C(C)C
Temperature: 100 °C

Procedure:
A thermometer, hydrogen chloride gas inlet tube, and reflux condenser were fitted to a stirrer-equipped 200 mL four-neck flask, and 80 g triisopropylsilane was then introduced into the flask. This was followed by the addition of 0.01 g platinum/divinyltetramethyldisiloxane complex and heating to 100° C. Hydrogen chloride gas was then introduced into the mixture. The introduction of hydrogen chloride gas was suspended after 4 hours. Vacuum distillation yielded 94 g triisopropylchlorosilane (purity≥99%). The triisopropylsilane yield was 97%.
Reaction SMILES: [H-].[Na+].C(O[CH2:7][C:8]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:11])(=O)C.O.C1(C)C=CC=CC=1>CN(C)C=O>[CH3:25][O:24][C:21]1[CH:20]=[C:9]2[C:8]([CH2:7][N:12]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:10]2=[O:11])=[CH:23][CH:22]=1
Reactant: COc1ccc(COC(C)=O)c(C(=O)NCc2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)N(Cc1cccnc1)C2
Temperature: 0 °C
Yield: 58.2 %

Procedure:
To a suspension of 136 mg of sodium hydride (about 60%) in 7 ml of dimethylformamide chilled at 0° C. was added 820 mg of 2-acetoxymethyl-5-methoxy-N-(3-pyridylmethyl) benzamide and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with water and shaken with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 386 mg of the titled compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:37])([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:9]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]2[C:11](=[CH:12][C:13]([C:26](OC)=[O:27])=[CH:14][CH:15]=2)[N:10]=1.O.[OH-].[Na+]>C1COCC1>[F:37][C:8]([F:7])([C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)[C:9]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]2[C:11](=[CH:12][C:13]([CH2:26][OH:27])=[CH:14][CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cc3)nc3cc(CO)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a suspension of LAH (0.26 g, 6.84 mmol) in THF (50 mL) at 0° C. was slowly added a suspension of methyl 2-(difluoro(4-fluorophenyl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-7-carboxylate (1.17 g, 2.74 mmol) in THF (30 mL). The mixture was stirred at 0° C. for 0.5 h and then at rt for 4 h. The mixture was cooled to 0° C., and water (0.26 mL) was added dropwise and the mixture was stirred for 30 min. Then 15% NaOH (0.39 mL) was added and the mixture was stirred for 1 h. Then water (1.3 mL) was added and the mixture was stirred at rt overnight. The mixture was filtered through Celite washing with 20% MeOH/DCM (500 mL), and the filtrate was concentrated under reduced pressure. The residue was partitioned between water (200 mL) and EtOAc (150 mL), and the separated aqueous phase was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC to afford a (2-(difluoro(4-fluorophenyl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yl)methanol as a white solid (901 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 4.70 (s, 2H), 5.49 (s, 1H), 6.31 (s, 1H), 7.35 (t, 2H), 7.56 (d, 2H), 7.70 (t, 2H), 7.77 (s, 1H), 8.63 (d, 1H), 10.64 (s, 1H), 12.18 (s, 1H); LC-MS (ESI) m/z 400 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([C:6](OCC)=[O:7])=[CH:4][CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[BH4-].[Na+].O>C(O)C>[OH:7][CH2:6][C:5]1[S:1][C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(CO)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
Diethyl 2,5-thiophenedicarboxylate (1.14 g, 5 mmol) synthesized in Production Example 71 was dissolved in ethanol, and sodium tetrahydroborate (113 mg, 3 mmol) was added thereto. The mixture was stirred for 3 days at a room temperature. After the completion of the reaction was confirmed by HPLC, water was added to the mixture, and the resulting mixture was concentrated under a reduced pressure. The residue was dissolved in ethyl acetate, washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by flash column chromatography (Yamazen Hi-Flash column, silica gel, hexane/ethyl acetate (volume ratio)=3:2) to give the title compound (491 mg, 52.7%) as an oily substance.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S(Cl)([Cl:16])=O>>[Cl:16][CH2:2][CH:3]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: OCC1CCCCCCCCCC1
Product: ClCC1CCCCCCCCCC1

Procedure:
The starting material 3-cycloundecylpropan-1-ol is obtained as follows: hydroxymethylcycloundecane is reacted with thionyl chloride to give chloromethylcycloundecane, which is reacted with malonic acid diethyl ester in the presence of sodium ethylate to give (cycloundecylmethyl)-malonic acid diethyl ester, which, after saponifying the ester group and decarboxylating the corresponding malonic acid, gives 3-cycloundecylpropionic acid. 3-Cycloundecylpropionic acid is reduced with lithium aluminum hydride in tetrahydrofuran to give 3-cycloundecylpropanol.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]C1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: c1ccc2c(c1)CCCN2c1cc2ccccc2[nH]1
Reactant: c1ccc2c(c1)CCCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: c1ccc2nc(-c3cc4ccccc4[nH]3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The indolyl-tetrahydroquinoline was made according to the established lanthanide triflate catalyzed Kobayashi chemistry (for a leading reference, see Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis, 1995, 1195-1202). The tetrahydroquinoline (50.0 mg, 0.102 mmol) was dissolved in 10 mL anhydrous dichloromethane and the solution was cooled to 0° C. under nitrogen atmosphere. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (47.6 mg, 0.210 mmol) in 2 mL dichloromethane was then added in a drop-wise fashion. The reaction mixture was stirred at 0° C. for additional 30 minutes. The reaction crude was filtered through celite and the solvent was evaporated in vacuo to supply a yellow solid. Further purification by flash column chromatography (alumina basic, CH2Cl2 /MeOH=20:1) yielded 27.5 mg of indolyl-quinoline 517.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:9][C:8](=[CH2:10])[CH2:7]1)=[O:5])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].[CH2:20]([O:22]CC)C>>[OH:5][CH2:4][CH:6]1[CH2:7][C:8](=[CH2:10])[CH:9]1[CH2:20][OH:22]
Reactant: CCOCC
Reactant: C=C1CC(C(=O)OCC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: C=C1CC(CO)C1CO
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirred solution of 40.0 g (0.188 mol) of 1,2-bis(ethoxycarbonyl-3-methylenecyclobutane (Cripps, H. N.; Williams, J. K.; Sharkey, W. H. J. Am. Chem. Soc. 1959, 81, 2723-2728) in 1.4 L of diethyl ether at 0° C. was added 14.4 g (0.379 mol) of lithium aluminum hydride in small portions. After 2 h at 0° C., 14.4 mL of H2O, 14.4 mL of 15% aq. NaOH, and then 44.0 mL of H2O were added sequentially. The resulting white solid was removed by filtration and washed thoroughly with diethyl ether. Concentration of the combined filtrates under reduced pressure afforded 17.1 g (71%) of the title compound as an oil, judged to be 95% pure by NMR: Rf 0.27 (silica gel, 1:1/acetone:hexane); IR (CDCl3) cm-1; 1H NMR (CDCl3) 1.66 (bs, 1H, OH), 2.24-2.41 (m, 2H), 2.44 (bs, 1H, OH), 2.57-2.71 (m, 1H), 2.87-2.96 (m, 1 H), 3.54, 3.58 (2 dd, 2H, J=J'=12 Hz, CH2O), 3.79, 3.84 (2 dd, 2H, J=10.5 Hz, J'=4.5 Hz, CH2O), 4.78, 4.82 (2 ddd, 2H, J=J'=J"=2.5 Hz, C=CH2); 13C NMR (CDCl3, CDCl3 =77.00 ppm)146.21, 105.39, 66.13, 63.74, 51.70, 38.67, 31.86; DCI- NH3MS, m/z 129 (M+1)+, 146 (M+NH4+)+.