Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>ClCCl.C(OCC)(=O)C.CCCCCC>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Temperature: 7.5 °C

Procedure:
A 22-L, 3-neck, round bottom flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 425 g (4.88 mol) of (3R)-3-hydroxypyrrolidine, 8 L of dichloromethane, and 1 L (7.17 mol) of triethylamine. The solution was cooled to 5-10° C. with an ice bath and then 1000 g (5.86 mol) of benzyl chloroformate was added dropwise over a period of about 1.5 h keeping the reaction temperature below 20° C. The reaction mixture was stirred for an additional h in the ice bath, then the bath was removed and the reaction mixture was allowed to warm to ambient temperature overnight. The mixture was poured into a large extractor containing about 15 L of saturated aqueous sodium bicarbonate solution. The aqueous phase was back-extracted with two 2-L portions of dichloromethane. The combined organics were dried over magnesium sulfate and concentrated to give an orange oil. The crude material was taken up in dichloromethane, applied to a 5-kg column of silica gel prepacked in 50% ethyl acetate/hexane, and eluted sequentially with 8 L of 50%, 16 L of 75%, then 100% ethyl acetate/hexane to provide the title compound as a yellow oil which crystallized upon standing.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([O:9][C:16](=[O:18])[CH3:17])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC(c1ccccc1)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(c1ccccc1)c1ccc(Cl)nc1
Reaction time: 16 h

Procedure:
To a solution of (6-chloro-pyridin-3-yl)-phenyl-methanol (2 g, 9.10 mmol) in dichloromethane (25 ml) were added acetic anhydride (3.5 ml, 36.4 mmol) and DMAP (1.10 g, 9.10 mmol). The reaction mixture was stirred for 16 hours, and then was washed with water, dried and concentrated to give acetic acid (6-chloro-pyridin-3-yl)-phenyl-methyl ester as a viscous liquid. LC/MS (m/z) 262.12 [(M+H)+]; HPLC Rt: 3.011 min.
Reaction SMILES: Cl.NO.[CH:4]1([C:7](=[O:23])[C:8](=[CH:19][N:20](C)C)[C:9]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)=[O:10])[CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:7]2[O:23][N:20]=[CH:19][C:8]=2[C:9]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)=[O:10])[CH2:6][CH2:5]1
Reactant: CN(C)C=C(C(=O)c1ncc(Cl)cc1Cl)C(=O)C1CC1
Agent: Cl
Agent: NO
Solvent: CCO
Product: O=C(c1cnoc1C1CC1)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of hydroxylamine hydrochloride (0.4 g) and 3-cyclopropyl-1-(3,5-dichloropyridin-2-yl)-2-(dimethyl amino)methylenepropan-1,3-dione (1.68 g) in ethanol was stirred at room temperature overnight. The solvent was removed by evaporation and the residue was dissolved in dichloromethane. The resulting solution was washed with water, dried (anhydrous magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography on silica eluted with a mixture of ethyl acetate and hexane to yield 5-cyclopropyl-4-(3,5-dichloropyridin-2-oyl)isoxazole (compound 1, 0.38 g) as a white solid, m.p. 81.9°-83.1° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.Br.Br.Br.[CH2:12]([C:14]1[C:15]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([C:31]4[NH:40][C:34]5[CH2:35][CH2:36][NH:37][CH2:38][CH2:39][C:33]=5[N:32]=4)=[N:27][NH:28]3)=[CH:24][CH:23]=2)=[CH:16][C:17]([F:21])=[C:18]([OH:20])[CH:19]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:15]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[NH:40][C:34]4[CH2:35][CH2:36][N:37]([C:6]([C:3]5[CH:4]=[CH:5][S:1][N:2]=5)=[O:8])[CH2:38][CH2:39][C:33]=4[N:32]=3)=[N:27][NH:28]2)=[CH:24][CH:23]=1)[CH3:13]
Reactant: O=C(O)c1ccsn1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccsn3)CC4)n[nH]c2c1
Yield: 25.6 %

Procedure:
The title compound was prepared from isothiazole-3-carboxylic acid (11 mg, 85 μmol) and 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) using the method of Example 8. The crude material was purified by HPLC Method B to afford 10.3 mg of the title compound.
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][NH:6][C:5]=2[CH:4]=1)=[O:2].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl>[OH:2][CH2:1][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][NH:6][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1c[nH]c2cc(C=O)sc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2cc(CO)sc2c1=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 76.8 %

Procedure:
To a 0° C. mixture of ethyl 2-formyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (Preparation 6, 0.628 g, 2.5 mmol) and acetic acid (0.71 mL, 12.5 mmol) in 1,2-dichloroethane (23 mL) was added sodium triacetoxyborohydride (1.06 g, 5.0 mmol). The mixture was stirred at 0° C. for 5 minutes and at room temperature for 24 hrs. A saturated solution of sodium bicarbonate (25 mL) and methylene chloride (25 mL) were added. After stirring vigorously for 5 minutes, the mixture was filtered. The collected solid was washed with water and methylene chloride, then dried in vacuo, leaving the title compound as a pale yellow solid (0.486 g).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.B(OCCCC)(OCCCC)[O:28]CCCC.OO.Cl>CCOCC>[OH:28][C:4]1[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: OO
Solvent: CCOCC
Product: Oc1cccc2c1sc1ccccc12
Temperature: 25 °C
Yield: 56.9 %

Procedure:
Dibenzothiophene (18.4 g, 0.10 mole) and N,N,N',N'-tetramethylethylenediamine (14.0 g, 0.12 mole) were dissolved in 200 ml dry ether. Butyl lithium (0.1 mole) in ether was added dropwise under stirring at room temperature. The reaction mixture was then refluxed for 1 hour. The mixture was cooled to -70°C and freshly distilled tributyl borate (23.0 g, 0.10 mole) was added. After stirring for 2 hours the solution was allowed to warm up to room temperature. Perhydrol (19 ml) was added dropwise and the mixture was refluxed for 1.5 hours. Hydrochloric acid was added and the ether was separated. The ether was washed with 10 % ferrous ammonium sulphate solution and then extracted with sodium hydroxide solution. The alkaline aqueous solution was acidified and extracted with ether, which after evaporation gave 11.4 g (57 %) beige crystals. Recrystallization from aqueous methanol gave light-brownish needles with m.p. 167°-168°.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]2[NH:22][CH2:23][CH2:24][O:25][C:20]=2[CH:19]=1>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:21]3[CH:26]=[CH:27][C:18]([O:17][CH3:16])=[CH:19][C:20]=3[O:25][CH2:24][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1ccc2c(c1)OCCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCOc3cc(OC)ccc32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 6.98 (s, 1H), 6.94 (d, J=9.6 Hz, 1H), 6.44-6.41 (m, 2H), 4.33-4.30 (m, 2H), 4.18-4.08 (m, 3H), 3.75 (s, 3H), 1.92-1.78 (m, 2H), 1.10-1.00 (m, 1H), 0.95 (t, J=7.3 Hz, 3H), 0.81-0.77 (m, 1H), 0.60-0.48 (m, 2H), 0.38-0.20 (m, 1H); HRMS (ESI) m/z 376.1452 [(M+H)+, calcd for C19H23N3O3Cl 376.1428].
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:16][N:17](CC)CC.C[Si](C#N)(C)C>C(#N)C.C(Cl)Cl>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:16]#[N:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc(Cc2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1cc(Cc2ccccc2)ccn1
Yield: 77.2 %

Procedure:
To a solution of 4-benzylpyridine-N-oxide (8.8 g, 48 mmol) in acetonitrile (50 mL) was added Et3N (9.9 mL, 71.2 mmol). Neat trimethylsilyl cyanide (15.8 mL, 118 mmol) was added dropwise. The resulting solution was heated at reflux for 10 h under nitrogen then after cooling, diluted with CH2Cl2 (150 mL). The resulting solution was washed with NaHCO3 (2×150 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by filtration on silica gel using EtOAc/n-hexane as eluant to afford the title compound as a pale yellow oil (7.2 g, 78%): 1H NMR (CDCl3) δ4.03 (s, 2H), 7.16 (d, J=7.2 Hz, 2H), 7.20-7.40 (m, 4H), 7.49 (s, 1H), 8.59 (d, J=5.1 Hz, 1H); IR (film) 2240, 1600, 1500 cm−1.
Reaction SMILES: [CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:26][CH2:25]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH:16]=[CH:25][CH3:26])=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1COCCO1
Reactant: CCCCCC1OCc2cc(C=O)ccc2O1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: CC=Cc1ccc2c(c1)COC(CCCCC)O2

Procedure:
A mixture of 4.8 g of 2-pentyl-1,3-benzodioxan-6-carboxaldehyde, 100 ml of dioxan, 5 g of finely powdered potassium carbonate and 11.5 g of ethyltriphenylphosphonium bromide is heated to boiling under reflux for 24 hours. The inorganic salts are filtered off and back-washed with dioxan and the filtrate is evaporated. The residue is stirred up with hexane. Insoluble triphenylphosphine oxide is filtered off and the filtrate is evaporated. The residue is distilled at 210° C./11 mmHg in a bulb-tube. The turbid distillate is re-distilled at 130° C./0.1 mmHg in a bulb-tube. 2.5 g of crude, oily 2-pentyl-6-propenyl-1,3-benzodioxan are obtained.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.CN.C[CH2:23][N:24](CC)CC>C1COCC1>[CH3:23][NH:24][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNc1ncc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
(100 mg, 0.38 mmol) 2-Methanesulfonyl-5-phenylethynyl-pyrimidine (Example 8, step 2), methylamine hydrochloride (52 mg, 0.77 mmol, 2 equiv.) and Et3N (220 μl, 1.55 mmol, 4 equiv.) were suspended in 1 ml THF and stirred for 1 hour at 65° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography by directly loading the crude material onto a silica gel column and eluting with (heptane:ethyl acetate 100:0->0:100). The desired methyl-(5-phenylethynyl-pyrimidin-2-yl)-amine was obtained as a white solid (38 mg, 47%), MS: m/e=210.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:9]1[C:10]([F:28])=[C:11]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:18]([SH:21])[NH:19][N:20]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44]Br>CN(C=O)C>[CH2:29]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:18]3[S:21][CH2:43][CH2:44][N:19]3[N:20]=2)[C:10]=1[F:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]c(S)c1-c1ccncc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1nn2c(c1-c1ccncc1)SCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
5-(3-Dibenzylamino-2,6-difluoro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (1.26 g, 2.6 mmol) was dissolved in dry DMF (33 mL) under nitrogen atmosphere. Solid potassium carbonate (1.8 g, 13 mmol, 5 eq) was added followed by 1,2-dibromoethane (0.252 mL, 2.86 mmol, 1.1 eq) and the suspension was stirred at room temperature for 4 hours. DMF was then removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The organic phase was washed with brine, dried over Na2SO4 and evaporated to dryness. 537 mg of dibenzyl-[2,4-difluoro-3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-amine were obtained as white solid (47% over 2 steps).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccnc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 250 mL round bottom flask, 2-fluoropyridine-3-carbaldehyde (2.5 g, 20 mmol) was dissolved in anhydrous ethanol (20 mL). The solution was cooled to 0° C. under nitrogen. NaBH4 (1.5 g, 40 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours and quenched by addition of water (5 mL). Na2SO4 (20 g) was added. After 10 minutes, the mixture was filtered. The filtrate was evaporated to provide (2-fluoropyridin-3-yl)methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][PH3+].N12CCCN=C1CCCCC2>C(#N)C>[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[CH:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccccc1OCc1ccccc1
Reactant: COCOc1ccccc1C[PH3+]
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCOc1ccccc1C=CCCc1ccccc1OCc1ccccc1
Yield: 64.4 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 2.51 g of 3-(2-benzyloxyphenyl)propanal, 5.6 g of 2-methoxymethoxybenzylphosphonium chloride (prepared as described in Preparation 2) and 1.91 g of 1,8-diazabicyclo[5,4,0]-undec-7-ene were reacted in 50 ml of acetonitrile. The crude product, extracted as described in the first part of Preparation 3, was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.52 g (yield 64%) of 1-(2-methoxymethoxyphenyl)-4-(2-benzyloxyphenyl)-1-butene as a colorless oil.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[C:19](C#N)[C:20]#[N:21].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[C:19]([C:20]#[N:21])=[N:7][NH:6][C:5]=1[Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#CC(C#N)=Cc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)c1[nH]nc(C#N)c1-c1cccs1
Reaction time: 0.33 h

Procedure:
After a solution of trimethylsilyldiazomethane in hexane (0.6 mol/L, 5 mL) was added to tetrahydrofuran (20 mL) under an argon atmosphere, to this reaction mixture was added a solution of n-butyl lithium in hexane (2.6 mol/L, 1.08 mL) in a dropwise manner over 5 minutes at −78° C., and this mixture was stirred at same temperature for 20 minutes. And then to this reaction mixture was added a solution of 2-thiophene-2-ylmethylene malononitrile (0.32 g) in tetrahydrofuran (5 mL) in a dropwise manner over 20 minutes. To this reaction mixture was added saturated aqueous ammonium chloride solution, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. This residue was washed with hexane to give 4-thiophene-2-yl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile (0.496 g). To the 4-thiophene-2-yl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile were added methanol (20 mL) and 1.0 mol/L aqueous sodium hydroxide solution (20 mL), and this mixture was heated to reflux for 2 hours. This reaction mixture was acidified (pH1) with adding 1.0 mol/L hydrochloric acid, the precipitated solid was collected by filtration. This obtained solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.154 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:21][C:22]1[C:23]([F:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2)C1C=CC=CC=1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[F:32][C:23]1[C:22]([O:21][C:12]2[C:11]3[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[CH:10]=3)[N:15]=[CH:14][N:13]=2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:31])[NH:27]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A solution of 6-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (1.32 g, 3 mmol), ammonium formate (1.94 g, 30 mmol) and 10% palladium on carbon (0.2 g) in DMF (15 ml) containing water (2 ml) was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether, filtered, washed with diethyl ether followed by water and dried under vacuum over P2O5 overnight to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (1 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH:40]3[CH2:43][CH2:42][CH2:41]3)=[CH:37][CH:38]=2)=CC=1)([O-])=O.C(Cl)Cl>CC(C)=O>[CH:40]1([O:39][C:36]2[N:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: O=C(Nc1ccc(OC2CCC2)nc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC5CCC5)nc4)CC3)c2cc1OC
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (114.1 mg, 418 μmol), as prepared in Example 1d, (6-cyclobutoxy-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester (151 mg, 459 μmol), as prepared in the preceding step, and DCM (818 μL) was treated with TEA (63 μL, 455 μmol) in one portion, and stirred under air at 45° C. for 30 min. The reaction mixture was then directly applied to a flash silica column (3:4 hex/acetone) to provide the title compound as a foam (141.1 mg, 73%). This material was taken up in 2 M K2CO3 (2 mL) and extracted with DCM (2×2 mL). The combined organic layers were dried (Na2SO4), concentrated, and repurified with a silica flash column (9:2 EtOAc/acetone) to provide analytically pure title compound as an off-white foam (84.4 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.97 (d, 1H), 7.77 (dd, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 6.67 (d, 1H), 6.39 (br s, 1H), 5.11 (m, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.60 (tt, 1H), 3.18 (td, 2H), 2.51-2.37 (m, 2H), 2.24-1.94 (m, 6H), 1.89-1.57 (m, 2H). LC-MS (ESI): calcd mass 463.2, found 464.3 (MH+). Anal. Calcd for C25H29N5O4: C, 64.78; H, 6.31; N, 15.11. Found: C, 64.64; H, 6.24; N, 15.04.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](=[CH:20]\[CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)/[C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:27]([Mg]Br)=[CH2:28].Cl>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:14](=[O:15])[CH:27]=[CH2:28])=[CH:20]\[CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution (10 mL) of (2E)-2-[4-(cyclopropylsulfonyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propan-2-enamide (1.13 g) in tetrahydrofuran was added vinylmagnesium bromide (1.0M tetrahydrofuran solution, 9 mL) under ice-cooling, and the mixture was warmed to room temperature and stirred overnight. An excess amount of 1M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (426 mg, yield 41%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 347 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>CCCCCC>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:11])=[CH:20][CH:21]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: CCCCc1ccc(CNCCCCCCO)cc1
Solvent: CCCCCC
Product: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2ccc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1.46 g of 2,4-dimethylphenyl isocyanate in 100 ml of hexane was added a solution of 2.63 of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol (prepared as described in Example 489) in 500 ml of hexane. The mixture was stirred at room temperature for 2 hours. Evaporation gave a gum. The gum was purified by chromatography to yield 2.81 g of the desired product as a colorles gum.
Reaction SMILES: [C:1]([C:4]1[C:16](O)=[CH:15][C:14]2[N:13](CCCN(C)C)[C:12]3[CH:11]=[CH:10][C:9]4[C:24](=[O:27])[CH2:25]C[C:8]=4[C:7]=3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]>O.Cl.C(O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[C:7]([C:6]=2[CH:5]=1)=[CH:8][C:9]([C:24](=[O:27])[CH3:25])=[CH:10][CH:11]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c3c4c(ccc3n(CCCN(C)C)c2cc1O)C(=O)CC4
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc2[nH]c3ccc(C(C)=O)cc3c2c1
Yield: 157.1 %

Procedure:
9-Acetyl-8-hydroxy-1,2-dihydro-6-(3-dimethylaminopropyl)-cyclopenta[c]carbazole-3-one (7.81 g, 21.46 mmol, 1 eq) was dissolved in a mixture of water (20 mL) and 10% HCl solution (20 mL) in ethanol (200 mL), and the homogeneous solution evaporated to dryness. The residue was dried in vacuum overnight to give 8.47 g of Example 4 as a gray solid.