Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].B(F)(F)F.CCOCC.[CH3:19][C:20]1([CH:26]=[CH2:27])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>O1CCOCC1.CCOCC>[CH3:19][C:20]1([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:26][CH2:27][C:4]2[C:3](=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][CH:5]=2)[O:9]1
Reactant: C=CC1(C)CCC(=O)O1
Reactant: Cc1cccc(O)c1C
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc2c(c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C

Procedure:
To a solution of 2,3-dimethylphenol (0.01 mol) and boron trifluoride diethyl etherate (0.016 mol) in dioxane (10 mL, dried on sodium) in a flask was added γ-methyl-γ-vinylbutyrolactone (0.016 mol) in dioxane (5.0 mL) via syringe pump over 50 min at 110° C. (oil bath, reflux) under nitrogen. The reaction mixture was cooled to room temperature and diluted with ether (200 mL), then washed with water (100 mL, 2×50 mL) and dried over sodium sulfate. Ether was then removed in vacuum. The residue was dissolved in methanol (30 mL), and solvent was removed in vacuum. The reaction mixture was purified by flash column chromatography on silica gel (eluant ethyl acetate/hexane, 1:1). Fractions containing the desired chroman were pooled, solvent was removed, and the compound was crystallized from ethyl acetate/hexane. M.P.: 93-94° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.[CH3:21][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][O:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH2:5][CH2:4][N:3]=1
Reactant: C[O+](C)C
Reactant: N#Cc1ccc(C2CCNC(=O)C2)cc1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Into a round-bottom flask, was placed a solution of 4-(2-oxopiperidin-4-yl)benzonitrile (347.2, 220 mg, 1.10 mmol, 1.00 equiv) in dichloromethane (10 mL). Trimethyloxonium tetrafluoroborate (244.2 mg, 1.65 mmol, 1.50 equiv) was slowly added and the resulting mixture was stirred for 2 h at room temperature. The pH was carefully adjusted to 8 with sodium bicarbonate (aq.). The organic layer was washed with 2×20 mL of H2O, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 212 mg (90%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][O:16][CH2:17]I.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:15][O:16][CH2:17][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 52.6 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35° C. for 5 min under nitrogen atmosphere then cooled to room temperature. Iodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35° C. for 3 h then cooled to room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silica cartridge (gradient: 0 to 50% AcOEt in hexanes) gave 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.45 g, 50% pure by LCMS, 26%) as a yellow liquid which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:15][C:14]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:13][C:5]2=[N:6][C:7]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10].[CH2:20]([O:22][CH:23]([N:25]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=2)=[N:28][N:27]=[N:26]1)[CH3:24])[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:29]4[N:25]([CH:23]([O:22][CH2:20][CH3:21])[CH3:24])[N:26]=[N:27][N:28]=4)=[CH:41][CH:40]=3)[C:5]2=[N:6][C:7]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10]
Reactant: CCOC(C)n1nnnc1-c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2nc(C(OC)OC)c(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc2cc(Br)c(C(OC)OC)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.3 %

Procedure:
0.61 g (1.86 mmole) of the compound obtained in step 8 was dissolved in 3 ml of DMF and thereto were added 0.79 g (2.05 mmole) of 2'-[1-(1-ethoxyethyl)-1H-tetrazol-5-yl]-biphenyl-4-ylmethylbromide and 0.51 g (3.72 mmole) of K2CO3. The resulting solution was stirred at room temperature for 5 hours and diluted with 50 ml of ethyl acetate. The resultant was washed with water (25 ml×3) and dried over Na2SO4, and then concentrated under reduced pressure and purified with column chromatography (hexane:ethyl acetate=1:1) to obtain 0.7 g of the title compound (yield 59%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[Cl:13][C:14]([Cl:38])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:27]=1.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:38][C:14]([Cl:13])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)=[O:34])[CH:27]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
(4-Trifluoromethyl-phenyl)-methanol (58 mg, 0.332 mmol) was added to a stirred mixture of 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (120 mg, 0.277 mmol), EDC×HCl (80 mg, 0.415 mmol), DMAP (3.4 mg, 0.028 mmol) and DCM (4 mL). The reaction mixture was stirred at rt overnight. More DCM was added and the mixture was washed with 0.25M HCl, the organic phase was dried through a phase separator and concentrated. The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as the eluent to yield the titled compound (105 mg, 64%) as a colourless oil; 1H NMR (400 MHz, CDCl3): δ 3.62 (s, 2H), 4.54 (s, 2H), 4.96 (s, 2H), 5.18 (s, 2H), 7.09-7.15 (m, 1H), 7.18-7.24 (m, 4H), 7.30-7.43 (m, 4H), 7.60 (d, 2H), 8.08 (d, 1H); Mass spectrum: M−H+ 590.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C@@:17]3([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)[C:16]3[CH:15]=[C:14]([Cl:24])[N:13]=[C:12]([F:25])[C:11]=3[O:10][C:7]2=[CH:8][CH:9]=1)=[N+]=[N-].[BH4-].[Na+].O>CO>[Cl:24][C:14]1[N:13]=[C:12]([F:25])[C:11]2[O:10][C:7]3[C:6]([C@@:17]4([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]4)[C:16]=2[CH:15]=1)=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3
Reactant: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Cl)nc(F)c1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(Cl)nc1F
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To a solution of (S)-7-azido-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.86 g, 2.384 mmol) in MeOH (15 mL) in a water bath was added sodium borohydride (0.420 ml, 11.92 mmol) in one portion. The resulting mixture was kept in the water bath and stirred for 10 min. The reaction went to completion and was carefully quenched with water, diluted with DCM and washed with 9:1 NH4OH/sat NH4Cl (10 mL). The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-5% MeOH/DCM to afford a pale yellow solid as (S)-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.354 g, 1.058 mmol, 44.4% yield).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CC#N>[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1cnn(C2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 4-(4-bromopyrazol-1-yl)piperidine hydrochloride (380 mg, 1.43 mmol) in CH3CN (10 ml) at 0° C. was added DIPEA (0.75 mlml, 4.3 mmol) followed by methanesulphonyl chloride (0.11 ml, 1.43 mmol), stirred at 0° C. for 1 hour then allowed to warm up to RT over 1 hour. The reaction then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (380 mg), which was used without further purification 1H NMR (400 MHz, Me-d3-OD): 7.84 (1H, s), 7.50 (1H, s), 4.40-4.27 (1H, m), 3.86 (2H, d), 3.05-2.93 (2H, m), 2.90 (3H, s), 2.25-2.01 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:25])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.I[CH2:27][CH3:28].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([O:25][CH2:27][CH3:28])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=3)[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=c1[nH]c2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a mixture of 8-chloro-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (437 mg), iodoethane (0.19 ml) and N,N-dimethylformamide (10 ml) was added potassium carbonate (326 mg) at room temperature, and the mixture was stirred at 80° C. for 15 hr, and allowed to be cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (116 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][CH:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]3[C:20]=2[N:19]=[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=32)=[CH:8][CH:9]=1)=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]3[C:20]=2[N:19]=[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=32)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCCCCC1C=CC(/C=C/c2ccc(C(=O)OC)o2)=C2N=C3CCCCC3=C21
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC1C=CC(CCc2ccc(C(=O)OC)o2)=C2N=C3CCCCC3=C21
Yield: 76 %

Procedure:
The hydrogenation of (E)-5-[2-(1,2,3,4-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)ethenyl]-2-furancarboxylic acid methyl ester from Example 33 was carried out at normal pressure and at room temperature. Thus 5.3 g of this material dissolved in 55 ml of absolute ethyl alcohol was hydrogenated in the presence of 0.3 g of 10% Palladium on carbon to give 4.0 g (76.0%) of 5-[2-(1,2,3,4tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-6yl)ethyl]-2-furancarboxylic acid methyl ester as a yellow oil after chromatographic purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2O.S([O-])([O-])=O.[NH4+:17].[NH4+].N>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:17]
Reactant: Cc1cnc2c(O)cccc2c1
Reactant: [NH4+]
Agent: N
Agent: O=S([O-])[O-]
Solvent: O
Product: Cc1cnc2c(N)cccc2c1
Yield: 91.3 %

Procedure:
3-methylquinolin-8-ol (Intermediate 30) (150 mg, 0.9 mmol) and ammonium sulphite (250 mg, 1.8 mmol) were added to aqueous ammonia (3 ml) and heated for 48 h. After cooling, water was added and the mixture was extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (130 mg, 86%).
Reaction SMILES: [N+](C1C=C[C:7]([C:8](Cl)=[O:9])=CC=1)([O-])=O.C(N)CCC.[CH2:18]([NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:8](=[O:9])[CH3:7])=[CH:26][CH:25]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(NC(C)=O)cc1

Procedure:
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-butyl amine in the amidation step. This yields N-n-butyl-4-nitrobenzamide (CPI1045).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([CH3:22])(C)[CH3:20])[C:11]([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:10]2OCCCC)(=O)=O.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].O>CN(C)C=O>[C:28]([O:27][C:25](=[O:26])[NH:24][CH2:23][C:11]1[N:12]([CH2:18][CH:19]([CH3:20])[CH3:22])[C:13](=[O:17])[C:14]2[C:9]([C:10]=1[C:7]1[CH:8]=[CH:9][CH:14]=[CH:15][CH:16]=1)=[CH:8][C:7]([CH2:6][N:41]1[C:37](=[O:47])[C:38]3[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:40]1=[O:42])=[CH:16][CH:15]=2)([CH3:29])([CH3:31])[CH3:30]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(COS(C)(=O)=O)cc12
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN3C(=O)c4ccccc4C3=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 165.9 %

Procedure:
To a solution of (3-{[(tert-butoxycarbonyl)amino]methyl}-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl)methyl methanesulfonate (1.1 g, 2.11 mmol) in N,N-dimethylformamide (20 mL) was added potassium phthalimide (0.47 g, 2.5 mmol), and the mixture was stirred at room temperature for 17 h. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL×2). The organic layers were combined, washed with 0.2N hydrochloric acid (100 mL), saturated aqueous sodium hydrogencarbonate (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2 (v/v)) to give tert-butyl{6-[(1,3-dioxo-1,3-dihydro-2H -isoindol-2-yl)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.99 g, 84%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([Cl:18])[C:3]=1[CH3:19].C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:2]([N:1]([C:30]([O:32][CH3:33])=[O:31])[C:30]([O:32][CH3:33])=[O:31])[C:3]([CH3:19])=[C:4]([Cl:18])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.094 mL, 0.54 mmol) followed by methyl chloroformate (0.033 mL, 0.43 mmol). The mixture was stirred at room temperature for 30 min. To the reaction mixture was added a catalytic amount of DMAP and another equivalent of methyl chloroformate. The reaction was stirred at room temperature over a weekend, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the bis-acylated product (67 mg, 50%). LCMS calculated for C19H18ClFNO5 (M+H)+: m/z=394.1. found: 394.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[OH:8][N:7]=[C:6]([Cl:11])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C=NO)cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(Cl)=NO)cn1

Procedure:
To a stirring mixture of 6-methylnicotinaldehyde oxime (500 mg, 3.67 mmol) in 4 mL DMF at room temperature, was added N-chlorosuccinimide (490 mg, 3.67 mmol) in roughly one tenth portions over 5 min. Additional N-chlorosuccinimide (175 mg, 1.31 mmol) was added after about 4 h. After a total of 6 h, the reaction mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and filtered. The filtrate was passed through a short silica gel column eluted with EtOAc. The eluant was concentrated under vacuum to provide the title compound as a light brown solid. All of this was used in the next step without further purification. HPLC: retention time=0.44 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:19])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:5]=[CH:4][N:3]=1
Reactant: OCCCN1CCCC1
Reactant: Oc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Product: Clc1ncnc2cc(OCCCN3CCCC3)cc(OC3CCOCC3)c12
Yield: 79.9 %

Procedure:
Using an analogous procedure to that described in Note [6] below Example 19, 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.112 g) was reacted with 1-(3-hydroxypropyl)pyrrolidine (0.062 g) to give 4-chloro-7-(3-pyrrolidin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline (0.125 g); NMR Spectrum: (CDCl3) 1.7–1.9 (m, 4H), 1.95–2.2 (m, 6H), 2.55 (br s, 4H), 2.65 (m, 2H), 3.65–3.75 (m, 2H), 4.0–4.1 (m, 2H), 4.2 (m, 2H), 4.75 (m, 1H), 6.6 (d, 1H), 6.95 (d, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 392 and 394.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11](=O)[C:10]2[CH:9]=[C:8]([CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:6][C:5]=2[CH2:4]1)[CH3:2].[H][H].Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:6][C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)c2cc(CC(=O)O)ccc2C1
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCC1CCc2cc(CC(=O)O)ccc2C1

Procedure:
5.4 g of 6-ethyl-5,6,7,8-tetrahydro-8-oxo-naphthalene-2-acetic acid are dissolved in 150 cc of acetic acid and hydrogenation is effected at 4 atmospheres of hydrogen pressure and 45° with the addition of 1 g of palladium/charcoal (10%) and 2 cc of 70% aqueous perchloric acid. After the take up of the calculated amount of hydrogen, filtration is effected, 2 g of sodium acetate are added and the solution is concentrated. The residue is divided between ether and water, the ether extract is dried over sodium sulphate and concentrated by evaporation. The resulting 6-ethyl-5,6,7,8-tetrahydronaphthalene-2-acetic acid is recrystallized from hexane and has a M.P. of 64°-66°.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][CH2:16][C:17]1([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=3)[CH:23]=[C:22]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:19][CH2:18]1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][CH2:16][C:17]1([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=3)[CH:23]=[C:22]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CC3)c2c1
Reaction time: 2 h
Yield: 107.5 %

Procedure:
TFA (120 mL) is added to a solution of crude diethyl 1-[(1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)methyl]-1H-indole-2,6-dicarboxylate (36 g, 81 mmol) in CH2Cl2 (700 mL) at room temperature. The reaction mixture is stirred for 2 h and the solvent is evaporated. The residue is dissolved in EtOAc (600 mL) and is washed with saturated NaHCO3 until the pH is about 7. The aqueous layer is extracted with EtOAc (2×100 mL) and the combined organic layers are dried (Na2SO4), and concentrated to afford the title compound (30 g, >99%) as a light yellow colored oil which is used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:22])=[CH:16][CH:15]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
Prepared from 6-aminoquinoline and 4-(dimethylamino)phenyl isocyanate. m/z (ES+) 307 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([Cl:22])=[C:16]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=1)=[O:11])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:22][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:9]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:7]([OH:6])[CH:8]=2)=[CH:17][C:16]=1[S:18]([NH2:21])(=[O:20])=[O:19]
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-benzoyl]-2-chloro-benzenesulfonamide (0.28 g, 0.61 mmol) dissolved in tetrahydrofuran (20 mL) is added 1 M tetrabutylammonium fluoride (1.23 mL, 1.22 mmol) in tetrahydrofuran. The reaction mixture is stirred at room temperature for 30 minutes The reaction is quenched with 1 N of HCl, and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate/methylene chloride provides 0.11 g (49%) of the title compound as a brown solid. 1H NMR (DMSO): δ 9.60 (s, 1H), 8.20 (d, J=2 Hz, 1H), 7.80 (m, 4H), 7.20 (m, 2H), 7.10 (d, J=8 Hz, 1H), 3.90 (s, 3H). Analytics calculated for C14H12ClNO3S: C, 49.20; H, 3.54; N, 4.10. Found: C, 49.90; H, 3.30; N, 5.06. MS (m/z): 342 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:15][C:14]=2[N+:24]([O-])=O)=O)C=C[CH:7]=1.O.O.Cl[Sn]Cl.[CH3:33][CH2:34][OH:35]>>[I:1][C:2]1[CH:7]=[C:9]([C:10]2[CH2:33][C:34](=[O:35])[NH:24][C:14]3[CH:15]=[C:16]([N:19]4[CH:20]=[CH:21][CH:22]=[CH:23]4)[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH:8]=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1cccc(I)c1)Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl[Sn]Cl
Solvent: O
Product: O=C1CC(c2cccc(I)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from 3-(3-iodo-phenyl)-N-(2-nitro-4-pyrrol-1-yl-phenyl)-3-oxo-propionamide (Example M8) by reductive cyclization with SnCl2.2H2O in EtOH at 70° C. according to the general procedure J (method b). Obtained as an olive solid (624 mg).