Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:19]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][C:39]([O:42][C:43](=[O:50])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:38][CH:37]=3)[S:33][C:32]=2[CH:51]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[ClH:1].[C:19]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[C:35]([C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:18][CH:17]=3)=[C:34]([C:36]3[CH:41]=[CH:40][C:39]([O:42][C:43](=[O:50])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:38][CH:37]=3)[S:33][C:32]=2[CH:51]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: O=C(Oc1ccc(-c2cc3ccc(OC(=O)c4ccccc4)cc3s2)cc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Oc1ccc(-c2sc3cc(OC(=O)c4ccccc4)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1)c1ccccc1

Procedure:
An acid chloride was formed from 18.1 g. of 4-(2-pyrrolidinoethoxy)benzoic acid, hydrochloride, as described in Example 1. The acid chloride was used to acylate 20 g. of 6-benzoyloxy-2-(4-benzoyloxyphenyl)benzo[b]thiophene as described above in Example 1, using 53.2 g. of aluminum chloride. A sample of the impure product, a tan foam, was recrystallized from denatured ethanol to obtain an analytical sample, m.p. 218°-222°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([O:32]COC)=[CH:28][CH:27]=1)[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5])[CH3:2].Cl.O.C(=O)([O-])O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]([CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[S:7]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CC(Cc1cccnc1)c1ccc(OCOC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)N(CC(Cc1cccnc1)c1ccc(O)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
To the solution of 8 ml of the solution of 1.11 g of N-ethoxycarbonyl-N-[2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide in dioxane was added 2 ml of aqueous 6N hydrogen chloride solution, and stirred at room temperature for 7 hours. To the reaction mixture were added water and methylene chloride, followed by further addition of sodium hydrogen carbonate. The organic phase was separated, which was then extracted with ethyl acetate from aqueous phase. The organic phases were combined and washed in saturated aqueous sodium chloride, followed by drying over magnesium sulfate to distill off the solvent under reduced pressure. The obtained residue was subjected to chromatography on a silica gel column, and from the fraction eluted with methanol-methylene chloride (1:99 v/v) was obtained 956 mg of N-ethoxycarbonyl-N-[2-(4-hydroxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:42])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:42])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCOCC4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(N4CCOCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M289) (383 mg, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (230 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:14]([N:18]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].Cl>>[CH:28]1([N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:22][CH:21]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: COc1cc(O)cc(OC)c1OC
Agent: Cl
Product: COc1cc(Oc2ccc(C(=O)N(C3CCCCC3)C(C)(C)C)cc2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and p-bromobenzoic acid N-tert-butyl-N-cyclohexyl amide (1.35 g, 4.0 mmol) 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: Cl.[CH:2](=[C:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH2:20](N1CCC(=O)CC1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:20]([N:12]1[CH2:13][CH2:14][C:9](=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C(=C1CCNCC1)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=C1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesis of 4-benzylidenepiperidine hydrochloride (1) In a stream of argon, 49.0 g (126 mmol) of benzyltriphenylphosphonium chloride was suspended in 100 ml of anhydrous tetrahydrofurane, and thereto 86 ml of butyllithium was added dropwise under cooling with ice. After stirring the mixture at room temperature for 1 hour, thereto was added dropwise a solution of 1-benzyl-4-piperidone in anhydrous tetrahydrofurane under cooling with ice and the obtained mixture was refluxed with heating for 15 hours. The reaction solution was filtrated, and diethyl ether and water were added to the filtrate, and the organic phase was taken out. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting oily matter was subjected to a column chromatography using 1 kg of silica gel and eluted with ethyl acetate-hexane (1:100 to 3:100) to obtain 22.6 g of 1-benzyl-4-benzylidenepiperidine.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[C:10]=1[N:16]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:17]1=[S:18]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Yield: 18.4 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.2 g of 2,6-dimethylphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (2.3 g) was obtained as a white solid (2.3 g). m.p. 128°-131° C. Anal. Calcd. for. C13H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.83; H, 6.50; N, 11.25. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[Cs+].[Cs+].BrCCl>C(#N)C>[CH2:11]1[O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=Cc1cccc(O)c1O
Reactant: O=C([O-])[O-]
Agent: ClCBr
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1cccc2c1OCO2
Temperature: 25 °C

Procedure:
To a mechanically stirred degassed mixture of 2,3-dihydroxy benzaldehyde (7.80 g, 56 mmol) and cesium carbonate (16.20 g, 84 mmol) in acetonitrile (110 ml) was added bromochloromethane (5.46 g, 84 mmol) and the resulting suspention was heated to reflux. After 5 hours the reaction was cooled to room temperature and filtered through celite with ethyl acetate washings. The filtrate was concentrated and directly chromatographed on silica gel using 9:1 hexane:ethyl acetate as eluent.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=[N:6][CH:5]=1.[BH4-].[Na+]>C(O)C>[F:20][C:17]([F:18])([F:19])[O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Reaction time: 4 h
Yield: 33.6 %

Procedure:
A solution of 535 mg (1.76 mmol) 5-(4-Trifluoromethoxy-phenyl)-nicotinic acid methyl ester in 16 ml Ethanol was treated at room temperature (r. t.) with 67 mg (1.76 mmol) of sodium borohydride. The mixture was stirred for 4 h. at r. t., then two days at 80° C. The mixture was poured on ice and extracted tree times with ethyl acetate. The combined organic phases were washed with water, dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/methanol 5:1) gave 159 mg (33%) of [5-(4-Trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH:5]=O.COC1C=CC(C)=CC=1[C:21](=C)[C:22]([OH:24])=[O:23].C(O)(=O)C=C>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH2:5][CH2:21][C:22]([OH:24])=[O:23]
Reactant: C=C(C(=O)O)c1cc(C)ccc1OC
Reactant: COc1ccc(C)cc1C=O
Agent: C=CC(=O)O
Product: COc1ccc(C)cc1CCC(=O)O
Yield: 899.7 %

Procedure:
10 mmol of the appropriate aldehyde are dissolved with 1.1 eq. of triethyl phosphonoacetate in 7 ml THF. At 0° C. 1 eq. of DBU is added and the reaction mixture is stirred over night at room temperature. Then, the reaction mixture is diluted with water, acidified with aq. HCl and extracted with diethyl ether. The organic layer is dried over MgSO4 and the solvent removed. This acrylic acid ester is used without further purification. The crude acrylic acid ester is suspended in 20 ml 1N NaOH and stirred over night. After the reaction is completed, the reaction mixture is acidified with 1N HCl and extracted with diethyl ether. The organic layer is dried over MgSO4 and the solvent evaporated; the desired acrylic acid is obtained in almost pure form. 11 mmol of the acrylic acid are dissolved in 20 ml MeOH, 1 eq. of NAHCO3 and 200 mg Pd/C (10%) are added and the reaction hydrogenated over night at room temperature and normal pressure. Filtration of the reaction mixture over Celite and removal of the solvent affords the desired product in good yield in pure form. In case one of the products is not sufficiently pure, one can also purify them via flash chromatography. According to the above-mentioned procedure, the following compound can be prepared: 2 g of 2-methoxy-5-methyl-benzaldehyde is transformed to 2.2 g of (2-methoxy-5-methyl-phenyl)-acrylic acid. 21 g of the before-mentioned acrylic acid are hydrogenated to yield 20 g of the desired 3-(2-methoxy-5-methyl-phenyl)-propionic acid. Further relevant starting compounds can be prepared similarly, such as e.g. 3-(2-methoxy-phenyl)-propionic acid, 3-(2-ethoxy-phenyl)-propionic acid or 3-(3-methoxy)-propionic acid, or 3-(1-methyl-imidazol-2-yl)-propionic acid.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][CH2:22][CH:23]=[CH2:24])=[O:19]>C1(C)C=CC=CC=1.O>[CH2:21]([O:20][C:18](=[O:19])[NH:10][C:8](=[NH:9])[S:7][CH3:6])[CH2:22][CH:23]=[CH2:24]
Reactant: CSC(=N)N
Reactant: C=CCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCCOC(=O)NC(=N)SC
Reaction time: 2.5 h
Yield: 15.9 %

Procedure:
To a solution of 2-methyl-2-thiopseudourea sulfate (12 g, 278 mmol) and potassium carbonate (12 g, 138 mmol) in toluene (50 ml) and water (50 ml) at 25° C. was added but-3-en-1-yl chloroformate (3.0 g, 134 mmol) then stirred for 2.5 h. The biphasic reaction mixture was separated, and the organic phase was washed with water (2×80 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to afford but-3-en-1-yl[imino(methylthio)methyl]carbamate (4.0 g, 96%). MS (EI) for C7H12N2O2S: 287 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)cn(C)c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(-c2ccccc2)c2ccc(C(=O)O)cc21
Reaction time: 4 h

Procedure:
A mixture of compound 16c (517 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) in THF/MeOH/H2O (4/4/4 mL) was stirred for 4 h. A 15% citric acid solution (20 mL) was added, and the mixture was then extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue, compound 16d, was dried under reduced pressure for 18 h.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8]>>[C:2]([Cl:4])(=[O:3])[C:1]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)(C)OC(=O)C(=O)Cl
Yield: 90.8 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step t-butyl alcohol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce t-butyl chlorooxalate having an assay of 100% and in a corrected yield of 90.8%. In the second step t-butyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product as described below:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:41])([CH3:40])[C@@H:11]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:31])[C:19]([CH3:30])([CH3:29])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13])(=[O:7])=[O:6].[N-:42]=[N+:43]=[N-:44].[Na+]>CS(C)=O>[N:42]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:41])([CH3:40])[C@@H:11]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:31])[C:19]([CH3:30])([CH3:29])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13])(=[O:7])=[O:6])=[N+:43]=[N-:44]
Reactant: CC(C)(COCc1ccccc1)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COCc1ccccc1)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]
Yield: 27.2 %

Procedure:
Following the general procedure for the preparation of azides of Description 16, [2,2-dimethyl-3-(phenylmethoxy)propanoyloxy]ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (46a) (0.47 g, 0.77 mmol, max.) dissolved in 4 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 90 mg (1.4 mmol) of sodium azide (NaN3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and n-heptane (Hptn) (EtOAc/Hptn=1:4) as eluent to provide a mixture of 0.13 g (27% yield) of the title compound (46b). Rf=0.17 (EtOAc/Hept=1:4). MS (ESI) m/z 642.20 (M+Na)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc2cc(Br)ccc2c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2cc(N3CCOCC3)ccc2c1
Temperature: 150 °C

Procedure:
To a solution of 6-bromo-naphthalene-2-carboxylic acid quinolin-7-ylamide, Example 32(b), (40 mg, 0.106 mmol) in dioxane (2 mL) was added tris(dibenzylideneacetone)dipalladium(0) (5 mg, Aldrich), biphenyl-2-yl-di-tert-butyl-phosphane (5 mg, Strem), morpholine (74 mg, 0.85 mmol, Aldrich) and lithium bis(trimethylsilyl)amide (0.53 ml of 1 M solution in THF, 0.53 mmol, Aldrich). The mixture was heated in microwave at 150° C. for 5 min, cooled to room temperature, and partitioned between satd NH4Cl (5 mL) and EtOAc (30 mL). The EtOAc layer was separated, washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (gradient, 5 to 10% (2 M NH3 in MeOH) in CH2Cl2) to provide the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 384 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:27][CH2:26][C:14]2([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH2:15]3)[CH2:26][CH2:27]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)C1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (585.5 g, 3.59 mmol) and tert-butyl 8-amino-2-azaspiro[4.5]decane-2-carboxylate (1.08 g, 4.24 mmol) in EtOH (10 mL) was added Et3N (722.3 mg, 7.14 mmol) and the reaction mixture was stirred at rt for 48 h then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as yellow oil (1.04 g, 76.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH2:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:31][C:32](=[O:34])[CH3:33])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1NC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
1-Amino-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (30 mg, 0.07 mmol) prepared in Example 21 was dissolved in dichloromethane (10 mL), and acetyl chloride (30.15 mg, 0.37 mmol) and triethylamine (40 mg, 0.37 mmol) were added thereto in order at 0° C. The mixture was stirred for 24 hrs at RT, washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 15 mg of the titled compound (yield: 45%).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4]OC.C(=O)([O-])O.[Na+].Cl.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[C:31]([O:33][C:34]([O:36][CH3:37])=[O:35])[C:30]([CH3:38])=[CH:29][C:28]=3[F:39])=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1.C([BH3-])#N.[Na+]>O.Cl.C(O)C.C(O)(=O)C>[F:39][C:28]1[CH:29]=[C:30]([CH3:38])[C:31]([O:33][C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([NH:15][CH2:4][CH2:3][O:2][CH3:1])=[CH:17][CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(N)ccc23)c(F)cc1C
Reactant: COCC(OC)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COCCNc1ccc2c(Nc3cc(OC(=O)OC)c(C)cc3F)ncnc2c1
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
A solution of methoxyacetaldehyde dimethyl acetal (1.27 g, 10 mol) in water (7 ml) and 2M hydrochloric acid (76 μl) was heated at 50-60° C. for 2 hours. The mixture was allowed to cool and adjusted to pH7.5 with saturated aqueous sodium hydrogen carbonate solution. This solution was added to a suspension of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (400 mg, 1 mmol), (prepared as described for the starting material in Example 30), in ethanol (32 ml) and acetic acid (95 μl, 1.5 mmol). The mixture was then stirred for 5 minutes, sodium cyanoborohydride (133 mg, 2 mmol) added and the solution adjusted to pH5.5 with glacial acetic acid. The mixture was stirred for 18 hours and the organic solvents removed by evaporation and the resulting aqueous mixture partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4 followed by 12/8) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-methoxyethylamino)quinazoline (308 mg, 77%) as a yellow foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]1([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=2[N:30]2[CH:34]=[N:33][N:32]=[N:31]2)[CH2:22][CH2:21]1.S(O)(C1C=CC(C)=CC=1)(=O)=O>CC(O)C>[CH:20]1([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]4)[C:5]([F:19])=[CH:4][N:3]=3)=[CH:25][C:24]=2[N:30]2[CH:34]=[N:33][N:32]=[N:31]2)[CH2:22][CH2:21]1
Reactant: Nc1ccc(C2CC2)c(-n2cnnn2)c1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3ccc(C4CC4)c(-n4cnnn4)c3)ncc2F)CC(C)(C)N1
Temperature: 100 °C

Procedure:
In a 100 mL round bottom flask to a solution of 2-chloro-5-fluoro-N-(2,2,6,6,-tetramethylpiperidin-4-yl)pyrimidin-4-amine (Compound 15; 0.18 g, 0.63 mmol) in 10 mL iPrOH, 4-cyclopropyl-3-(1H-tetrazol-1-yl)benzeneamine (0.18 g, 0.88 mmol) and TosOH (0.095 g, 0.50 mmol) were added. The reaction mixture was heated at 100° C. for 3 hours. LCMS analysis indicated the complete consumption of the mono-SNAr product and appearance of Compound III-118. The reaction mixture was then cooled to room temperature and volatiles were removed under reduced pressure. The crude reaction mixture was purified by column chromatography using DCM/2 M NH3 in MeOH to get tan solid that was further purified by tituration using DCM/hexanes.