Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:25])[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([C:22](O)=[O:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[O:10])[CH:7]=1.Cl.C[O:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:34])[CH3:33])[NH2:31].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:25][C:4]1[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:20])([CH3:21])[C:22]([NH:31][CH:30]([CH:32]([CH3:34])[CH3:33])[C:29]([OH:28])=[O:35])=[O:23])=[CH:14][CH:13]=2)=[O:10])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)O)cc2)c1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)NC(C(=O)O)C(C)C)cc2)c1

Procedure:
Using RSR13 acid (1.5 g, 4.4 mmol), valine methyl ester hydrochloride (739 mg, 4.4 mmol) and 1-hydroxybenzotriazole hydrate (635 mg, 4.8 mmol), N-methylmorpholine (666 mg, 6.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.01 g, 5.3 mmol) in dimethylformamide (30 mL), the three isomers were prepared in 1.9 g yield (99%).
Reaction SMILES: [CH2:1]([S:6]([CH2:8][CH2:9][CH2:10]Cl)=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Na+]>>[CH2:1]([S:6]([CH2:8][CH2:9][CH2:10][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCS(=O)CCCCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCS(=O)CCCN1CCCCC1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
Heat 3-chloropropyl isopentyl sulfoxide (400 mg, 2.03 mmol) and piperidine (1.0 g, 12 mmol) at 125° C. for 45 minutes. Cool to room temperature, treat with 5N sodium hydroxide, extract with ethyl acetate (3×25 mL), and dry (MgSO4). Concentrate in vacuo to yield 240 mg yellow oil. Purify by silica gel chromatography (50% ethyl acetate/methanol) to yield 180 mg of the title compound as a clear oil.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)=[CH:9][C:8]=1[F:26])(C)(C)C>C(O)(C(F)(F)F)=O>[Cl:13][C:11]1[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)=[CH:9][C:8]([F:26])=[C:7]([CH:12]=1)[C:6]([OH:27])=[O:5]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
t-butyl-5-chloro-4-(4-chloro-3-(trifluoromethyl)phenoxy)-2-fluorobenzoate (Preparation 50, 245 mg, 0.58 mmol) was dissolved in TFA (4 mL) and the reaction stirred at room temperature for 2 h. The TFA was removed under reduced pressure to give the title compound (219 mg, quant.) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.[C:13](#[N:15])C.ClS(N=C=O)(=O)=O.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]#[N:15]
Reactant: CC#N
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]c(C)c(C#N)c2c1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a 0° C. solution of 5-Methoxy-2-methyl-1H-indole (5 g, 31.0 mmol), dry acetonitrile, (90 mL) was slowly added chlorosulfonyl isocyanate (3 mL, 34.1 mmol). The reaction was stirred and allowed to warm to room temperature and stirred for an additional four hours followed by the addition of dimethyl formamide (4.8 mL (62.0 mmol)and then stirred for an additional 1.5 hours at room temperature. The reaction was poured into water and extracted with diethyl ether. The aqueous layer was adjusted to pH 9 with 1M potassium carbonate, and extracted with diethyl ether. The ether layers were combined and dried over magnesium sulfate, filtered and concentrated. Crystallization of the residue from ether and hexane gave 5-methoxy-2-methyl-1H-indole-3-carbonitrile (3.86 g) in 67% yield as a light pink solid. C11H10N2O: GC/MS r.t.=4.06 min., m/z 186; 1H NMR (CDCl3): δ 7.22 (d, 1H, J=8.3 Hz), 7.08 (s, 1H), 6.86 (d, 1H, J=8.3 Hz), 3.86 (s, 3H), 2.60 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[SH:11].Br[C:13]1[O:17][CH:16]=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=1>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[S:11][C:13]1[O:17][CH:16]=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=1
Reactant: Fc1cc(F)c(F)c(S)c1F
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2c(F)c(F)cc(F)c2F)c1

Procedure:
In an open flask, cuprous oxide (1.95 g., 13.7 mmoles) was combined with 2,3,5,6-tetrafluorothiophenol (5.0 g., 27.4 mmoles) in 40 ml. of dimethylformamide and heated at 140° C. for 2 hours. The reaction was cooled, 5-bromofuran-3-carboxylic acid (2.62 g., 13.7 mmoles) in 50 ml. of dimethylformamide was added, the reaction mixture refluxed for 2 hours, and product (2.75 g.) isolated according to the procedure of Example 9. Recrystallization from methanol/water gave purified 5-(2,3,5,6-tetrafluorophenylthio)furan-3-carboxylic acid (1.78 g., m.p. 150°-153° C., m/e 292).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)c(C(C)=O)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)c(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-acetyl-4-methylbenzoate (compound 27.1, 200 mg, 1.04 mmol) in chloroform (4 mL). Bromine (53 μL, 1.04 mmol) was added drop-wise and the solution was stirred for 2 h at room temperature, then concentrated under reduced pressure. Obtained 300 mg (crude) of the title compound as a brown solid.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[O:8][C:9]4[C:14]([O:15][C:16]=3[C:17](=O)[NH:18][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][CH:12]=[CH:11][CH:10]=4.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:17]1[N:18]=[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]2=[C:7]2[C:16]=1[O:15][C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[O:8]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2c2c1Oc1ccccc1O2
Product: Clc1nc2ccccc2c2c1Oc1ccccc1O2

Procedure:
Under an inert atmosphere, [5H]-7,12-dioxa-5-azabenz[a]anthracen-6-one is brought to reflux of phosphorus oxychloride for 6 hours. The solvent (phosphorus oxychloride) is then evaporated off under vacuum and the crude mixture is chromatographed by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][C:22]3([OH:25])[CH2:24][CH2:23]3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1.[CH3:28][C:29]1[N:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][C:22]4([OH:25])[CH2:24][CH2:23]4)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=3[N:3]=[C:2]2[O:35][C:32]2[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cn1c(=O)n(CCC2(O)CC2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2nc3c(c(=O)n(CCC4(O)CC4)c(=O)n3C)n2Cc2ccc(Cl)cc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (128 mg, 0.282 mmol, intermediate 56) in DMF (5 mL) was added 6-methylpyridin-3-ol (37 mg, 0.338 mmol), followed by potassium carbonate (58 mg, 0.423 mmol). The reaction was stirred at 80° C. for 2 h. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-((6-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione (110 mg, 80.9% yield) as white solid. 1H-NMR (CD3OD) δ 8.457-8.451(d,1H), 7.776-7.748(d,1H), 7.470-7.374(m, 5H), 5.519(s,2H), 4.291-4.256(t,2H), 3.411(s,3H), 2.584(s,3H), 1.867-1.832(t,2H), 0.618-0.610(m, 2H), 0.403-0.387(m,2H). LCMS retention time 2.619 min; LCMS MH+ 482.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:29]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:30])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25]
Reactant: O=COc1ccccc1
Reactant: CC(c1cnc(OCC(F)(F)C(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Product: CC(c1cnc(OCC(F)(F)C(F)F)c(Cl)c1)N1Cc2c(ccnc2C(=O)Oc2ccccc2)C1=O
Yield: 70 %

Procedure:
The title compound is prepared in 70% yield (130 mg, brown oil) from 4-chloro-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.34 mmol, Intermediate-77, single enantiomer) and phenyl formate (84 mg, 0.69 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [OH:1][N:2]([CH3:13])[C:3](=[NH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:24]([O:23][C:21]([C:14]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:1][N:2]([CH3:13])[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])=[N:12]1)=[O:22])[CH3:25]
Reactant: COc1ccccc1C(=N)N(C)O
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2ccccc2OC)N(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a stirred solution of N-hydroxy-2-methoxy-N-methyl-benzamidine (3.3 g) in ethanol (100%) was added diethyl acetylenedicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred for 2 h at room temperature. The reaction mixture was then concentrated and purified on silica gel column using (3:7 to 2:3 ethyl acetate/hexanes) to afford the title product as a yellow oil (4.93 g, 70% yield). 1HNMR (500 MHz, CDCl3) δ: 7.56 (1H, dd, 7.6, 1.5 Hz), 7.44 (1H, td, J=7.6, 1.6 Hz), 6.99 (1H, t, 7.5 Hz), 6.95 (1H, d, J=8.2 Hz), 4.36–4.10 (4H, m), 3.85 (3H, s), 3.43 (1H, d, J=16.48 Hz), 3.05 (3H, s), 3.04 (1H, d, J=16.48 Hz), 1.32 (3H, t, J=7.02 Hz), 1.25 (3H, t, J=7.02 Hz). HRMS (ESI) calcd for C17H23N2O6 (M+H): 351.1556; found: 351.1553.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:8]=[CH:7][NH:6][C:5]=1[C:9]([O:11]C)=[O:10].C1COCC1.Cl>CO>[Cl:3][C:4]1[CH:8]=[CH:7][NH:6][C:5]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1[nH]ccc1Cl
Temperature: 60 °C
Yield: 86.4 %

Procedure:
A solution of 1M LiOH (7.415 ml, 7.415 mmole) was added to methyl 3-chloro-1H-pyrrole-2-carboxylate (0.2958 g, 1.854 mmole) dissolved in methanol (4 ml). To the solution was added THF (4 ml) and the resulting mixture was heated to 60° C. for 4 h. The mixture was acidified with 1M HCl and partitioned with EtOAc. The organic phase was dried over MgSO4 and evaporated to afford the title compound (0.2331 g, 86%) as a brownish solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 11.01 (br. s., 1H), 7.03 (t, 1H), 6.23 (t, 1H). MS: m/z 146.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([Cl:1])[N:6]([CH3:7])[N:5]=1
Reactant: BrBr
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(CBr)c([N+](=O)[O-])c1Cl

Procedure:
5-Chloro-1,3-dimethyl-4-nitropyrazole (43 g, 0.29 moles) was dissolved in carbon tetrachloride (430 ml), bromine (12 ml) was added and the reaction mixture stirred at reflux for 48 hours whilst illuminating with a 500 W light source. A second portion of bromine (12 ml) was added and the reaction mixture refluxed for a further 48 hours. The reaction mixture was cooled and chromatographed on silica (gradient elution commencing with hexane and increasing the proportion of dichloromethane from 0 to 100%). Fractions containing the product were evaporated yielding the title compound as a white solid. (35 g. 47%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][Si:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH:29]=O>C(Cl)Cl.CCOCC>[Br:21][C:20]([Br:24])=[CH:29][CH2:28][CH2:27][Si:26]([CH3:32])([CH3:31])[CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)CCC=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[Si](C)(C)CCC=C(Br)Br
Reaction time: 0.5 h
Yield: 62 %

Procedure:
This known compound was prepared by a modification of the procedure in Piers, E.; Gavai, A. V. J. Org. Chem. 1990, 55, 2374. To a flame dried flask was added dry CH2Cl2 (150 mL) and triphenylphosphine (16 g, 61.2 mmol) The temperature was lowered to 0° C. and CBr4 (10.15 g, 30.6 mmol) was added portionwise. After 30 min, a solution of 3-trimethylsilylpropanal (2.0 g, 15.3 mmol) in dry CH2Cl2 (20 ml) was added. After 1 h at 0° C., the reaction was diluted with ether and filtered through celite. The celite was rinsed with ether (4×50 mL) and the combined ether solution was extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NH4Cl (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give a crude white solid. The solid residue was washed with pentane. The pentane solution was concentrated and the oily residue was chromatographed on silica gel (pentane 100%) to give (4,4-dibromo-but-3-enyl)trimethylsilane as a clear oil weighing 3.7 g. 1H NMR showed 27% contamination by remaining pentane which gives a corrected yield of 62%: IR (neat, cm−1) 2953, 2922, 2898, 1620, 1443, 1413, 1249, 1176, 1034, 986, 859, 837; 1H NMR (300 MHz, CDCl3) δ0.03 (s, 9 H), 0.62-0.67 (m, 2 H), 2.06-2.14 (m, 2 H), 6.41 (t, J=7 Hz 1 H); 13C NMR (75 MHz, CDCl3) δ−1.9, 15.1, 27.7, 87.5, 141.2.
Reaction SMILES: [NH2:1][CH:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1>Cl(O)(=O)(=O)=O>[NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 37 °C
Reaction time: 20 h

Procedure:
The microbial cells recovered from 10 ml of the culture medium obtained in Examples 1, 2, and 3 were suspended in 10 ml of the reaction medium (2.5 g/L D,L-tryptophan, 0.05 mM pyridoxal 5'-phosphate, 300 mM potassium phosphate buffer (pH 8.0)) and the reaction was carried out with shaking at 37° C. for 20 hours. The optical purity and amount of tryptophan after the reaction were determined with Crown Pak CR(+) (product of Daicel Chemical Industries, Ltd.) using perchloric acid solution (pH 2.0) as eluent at 40° C. The results of the reaction were shown in Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)([C:14]([O:16]C)=O)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>CCCCCCC>[O:16]=[C:14]1[C@:12]2([CH:11]=[CH:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13]2)[CH2:18][CH2:19][O:20]1
Reactant: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@]2(CCOC2=O)C1
Temperature: 19 °C
Reaction time: 1 h

Procedure:
A 12-L three-neck round bottom flask with overhead mechanical stirrer, 2-L addition funnel and nitrogen inlet was charged the product of Example 1, Step A (1149 g, 2.875 mol, 1 eq) and THF (5.75 L). The addition funnel was charged with TBAF (1M solution in THF, 2.875 L, 2.875 mol, 1 eq) and this solution was added dropwise over ˜1 h. The temperature increased from 17 to 21° C. and the reaction was clear orange at the end. The reaction was stirred for 1 h at rt, when it was judged complete by TLC and HPLC. The reaction was poured into a 22-L separatory flask charged with EtOAc (4 L) and the organic layer was washed with brine (2 L). The organic layer was washed with additional brine (3×2 L) and these aqueous fractions were discarded. Heptane (4 L) was added and the organic layer was washed with water (3×2 L), brine (2×2 L) and the clear organic layer was checked by NMR for removal of n-Bu4NX. The organic layer was evaporated at 45° C. to about 750 mL, when the solution became hazy, heptane (800 mL) was added and instant crystallization of a white solid resulted. More heptane (300 mL) was added and the mixture was swirled at 40° C. for 10 min on the rotovap bath. Ice was added to bath and the suspension was stirred at 13° C. for 10 min. The solid was filtered on a Buchner funnel, washed with heptane (3×100 mL) and provided the product of Step A. 1H NMR (CHLOROFORM-d) δ: 6.02 (dd, J=5.4, 2.4 Hz, 1H), 5.77 (d, J=5.4 Hz, 1H), 5.21 (d, J=9.0 Hz, 1H), 4.91 (t, J=8.7 Hz, 1H), 4.37 (dd, J=7.5, 6.5 Hz, 2H), 2.21-2.39 (m, 3H), 2.07 (dd, J=13.8, 2.6 Hz, 1H), 1.44 (s, 9H). Calculated for C13H19NO4: 276.1 (M+23). found: 276.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[CH:35]=[CH:34]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[CH:35]=[CH:34]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4c(ccn4C)c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (335 mg, 0.68 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (281.5 mg, 2.04 mmol), 5-hydroxy-1methylindole (100 mg, 0.68 mmol) and DMA (4.0 ml) for 5 minutes. The mixture was then stirred at 90° C. for 4 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was purified by trituration with methanol then water to give 6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (148 mg, 49%).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cccc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (0.2 ml) was added to a solution of 10.07 g (72.9 mol) of 3-hydroxybenzoic acid in 10 ml of acetic anhydride. The resulting mixture was stirred at 60° C. for 1 hour and was then allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with benzene, and then dried in air. The precipitate was recrystallized from acetone-hexane, whereby 8.92 g of 3-acetoxybenzoic acid were obtained as colorless prisms (yield: 67.9%, melting point: 149-151° C.). A mixture of 8.92 g (49.5 mmol) of 3-acetoxybenzoic acid and 26.33 g (198 mmol) of aluminum chloride was then heated at 160° C. for 3 hours. Subsequent to the addition of ice and 1N hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and was then dried over MgSO4. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol, whereby 1.61 g of the title compound were obtained as pale yellow powder (yield: 18%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([CH2:45][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:43][CH:42]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(CCN2CCCCCC2)cc1
Agent: Cl
Product: COc1cc(NCCCc2ccc(CCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 48.5 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(2-azepan-1-ylethyl)benzoic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (32 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23]N.C(Cl)(Cl)Cl.CO>CO>[C:11]1([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:6]2[C:5](=[O:19])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Reactant: COC(CN)OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(Cn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO)OC
Reaction time: 72 h

Procedure:
To a suspension of 3.33 g of 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-4-pyridone in 20 ml of methanol is added 11.35 g of 2,2-dimethoxyethylamine at room temperature, and the mixture is stirred for 3 days. The reaction mixture is condensed under reduced pressure, and subjected to flash column chromatography on 100 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (20:1) to perform separation and purification. The title compound is obtained as colorless foam in a yield of 2.062 g.