Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N:4][CH:3]=1.[O:16]1[C:25]2[CH:24]=[C:23]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:22]=[CH:21][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:38]2[CH2:37][CH2:36][CH:35]([N:27]([CH2:26][C:23]3[N:22]=[CH:21][C:20]4[O:19][CH2:18][CH2:17][O:16][C:25]=4[CH:24]=3)[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:40][CH2:39]2)=[N:4][CH:3]=1
Reactant: O=CCn1c(=O)ccc2ncc(Br)cc21
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.5 %

Procedure:
To 7.00 g of (7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, a solution of 10.07 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 140 mL of chloroform and 1.57 g of acetic acid were added, and the mixture was stirred at room temperature for 19 hours, then, 8.77 g of sodium triacetoxyborohydride was added thereto and the mixture was stirred for 2 hours. To the reaction mixture, 140 mL of a saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, then washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and gradient elution with hexane:ethyl acetate=50:50 to 5:95, and then recrystallized in 24 mL of ethanol to obtain 11.26 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=3)[C:21]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc(CO)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 42.4 %

Procedure:
A solution of (3-Hydroxymethylphenyl)boronic acid (24 mg, 0.13 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA26 (8.4 mg, 42% yield). ESI-MS (M+H)+ m/z calcd 283.1, found 284.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=3)=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#Cc1cc(Br)cs1
Product: CC1(C)OC(=O)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
The product was prepared, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophenecarbonitrile according to the procedure outlined in Example 5, as a yellowish solid: mp 230–231° C. (decomposed); 1H-NMR (CDCl3) δ 8.32 (s, 1H, D2O exchangeable), 7.83 (d, 1H, J=1.5 Hz), 7.61 (d, 1H, J=1.4 Hz), 7.43 (dd, 1H, J=8.2, 1.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 6.85 (d, 1H, J=8.2 Hz), 1.78 (s, 6H); MS (EI) m/z 283 ([M−H]−, 100%); Anal. Calc. For C15H12N2O2S0.2H2O: C, 62.57, H, 4.34, N, 9.73. Found: C, 62.48, H, 4.31, N, 9.64.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=[C:29]([F:28])[CH:30]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(C(F)(F)F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 2-(3′-fluoro-5-hydroxy-5′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example B) and 3-fluoro-5-trifluoromethylbenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[S:21](=[O:31])(=[O:30])[N:20]=1>C(O)C>[CH2:2]([O:9][NH:10][C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[S:21](=[O:30])(=[O:31])[N:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C(NOCc2ccccc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
To a solution of O-benzylhydroxylamine hydrochloride (500 mg) and triethylamine (200 mg) in ethanol (10 ml) was added 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg). The mixture was stirred for 3 h and concentrated in vacuo. The crude product was taken up in hot ethyl acetate (50 ml) and cooled to room temperature and the precipitate was collected by filtration to give the title compound (200 mg, 59%); m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 11.2 (br s, 1H, NH), 7.7-7.35 (m, 9H, arom. and NH), 4.49 (s, 2H, CH2). Analysis: C14H12ClN3O3S requires C, 49.78; H, 3.58; N, 12.44; (found C, 49.49; H, 3.80; N, 12.09).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:29](=[O:37])[N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:28]=[CH:27][C:16]([C:17]([O:19]CC4C=CC=CC=4)=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[N:8]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[CH2:3][C:4]([C:29](=[O:37])[N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:28]=[CH:27][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCc4ccccc4)cc3)cc2N=C(N)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)O)cc3)cc2N=C(N)C1

Procedure:
Benzyl 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (0.025 g, 0.0504 mmol) was suspended in 1 ml of methanol, and 25 mgs of 10% Pd/C (Degussa type) was added and the mixture was hydrogenated under a balloon of hydrogen for one hour. This mixture was then filtered through GF/F filter paper, and the filtrate was concentrated to 16 mgs of 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoic acid (78%). 1H-NMR (400 MHz, DMSO-d6) δ 7.98-8.03 (m, 2H), 7.76-7.82 (m, 2H), 7.38-7.43 (m, 1H), 7.33-7.37 (m, 1H), 7.27-7.31 (m, 1H), 6.92 (br s, 1H), 6.76 (s, 1H), 3.28-3.36 (m, 4H, partially obscurred by water peak), 2.74 (s, 2H), 1.51-1.62 (m, 4H), 0.71-0.97 (m, 6H); m/z (APCI-pos) M+1=406.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S-:9])[CH:6]=[CH:7][CH:8]=1.[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: COc1cccc([S-])c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A solution of potassium 3-methoxybenzenethiolate (6.37 g, 35.7 mmol) and 4-chloronitrobenzene (5.11 g, 32.5 mmol) in dimethylformamide (30 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and a yellow solid was collected by filtration. Recrystallization from 90% ethanol yielded the title anisole (7.79 g, 92%) as a yellow solid; mp 81°-83° C. 1H-NMR (250 MHz, d6-DMSO): 3.80 (s, 3H, OCH3) 7.10-7.19 (m, 3H, aromatic) 7.32 (d, 2H, J=7.1 Hz, aromatic) 7.43-7.49 (m, 1H, aromatic) 8.15 (d, 2H, J=7.0, aromatic). MS (CI, CH4): 262 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([Cl:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1cccc(Cl)c1
Product: Clc1cccc(C(Cl)c2ccccc2)c1
Temperature: 25 °C
Yield: 37 %

Procedure:
A solution of (3-chlorophenyl)(phenyl)methanol (500 mg, 2.3 mmol) in thionyl chloride (3 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel column (eluting with petroleum ether/ethyl acetate=100/1) to give the desired product (200 mg, 37%) as yellow oil.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].Cl.[CH3:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>C(#N)C>[CH3:15][N:16]([CH2:18][CH2:19][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH3:17]
Reactant: CN(C)CCCl
Reactant: COC(=O)c1ccccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccccc1OCCN(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
15.2 g of methyl salicylate are dissolved in 200 ml of anhydrous acetonitrile and stirred with 4.4 g of 60% sodium hydride suspension in oil at ambient temperature for 60 minutes. To this solution is added 200 ml of absolute acetonitrile, then it is mixed with 17.4 g of 2-(N,N-dimethylamino)ethylchloride hydrochloride and 5.2 g of 60% sodium hydride suspension in oil. This solution is also stirred for 60 minutes at ambient temperature. The combined solutions are refluxed for 1 hour and then evaporated down in vacuo. The residue is mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue is chromatographed on silica gel with ethyl acetate/methanol (1:1). In this way, 14.6 g of a yellow oil are obtained (65% of theory).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CC(=O)OCC.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:36]1[CH2:37][CH2:38][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[CH2:34][CH2:35]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: OCc1cc2ccccc2s1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc(N2CCN(Cc3cc4ccccc4s3)CC2)nc1

Procedure:
The product from Example 8A (300 mg 1.8 mmol), methane sulfonic anhydride (313 mg, 1.8 mmol), and D1 EA (200 μL 5.4 mmol) were combined. After stirring, 1-(2-pyridinyl)piperazine (328 mg, 2.9 mmol) in 4 ml DCM was also combined and the mixture was processed as described in Example 8B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (m, 4H) 3.50 (m, 4H) 3.84 (s, 2H) 6.63 (m, 2H) 6.81 (d, J=8.48 Hz, 1H) 7.32 (m, 2H) 7.52 (m, 2H) 7.77 (m, 1H) 7.90 (m, 1H). (ESI) m/z 310 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:4].[CH2:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][CH2:23][C:24]#[CH:25]>CCCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:25]#[C:24][CH2:23][CH2:22][CH2:21][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:4]
Reactant: C#CCCCc1ccccc1
Reactant: COC(=O)c1sccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COC(=O)c1sccc1C#CCCCc1ccccc1

Procedure:
This product was prepared from 3-(toluene-4-sulfonyloxy)-thiophene-2-carboxylic acid methyl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 4:6; yield (114 mg, 80%); 1H NMR δ (CDCl3): 7.33 (d, J=4.93 Hz, 1H), 7.16-7.09 (m, 5H), 7.01 (d, J=4.95 Hz, 1H), 3.81 (s, 3H), 2.77 (t, J=7.11 Hz, 2H), 2.42 (t, J=7.16 Hz, 2H), 1.94 (p, J=7.22 Hz, 2H); LCMS m/z: 284.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH:1]1([NH:4][C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH:13][S:16]([CH3:15])(=[O:18])=[O:17])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(=O)NC2CC2)ccc1F
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C(=O)NC2CC2)ccc1F

Procedure:
N-cyclopropyl-4-fluoro-3-methanesulfonylaminobenzamide was prepared by treatment of N-cyclopropyl-4-fluoro-3-aminobenzamide (prepared by a procedure similar to Example 1) with methanesulfonyl chloride in the presence of pyridine by standard procedure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Hg](C#N)C#N.[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[CH2:26][S:25][C@@H:24]1Br)(=[O:21])[CH3:20]>>[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[CH2:26][S:25][C@H:24]1[S:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:21])[CH3:20]
Reactant: COc1cc(S)cc(OC)c1OC
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: COc1cc(S[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc(OC)c1OC
Yield: 28 %

Procedure:
If the procedure described in Preparation I is followed starting from 11.35 g (57.10-3 mol) of 3,4,5-trimethoxybenzenethiol, 14.32 g (57.10-3 mol) of mercuric cyanide, Hg(CN)2, and 22.15 g (62.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 7.52 g (yield: 28%) of the expected product are obtained.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][O:28][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:18]=[CH:17][N:16]=[C:15]2[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCC1
Temperature: 110 °C
Yield: 14.8 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (1.27 g, 7.5 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.7 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (3.9 g, 28.3 mmol) in DMF (30 ml). The mixture was heated at 110° C. for 4 hours and allowed to cool. The mixture was filtered, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/ammonia, (100/8/1) to give an oil which was triturated with ethyl acetate to give 6-methoxy-4-phenoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (200 mg, 15%) as a white solid.
Reaction SMILES: BrC1C2[C:10](=CC=CC=2)[C:9]([C:16]2[CH:17]=[C:18]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25]4[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=4N=3)C=CC=2)=C2C=1C=CC=C2.[Br:37][C:38]1[C:39]2[C:44]([C:45](Br)=[C:46]3[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]3)=[CH:43][CH:42]=[CH:41][CH:40]=2.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Br:37][C:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]([C:29]2[CH:28]=[C:27]([N:26]3[C:25]4[CH:24]=[CH:36][CH:35]=[CH:34][C:33]=4[C:10]4[C:22]3=[CH:18][CH:17]=[CH:16][CH:9]=4)[CH:32]=[CH:31][CH:30]=2)=[C:46]2[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]2
Reactant: Brc1c2ccccc2c(-c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)c2ccccc12
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1c2ccccc2c(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c2ccccc12
Yield: 68 %

Procedure:
Following the procedure as outlined above for synthesizing Compound 5, Compound (2.686 g, 7.274 mmol), 9,10-dibromoanthracene (7.333 g, 21.82 mmol), tetrakis(triphenylphosphine)palladium(0) (0.420 g, 0.364 mmol), Na2CO3 (9.539 g, 90.00 mmol), H2O (90 mL) and THF (150 mL) yielded Compound 8 (2.45 g, 68%) as a light yellow solid after flash chromatography (SiO2, 19:1 to 9:1 hexanes-dichloromethane).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.[NH2:17][C:18]([NH2:20])=[O:19].Cl.CO>C(O)C>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[N:17][C:18]([OH:19])=[N:20][CH:5]=1)([O-:15])=[O:14]
Reactant: NC(N)=O
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])c1ccccc1-c1cnc(O)nc1
Temperature: 70 °C
Yield: 17.7 %

Procedure:
A solution of 3-(dimethylamino)-2-(2-nitrophenyl)acrylaldehyde (2.00 g, 9.08 mmol), urea (0.60 g, 9.99 mmol) and concentrated hydrochloric acid (0.50 ml) in ethanol (25 ml) was heated at 60° C. for 18 hours under a nitrogen atmosphere. An additional aliquot of concentrated hydrochloric acid (0.50 ml) was added followed by heating at 70° C. for 24 hours. The solvent was removed by evaporation under reduced pressure. The residue was crystallised from methanol yielding the title compound (0.35 g, 18% yield) as a yellow solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])[NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])[N:16]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=P(N=Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 39.6 %

Procedure:
P,P-diphenyl-N-phenylmethylene phosphinic amide was prepared following the method of Jennings (ibid) by adding titanium tetrachloride (635 ml; 5.78 mmol) in dry dichloromethane (10 ml) to a stirred solution of benzaldehyde (1.17 ml; 11.59 mmol), P,P-diphenylphosphinic amide (2.52 g; 11.59 mmol) and anhydrous triethylamine (4.84 ml; 34.78 mmol) in dry dichloromethane (50 ml) at 0° C. Upon completion of the addition, the stirring was maintained at 0° C. for a further 4 hours. Subsequent work-up gave P,P-diphenyl-N-phenylmethylene phosphinic amide (1.4 g; 40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:7]=[C:6](Br)[CH:5]=1.[CH2:18]=[C:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[NH:25]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=O)[C:26]1=[O:27]>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([N:25]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@:28]3([C:19]4([CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:18]3)[C:26]2=[O:27])[CH:7]=[C:8]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:9]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: COC(=O)c1cc(Br)cc(N2CCOC2=O)c1
Reactant: C=C1CCOCC1
Product: COC(=O)c1cc(N2CCOC2=O)cc(N2C(=O)[C@]3(CC34CCOCC4)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 101 starting from methyl-3-bromo-5-(2-oxooxazolidin-3-yl)benzoate prepared as in Example 101, 4-methylenetetrahydro-2H-pyran, isatin (commercially available) according to Scheme 2. LC/MS m/e calcd. for C25H24ClN2O6: 448, observed (M+H)+: 449.21 1HNMR (400 MHz, DMSO-d6) δppm 1.72-1.81 (m, 1 H) 1.83 (d, J=4.55 Hz, 1 H) 1.92-1.99 (m, 3 H) 2.07-2.15 (m, 1 H) 3.38-3.47 (m, 1 H) 3.51-3.57 (m, 1 H) 3.57-3.66 (m, 2 H) 3.90 (s, 3 H) 4.16 (t, J=7.83 Hz, 2 H) 4.49 (t, J=7.83 Hz, 2 H) 6.90 (d, J=7.83 Hz, 1 H) 7.08 (t, J=7.58 Hz, 1 H) 7.23 (t, J=7.71 Hz, 1 H) 7.29 (d, J=7.58 Hz, 1 H) 7.74 (s, 1 H) 7.93 (s, 1 H) 8.24 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7].[F:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.Cl([O-])(=O)(=O)=O.[Li+].O>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7]
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Reactant: Cc1ccc(C[C@@H]2CCCN2)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
A mixture of methyl (2E)-3-(2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)prop-2-enoate (237 mg, 0.90 mmol) described in WO 2004/106280, (2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidine (167 mg, 0.86 mmol), which had been obtained in Example 1 (1e), and lithium perchlorate (55 mg, 0.52 mmol) in toluene (9 mL) was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a yellow oily substance (238 mg, yield 61%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[N:29]1([CH2:34][CH2:35][NH2:36])[CH:33]=[CH:32][CH:31]=[N:30]1>>[CH3:1][N:2]1[C:10]([CH2:11][NH:36][CH2:35][CH2:34][N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: NCCn1cccn1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCCn3cccn3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2-(1H-pyrazol-1-yl)ethanamine were reacted to give 431. [M+H]+ 473.3