Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[OH:11])[CH:6]=[O:7].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH3:29].C(Cl)Cl>CN(C=O)C.O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[O:11][CH2:27][CH2:28][CH3:29])[CH:6]=[O:7]
Reactant: CCCBr
Reactant: CSc1cc(C=O)cc(OCc2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCOc1c(OCc2ccccc2)cc(C=O)cc1SC
Reaction time: 8 h

Procedure:
64.5 g of 3-Methylthio-4-hydroxy-5benzyloxybenzaldehyde dissolved in a 75 mL of DMF was treated with 50 g of K2CO3 and 32 g of 1-bromopropane and stirred overnight at 70°. The next day about 1.5 liters of methylene chloride and an equal amount of water was added to the reaction mixture. The organic layer was removed, washed three times with distilled water, dried over MgSO4 and evaporated to a viscous liquid that solidified slowly: NMR(200 MHz, CDCl3) δ 1.02 (t, CH2CH2CH3), 1.82(m, CH2CH2CH3), 2.48(s, SCH3), 4.12(t, OCH2CH2CH3), 5.18(s, OCH2Ar), 7.26-7.52(m, ArH), 9.86(s, ArCHO).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([N:11]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[CH3:22][C:23]([S:26]([N:28]=[C:29]1[CH2:32][O:31][CH2:30]1)=[O:27])([CH3:25])[CH3:24]>C1COCC1>[NH2:11][C:10]1[CH:20]=[CH:21][C:7]([C:29]2([NH:28][S:26]([C:23]([CH3:25])([CH3:24])[CH3:22])=[O:27])[CH2:32][O:31][CH2:30]2)=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2ccc(N)cc2)COC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of n-butyllithium in hexanes (1.65 M, 5.14 mL) was added dropwise to a solution of 4-bromo-N,N-bis(trimethylsilyl)aniline (2.52 mL) in THF (14 mL) at −78° C. The resulting mixture was stirred for 1 h at −78° C. before a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide in THF (2.8 mL) was added dropwise over the course of 15 minutes at −78° C. The reaction mixture was stirred for an additional 1 h at −78° C. then allowed to warm to room temperature. After being stirred for 18 h at room temperature, the reaction mixture was poured into ice cooled saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue was diluted with diisopropylether and extracted with 1 M citric acid solution. The aqueous extracts were combined and basified with sodium bicarbonate solid to pH>7. The basic aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by recrystallization with ethyl acetate and column chromatography (30-100% ethyl acetate in hexanes) gave the product (1.37 g, 90%). 400 M Hz 1H-NMR (DMSO-d6) δ: 7.07 (d, J=8.7 Hz, 2H), 5.56 (d, J=8.7 Hz, 2H), 6.05 (s, 1H), 5.10 (brs, 2H), 4.94 (dd, J=6.0 and 2.3 Hz, 2H), 4.83 (d, J=6.0 Hz, 1H), 4.60 (d, J=6.0 Hz, 1H), 1.08 (s, 9H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32]C(OC)=O)[C:26]=1[C:37](=O)[CH3:38])(=[O:3])[CH3:2].[Br:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1.[OH-].[K+].Cl>C(O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:26]2[C:37](/[CH:38]=[CH:45]/[C:44]3[CH:47]=[CH:48][C:41]([Br:40])=[CH:42][CH:43]=3)=[CH:32][O:31][C:27]=2[CH:28]=[CH:29][CH:30]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1C(C)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(/C=C/c4ccc(Br)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a suspension of 2′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6′-(methoxycarbonylmethoxy)acetophenone (0.55 g) and 4-bromobenzaldehyde (0.19 g) in ethanol (9 mL) were added water (3 mL) and potassium hydroxide (0.67 g), and the mixture was stirred at room temperature for three days. To the reaction mixture was added 2 mol/L hydrochloric acid (7 mL), and the resulting mixture was extracted with ethyl acetate twice. The extracts were combined and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To the residue were added sodium acetate (1.97 g), acetic acid (5 mL) and acetic anhydride (2.08 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was cooled to room temperature and poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-3/2) to give the title compound (0.2 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS[C:23]([NH:28]C)=[CH:24][N+:25]([O-:27])=[O:26].[CH3:30]COCC>O.C(O)(C)C.C(OCC)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:30])[C:23]([NH2:28])=[CH:24][N+:25]([O-:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCC
Reactant: NCCCCCOc1cccc(CN2CCCCC2)c1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CN(CCCCCOc1cccc(CN2CCCCC2)c1)C(N)=C[N+](=O)[O-]

Procedure:
A solution of 5-[3-(1-piperidinylmethyl)-phenoxy]-pentanamine (1.0 g) and 1-methylthio-1-methylamino-2-nitroethene (0.53 g) in water (20 ml) was stirred overnight at room temperature. The water was removed in vacuo and the resulting oil triturated with ethyl acetate to give a yellow solid which was dissolved in isopropanol:ethyl acetate (75:25). Addition of ether to the solution afforded the title compound (0.16 g) as a white crystalline solid, m.p. 112°-113° .
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][C@@H:35]([CH2:54][CH3:55])[C@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[C:47]([CH3:52])=[N:48][CH:49]=[CH:50][CH:51]=2)[C:41]1=[O:53])[C:37](O)=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[C:47]([CH3:52])=[N:48][CH:49]=[CH:50][CH:51]=2)[C:41]1=[O:53])[CH:35]([CH3:34])[CH2:54][CH3:55])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccnc2C)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccnc2C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A solution containing the product from Example 8B (2.0 g, 4.40 mmol) in DMF (10 mL) was treated with the product from Example 15C (1.34 g, 4.39 mmol), EDAC (1.01 g, 5.27 mmol), HOBT (0.7 g, 5.19 mmol), and NMM (0.96 mL, 8.72 mmol), stirred at 25° C. for 16 hours, treated with Example 15C (0.13 g), EDAC (0.5 g), HOBT (0.35 g), NMM (1 mL), and DMF (5 mL), stirred for 64 hours at 25° C. and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-4% methanol/dichloromethane to give the title compound (1.76 g, 54% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.62 Hz, 3 H), 0.81 (m, 15 H), 1.26 (m, 1 H), 1.49 (m, 2 H), 1.78 (m, 1 H), 2.45 (m, 5 H), 2.70 (m, 3 H), 2.90 (m, 2 H), 3.04 (m, 2 H), 3.59 (m, 4 H), 3.87 (m, 2 H), 4.13 (m, 2 H), 4.31 (s, 2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d, J=9.19 Hz, 1 H), 7.05 (s, 3 H), 7.19 (m, 5 H), 7.51 (m, 2 H), 7.86 (d, J=8.82 Hz, 1 H), 8.36 (d, J=3.68 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[N:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[Br:22]Br.O>CC(O)=O>[Br:22][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: O=C(NNc1nccnc1Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of 2.40 g of the product of Step A and 1.97 g of pyridine in AcOH (10.0 mL) at 0° C. was stirred as a solution of 1.92 g of bromine in AcOH (1.0 mL) was added dropwise. The resulting mixture was stirred at 0° C. for one h and then warmed to ambient temperature and stirred for an additional 16 h. The reaction mixture was poured into water and extracted with EtOAc (2×). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil that was purified by silica gel chromatography to provide trifluoroacetic acid N′-(5-bromo-3-chloro-pyrazin-2-yl)-hydrazide as a white solid. MS (M+H+)=320.1.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1NC2C=CC=C3C(=O)NCCC=1C=23.[Br:36]C1C=CC(B(O)O)=CC=1>>[Br:36][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C1NCCc2c(I)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(Br)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, 2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (85 mg, 0.28 mmol; see Example NN below) and 4-bromophenylboronic acid (62 mg, 0.31 mmol) were coupled to yield 2-(4-bromophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 19 mg (20%), as a white solid. mp 160° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.39 (m, 2H), 7.23 (app t, 1H, J=7.5 Hz), 7.56 (dd, 1H, J=8.1, 0.9 Hz), 7.60 (d, 2H, J=8.7 Hz), 7.69 (dd, 1H, J=7.5, 0.6 Hz), 7.73 (d, 2H, J=8.4 Hz), 8.09 (br t, 1H), 11.64 (br s, 1H); MS (FAB, MH+) 341/343; Anal. (C17H13BrN2O. 0.6 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1B(O)O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O1CCOCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:3]2[CH:4]=[CH:5][C:6]([CH:8]=[O:9])=[CH:7][C:2]=2[F:1])=[CH:16][CH:15]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=Cc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(-c2ccc(Cl)cc2)c(F)c1
Yield: 89.5 %

Procedure:
2-Fluoro-4-formylphenyl boronic acid (263 mg, 1.57 mmol) was added to the mixture of 1-chloro-4-iodobenzene (250 mg, 1.05 mmol), PdCl2(PPh3)2 (36 mg, 0.5 mmol), and disodium carbonate (332 mg, 3.13 mmol) in a solution of water (1 mL) and dioxane (2 mL). The mixture was reacted at 130° C. for 22 min in a microwave reactor. After cooling, water was added, and the mixture was extracted with ethylacetate. The organic solvent was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in heptane to give the title compound (220 mg, 0.94 mmol, 90%) as a white solid. 1H NMR (D2O) δ 10.02 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.67 (d, J=10.4 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:18])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.C(OCC)(=O)C>O>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:18])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)c(-c3ccccc3)[nH]c2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)[nH]c2cc(O)ccc12
Temperature: 25 °C

Procedure:
6-Methoxy-3-methyl-2-phenyl-1H-indole (5.00 g; synthesized according to the process described in Tetrahedron, vol. 41, p. 4615 (1985)) and pyridine hydrochloride (11.56 g) were stirred at 180° C. for 100 minutes. After the reaction mixture was cooled down to room temperature, ethyl acetate and water were added. After the layers were separated, the organic layer was washed sequentially with aqueous 0.5 N hydrochloric acid and saturated brine, and dried. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography to yield the title compound (4.50 g).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([O:8][CH2:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:9][C:2]=1[C:1]([O:11][CH3:12])=[O:10]
Reactant: C[Si](C)(C)CCCCl
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCC[Si](C)(C)C)ccc1O
Temperature: 90 °C

Procedure:
To a mixture of methyl gentisate (16.8 g, 0.1 mol) and potassium carbonate (15.2 g, 0.11 mol) in 80 ml of DMF, under a nitrogen atmosphere at 80° C., was added chloropropyltrimethylsilane (16.6 g, 0.11 mol) dropwise over 20 minutes. The mixture was heated at 90° C. for 8 hours. It was cooled and poured into 200 ml of water. The mixture was extracted with diisopropyl ether. The organic phase was washed with water, dried over sodium sulphate and then concentrated. After chromatography on silica of the yellow oil obtained (eluent: 90/10 heptane/CH2Cl2), 3.3 g of a clean fraction of methyl 2-hydroxy-5-(3-trimethylsilanylpropyloxy)benzoate were recovered.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH3:10].[Cl:14][C:15]1[N:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([N:25]3[CH:33]([OH:34])[C:32]4[C:27](=[CH:28][C:29]([C:35]([F:38])([F:37])[F:36])=[CH:30][CH:31]=4)[C:26]3=[O:39])=[N:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[Cl:14][C:15]1[N:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([N:25]3[CH:33]([O:34][C:12]([NH:11][CH2:7][CH2:8][CH2:9][CH3:10])=[O:13])[C:32]4[C:27](=[CH:28][C:29]([C:35]([F:37])([F:38])[F:36])=[CH:30][CH:31]=4)[C:26]3=[O:39])=[N:22]2)=[CH:17][CH:16]=1
Reactant: CCCCN=C=O
Reactant: O=C1c2cc(C(F)(F)F)ccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC(=O)OC1c2ccc(C(F)(F)F)cc2C(=O)N1c1ccc2ccc(Cl)nc2n1

Procedure:
Pyridine (10 cc.) and butyl isocyanate (11.2 cc.) are added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-6-trifluoromethyl-isoindolin-1-one (3.8 g.) in acetonitrile (380 cc.). The mixture is heated to the reflux temperature and triethylamine (0.5 cc.) is added. Refluxing is continued for 50 minutes until dissolution. After cooling the solution, the precipitate formed is filtered off and washed with water (30 cc.). After drying, a first crop of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-n-butylaminocarbonyloxy-6-trifluoromethyl-isoindolin-1-one (2.8 g.) is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[NH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[NH:17][C:16]=2[Br:25])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2[nH]cc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]c(Br)c(-c3cccc(OCc4ccccc4)c3)c12
Reaction time: 8 h

Procedure:
To a solution of 20 g (63.2 mmol) 5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (see WO 97/28161) in 1 l dry N,N-dimethylformamide, 12.4 g (69.5 mmol) N-bromosuccinimide are added at ca. 10° C. Stirring was continued at ca. 10° C. for 30 min and overnight at RT. The precipitate formed is filtered off and washed thoroughly with N,N-dimethylformamide and hexane. After drying for 24 h at 30-35° C. under vacuum, the title compound is used in the next step without further purification. Additional material can be obtained from the mother liquor through chromatography on silicagel. Analytical HPLC: tR=10.07 min (Grad 1); ES-MS: m/eo=394.9 and 396.9; NMR (DMSO-d6): 12.55/s (NH); 8.06/s (1H), 7.25-7.5/several m's (6H), 7.07/“d” (1H); 7.03/s (1H); 6.98/“d” (1H); 5.5-6.0/b (NH2); 5.12/s (2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8](C(OCC)=O)[S:7][C:6]=2[CH:15]=1.[CH3:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19].[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:22][CH2:21][S:18]([NH:17][CH3:16])(=[O:20])=[O:19])=[CH:8][S:7][C:6]=2[CH:15]=1
Reactant: CNS(C)(=O)=O
Reactant: CCOC(=O)c1cc2ccc(Br)cc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNS(=O)(=O)CCc1csc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 11 h

Procedure:
A mixture of the product from Example 46, Part D (0.100 g, 0.382 mmol), N-methylmethane-sulfonamide (45.9 mg, 0.421 mmol) and potassium carbonate (0.127 g, 0.918 mmol) in N,N-dimethylacetamide (5 mL). The mixture was stirred at 80° C. for 11 h, cooled to room temperature and partitioned between diethylether and water (3×), dried overmgSO4, filtered and concentrated in vacuo to give the title compound as a colorless waxy solid (0.128 g, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1OC)[C:6](C1C=CN=CC=1)=[O:7].C([Li])CCC.Br[C:25]1[CH:26]=[C:27]([O:33][CH3:34])[C:28]([O:31][CH3:32])=[CH:29][CH:30]=1.[CH3:35][O:36]C1C=C(C=C(OC)C=1)C#N>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:6]([C:5]1[CH:14]=[C:15]([O:36][CH3:35])[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:7]
Reactant: COc1cc(C#N)cc(OC)c1
Reactant: COc1ccc(C(=O)c2ccncc2)cc1OC
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1

Procedure:
3,4,3',5'-Tetramethoxybenzophenone was prepared analogously to 4-(3,4-dimethoxybenzoyl)pyridine using butyl lithium (9 mL, 22 mmol, 2.5M), 4-bromoveratrole (2.9 mL, 20 mmol) and 3,5-dimethoxybenzonitrile (3.75 g, 23 mmol). The crude product was purified by flash column chromatography (silica gel, methylene chloride) to afford 1.54 g (26%) of the product: mp 107-110° C.; 1H NMR (CDCl3) δ 7.53-7.39 (m, 2 H), 6.95-6.84 (m, 3 H), 6.70-6.60 (m, 1 H), 3.96 (s, 3 H), 3.95 (s, 3 H), 3.83 (s, 6 H); 13C NMR (CDCl3) δ 195.0, 160.4, 153.0, 148.9, 140.1, 130.0, 125.4, 112.0, 109.7, 107.5, 104.1, 56.0, 55.5; Anal. Calcd for C17H18O5. Theoretical: C, 67.54; H, 6.00. Found: C, 67.38; H, 5.96.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C=O)C>C1COCC1>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccccc43)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
A solution of oxindole (1.2 g, 9 mmol) in THF (10 ml) was added dropwise to a suspension of sodium hydride (360 mg of a 60% suspension in paraffin oil, 9 mmol) in THF (15 ml) over 15 minutes under nitrogen. The resulting white suspension was stirred for 15 minutes at ambient temperature and a solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (900 mg, 3 mmol) in THF (10 ml) was added followed by DMF (5 ml). The resulting reddish solution was stirred for 30 minutes at ambient temperature followed by 1 hour at 65° C. The mixture was concentrated to half its volume by evaporation and was partitioned between ethyl acetate and water. The aqueous layer was separated, adjusted to pH7 with 2M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, followed by ethyl acetate and ether and dried under vacuum to give 7-benzyloxy-6-methoxy4-(oxindol-3-yl)quinazoline (1 g, 83%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@H:9]1[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]N(C)C(=N)N(C)C.[N+:26]([CH3:29])([O-:28])=[O:27]>>[C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@H:9]1[CH:11]([CH2:18][CH2:29][N+:26]([O-:28])=[O:27])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CN(C)C(=N)N(C)C
Reactant: CCOC(=O)C=C[C@@H]1C[C@@H]1C(=O)OC(C)(C)C
Product: CCOC(=O)CC(CC[N+](=O)[O-])[C@@H]1C[C@@H]1C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
To 60 ml of a nitromethane solution of 6.07 g (25.2 mmol) of ethyl 3-(cis-2-t-butoxycarbonylcyclopropyl)acrylate was added 3.48 ml (27.7 mmol) of tetramethylguanidine at room temperature, and the mixture was stirred for 6 hours. To the reaction mixture was further added 0.32 ml (2.52 mmol) of tetramethylguanidine, followed by stirring for 18 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=85:15) to give 6.536 g (85.9%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1.[OH:24]O>C(O)(=O)C>[O:24]=[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1ccc2cc(N3CCNCC3)nc(N3CCSCC3)c2c1
Reactant: OO
Solvent: CC(=O)O
Product: O=S1CCN(c2nc(N3CCNCC3)cc3ccc(Cl)cc23)CC1
Yield: 13 %

Procedure:
1-(1-Oxido-thiomorpholino)-3-piperazino-7-chloro-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-7-chloro-isoquinoline by oxidation with hydrogen peroxide in glacial acetic acid. M.p. 209°-211°C; yield: 13% of theory.