Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].[C:14]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:14]1([S:20]([NH:23][C:9]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=2)=[O:11])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 97.3 %

Procedure:
4-Methoxycarbonyl-benzoic acid (from Preparation 11) (5.0 g, 28 mmol) was dissolved in 100 mL of anhydrous dichloromethane. After the addition of DMAP (3.39 g, 28 mmol) and benzenesulfonamide (4.36 g, 28 mmol), EDCI (5.85 g, 31 mmol) was gradually added to the stirred mixture. After 18 hours at room temperature, rotary evaporation of the mixture gave a residue which was mixed with ethyl acetate and 1N HCl. The organic phase was washed with water (1×) and brine (2×), dried (Na2SO4), rotary evaporated, and dried at high vacuum to afford 8.7 g (98%) of methyl 4-phenylsulfonamidocarbonyl-benzoate (4--C6H5SO2 --NHCO--C6H4 --COOCH3) as a white solid. A solution of this material (3.2 g, 10 mmol) in 130 mL of dioxane/water (3:1) was cooled to 0° C. 1N Sodium hydroxide was added dropwise, followed by vigorous stirring at 0° C. for 20 minutes, then at room temperature for 2 hours. The mixture was again cooled to 0° C., and then acidified to pH 2 by gradual addition of 1N HCl. The mixture was rotary evaporated, and the aqueous residue was extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (Na2SO4), rotary evaporated, and dried at high vacuum to afford the product (4--C6H5SO2NHCO--C6H4 --COOH), m.p. 267°-270° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1.[H-].[Na+].[CH3:33]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[N:21]([CH3:33])[C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3c4[nH]c5ccc(OC)cc5c4c4c(c3c2c1)C(=O)N(C)C4=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(C)c35)C(=O)N(C)C4=O)c2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 1 g (2.5 mmol) 6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole in 50 ml dry dimethylformamide is added dropwise at 20° C. to a suspension of 91 mg (3.0 mmol) sodium hydride (80% in paraffin oil) in 5 ml dimethylformamide under an atmosphere of argon. After stirring for 1 hour at 20° C., 0.2 ml (3.2 mmol) methyl iodide are added thereto and the reaction mixture is stirred for 16 hours at 20° C. It is then evaporated in a vacuum and the residue is partitioned between ethyl acetate and water. The ethyl acetate phase is separated off, dried over anhydrous sodium sulphate, filtered and evaporated. The residue is stirred with 30 ml diisopropyl ether/ethyl acetate (2:1 v/v) and the undissolved product is filtered off. 6,7,12,13-Tetrahydro-3,9-dimethoxy-6,12-dimethyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole is obtained in the form of a pale brown amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([CH:16]([OH:18])[CH3:17])[CH:3]=1.C(Cl)Cl.FC(F)(F)C(O)=O>>[NH2:8][C:5]1[C:4]([CH:16]([OH:18])[CH3:17])=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1
Reactant: CC(O)c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)c1cc(Cl)ncc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl 6-chloro-4-(1-hydroxyethyl)pyridin-3-ylcarbamate (823 mg, 3.02 mmol) in methylene chloride (40 mL, 500 mmol) was added trifluoroacetic acid (2 mL, 20 mmol). The reaction mixture was stirred at room temperature for 5 hours and then evaporated in vacuo. The resulting residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated in vacuo to yield 455.2 mg (87%) of 1-(5-amino-2-chloropyridin-4-yl)ethanol which was carried forward without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2.Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2
Reactant: ClCCN1CCCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(CCN2CCCC2)CC1
Temperature: 50 °C
Yield: 13.8 %

Procedure:
A mixture of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (600 mg, 1.43 mmol), (prepared as described in Example 70), 1-(2-chloroethyl)-pyrrolidine (292 mg, 1.72 mmol) in methanol (14 ml) containing sodium carbonate (262 mg, 4.3 mmol) and potassium iodide (48 mg, 0.29 mmol) was heated at 50° C. for 20 hours. After cooling, the volatiles were removed under vacuum. The residue was purified by preparation HPLC on reverse C18 silica eluting with methanol/aqueous ammonium carbonate (2 g ammonium carbonate per liter saturated with CO2) (60/40 followed by 70/30). The fractions containing the expected product were combined and the volatiles were removed under vacuum. The residue was triturated with ether and the solid was filtered, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-(pyrrolidin-1-yl)ethyl)-piperidin-4-ylmethoxy)quinazoline (102 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:20])[CH2:18][CH3:19])=[C:5]2C.[Cl:27][C:28](=[CH2:31])[CH2:29][NH2:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:20])[CH2:18][CH3:19])=[C:5]2[NH:30][CH2:29][C:28]([Cl:27])=[CH2:31]
Reactant: C=C(Cl)CN
Reactant: CCC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Product: C=C(Cl)CNc1c(C(=O)CC)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 71 %

Procedure:
6- Chloro-4-methylsulfoxy-3-propionyl-8-trifluoromethyl-2-quinolinone (365 mg, 1 mmol) and 2-chloroallylamine (92 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (279 mg, yield: 71%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 62.7 %

Procedure:
In an argon atmosphere, 4-bromoaniline (344 mg, 2.00 mmol) was dissolved in dimethylformamide (5 mL), and to the solution were added sodium hydride (200 mg, 5.00 mmol) and benzyl bromide (0.52 mL, 4.4 mmol) under ice-cooling, followed by stirring at room temperature for 11 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to obtain 4-bromo-N,N-dibenzylaniline (442 mg, 63%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:22])[F:23])[CH:12]=2)[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.3 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (prepared as in Example 89A, 2.92 g, 7.72 mmol) in tetrahydrofuran/water (88 mL, 3:1) was treated with lithium hydroxide (647 mg, 15.43 mmol). The reaction was stirred at 25° C. for 3 d. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (50 mL) and extracted with ether (25 mL). The aqueous layer was acidified to pH=1 with a 3N aqueous hydrochloric acid solution. The product was extracted into ethyl acetate (3×75 mL) and ether (1×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×100 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (2.37 g, 84.5%) as a pale-yellow semi-solid: EI-HRMS m/e calcd for C16H19F3O4S (M+) 364.0956, found 364.0958.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:21][CH2:22][CH2:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:21][CH2:22][CH2:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCCC)C2)oc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1C
Yield: 44.4 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-propoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (114b) (0.67 g, 1.98 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.22 g of the title compound as a colorless amorphous solid (44%).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Fc1ccccc1CBr
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccccc4F)CC3)cccc2n1
Yield: 50 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-fluorobenzyl bromide (69.9 mg; 0.37 mmol) to obtain 35.3 mg. (50% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 10.0 (s, 1H), 8.99 (s, 1H), 7.72 (m, 2H), 7.46 (t, J=6.8 Hz, 1H), 7.33 (m, 5H), 3.64 (s, 2H), 3.03 (br d, J=10.8 Hz, 3H), 2.91 (m, 3H), 2.34 (m, 2H). ESIMS+353.6 m/z
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([C@@H:24]1[CH2:28][C@@H:27](O)[CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23].C(Br)(Br)(Br)[Br:38].C(O)C>ClCCl>[CH3:20][O:21][C:22]([C@@H:24]1[CH2:28][C@H:27]([Br:38])[CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
Add triphenylphosphine (0.88 mol, 231 g) in portions to a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.58 mol, 144 g) and CBr4 (0.88 mol, 292 g) in dry dichloromethane (1.44 L) at 0° C. Upon complete addition, warm the reaction mixture to room temperature and stir for 4 h. Add ethanol (1.44 L) and stir for an additional 2 h. Add diethyl ether (1.44 L) to the reaction mixture, filter the precipitated triphenylphosphine oxide, and concentrate the filtrate under reduced pressure. Purify by column chromatography using 5% ethyl acetate in hexanes as eluent to obtain the title compound (155 g, 85%) as a thick oil. ES-MS m/z 308 [M+1]+.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:22]1(=O)[CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:22]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:12]=[CH:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)Nc1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]methanesulfonamide (may be prepared as described in Description 40) (12 mg, 0.04 mmol) in dichloromethane (2 ml) was added cyclobutanone (14 mg, 0.20 mmol) and acetic acid (1 drop). The resulting mixture was stirred at room temperature, under argon, for 30 minutes. Sodium triacetoxyborohydride (42 mg, 0.20 mmol) was added and stirring continued for 1 hour. The resulting reaction mixture was diluted with methanol and purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E29). MS (ES+) m/e 361 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14]2[C:6](=[CH:7][C:8]3[O:12][CH2:11][O:10][C:9]=3[CH:13]=2)[C@@H:5]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([OH:23])=[C:17]([O:24][CH3:25])[CH:16]=2)[C@H:4]2[C:26](=[O:29])[O:27][CH2:28][C@H:3]12.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].N1C=CN=C1>CN(C)C=O>[NH2:1][C@@H:2]1[C:14]2[C:6](=[CH:7][C:8]3[O:12][CH2:11][O:10][C:9]=3[CH:13]=2)[C@@H:5]([C:15]2[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:23][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[C:19]([O:21][CH3:22])[CH:20]=2)[C@H:4]2[C:26](=[O:29])[O:27][CH2:28][C@H:3]12
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
A 63.4 mmol solution of (5R,5aR,8aS,9S)-9-amino-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one, 111.8 mmol of tert-butyldimethylsilyl chloride and 510 mmol of imidazole in 1.6 l of anhydrous dimethylformamide is stirred for 20 hours at ambient temperature. The reaction mixture is then washed with 2 l of water then 1 l of ether. The ether phase is then decanted and the aqueous phase extracted with ether. The organic phases are then dried on magnesium sulfate, are filtered and concentrated under reduced pressure. The expected product is obtained by recrystallization in a benzene/heptane mixture.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([N:13]2[C:14]3[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cccc(-n2ccc3ccccc32)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 74.2 %

Procedure:
To a mixture of 4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 2.02 g (74%) of the product 4 (3-bromo-phenyl)-1H-indole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[Cl:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[NH:1][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(N)c(Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2Cl)cc1
Yield: 54.7 %

Procedure:
4-Amino-3-chlorobenzonitrile (1.50 g (9.83 mmol)) was dissolved in 5.0 ml of pyridine. To this, p-toluenesulfonyl chloride (1.90 g (9.97 mmol)) was added under cooling with ice and with stirring. After stirring for 18 hours at room temperature, water (100 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered, washed with water and then dissolved in an aqueous solution of sodium hydroxide. The resulting solution was washed with diethyl ether, and the water layer was made acidic again with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.65 g (55%) of 2′-chloro-4′-cyano-p-toluenesulfonanilide as white crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6]2.[BrH:21]>C(O)(=O)C>[BrH:21].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6]2
Reactant: CCCCCCCCN1CCc2cc(OC)ccc2C1
Agent: Br
Solvent: CC(=O)O
Product: CCCCCCCCN1CCc2cc(O)ccc2C1

Procedure:
5.8 g of the compound prepared under (b) are heated under reflux for 16 hours with a mixture of 100 ml of glacial acetic acid and 48% strength aqueous hydrobromic acid in the volume ratio 1:1. After cooling, the acid mixture is distilled off under waterpump vacuum, and the residue is boiled with a little ethanol. On cooling and scratching, 4.0 g of colorless crystals crystallize out (47% of theory over all stages), melting point: 165-166°.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]2[CH3:16])=[O:8])[N:6]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][CH:10]1[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[N:9]1[C:7]([C:5]1[N:6]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])[S:3][CH:4]=1)=[O:8]
Reactant: CC1CCCC(C)N1C(=O)c1csc(Br)n1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccccc1-c1nc(C(=O)N2C(C)CCCC2C)cs1
Temperature: 90 °C
Yield: 72.1 %

Procedure:
A mixture containing (2-bromo-thiazol-4-yl)-(2,6-dimethyl-piperidin-1-yl)-methanone (Step 1; 91 mg, 0.3 mmol), 2-methylphenylboronic acid (45 mg, 0.33 mmol), Pd(dppf)Cl2 (Dichloro-(1,1-bis(diphenylphosphino)-ferrocene) palladium(II)) (11 mg, 0.015 mmol), and potassium carbonate (0.3 mL, 2 M aqueous, 0.6 mmol) in DME (2 mL) was heated to 90° C. for 8 hrs. The solvent was evaporated and water (5 mL) was added. The mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography with a solvent gradient of 0-30% ethyl acetate in hexanes to give (2,6-dimethyl-piperidin-1-yl)-(2-o-tolyl-thiazol-4-yl)-methanone (68 mg, 75%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S([O-])(=O)(=O)C.CS(O[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:41][CH2:42][CH2:43][CH3:44])=[C:25]([C:27]2[NH:28][C:29](=[O:40])[C:30]3[N:35]([CH3:36])[N:34]=[C:33]([CH2:37][CH2:38][CH3:39])[C:31]=3[N:32]=2)[CH:26]=1)(=O)=O>C(#N)C>[CH3:36][N:35]1[C:30]2[C:29](=[O:40])[NH:28][C:27]([C:25]3[CH:26]=[C:21]([CH2:20][O:19][CH2:18][CH2:17][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:22]=[CH:23][C:24]=3[O:41][CH2:42][CH2:43][CH3:44])=[N:32][C:31]=2[C:33]([CH2:37][CH2:38][CH3:39])=[N:34]1
Reactant: C1COCCN1
Reactant: CCCOc1ccc(COCCOS(C)(=O)=O)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: CS(=O)(=O)[O-]
Solvent: CC#N
Product: CCCOc1ccc(COCCN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 49.7 %

Procedure:
Morpholine (0.19 g, 0.0021 mol) was added to a solution of the above mesylate, namely 5-[5-(2-methanesulphonyloxyethoxymethyl)-2-n-propoxyphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one, (0.20 g, 0.00042 mol) in acetonitrile (25 ml) and the stirred mixture was heated under reflux for 18 hours. The solvent was removed by evaporation under vacuum, the residue dissolved in saturated aqueous sodium carbonate solution and the solution extracted with ethyl acetate (3×20 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum, and the residue was chromatographed on silica gel (4g) using an elution gradient of methanol in dichloromethane (0-2% methanol). Evaporation under vacuum of the appropriate fractions, followed by crystallisation from hexane, gave the title compound as white crystals (0.098 g, 48%), m.p. 65°-66° C. Found C,64.17; H,7.69; N,14.96. C25H35N5O5 requires C,63.94; H,7.51; N,14.91%.