Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[CH2:31]([O:30][C:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:29])[CH3:32]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture containing 3 g of benzyl 2-indolecarboxylate in 30 ml of anhydrous DMF and 500 mg of sodium hydride at 60% in oil is left stirring under a nitrogen atmosphere for 1 hour. 3 g of ethyl 6-bromohexanoate in 10 ml of DMF are added, at 0° C., and the mixture is left stirring overnight at RT. The solvents are evaporated off and the residue is taken up in EtOAc, washed with water, dried over MgSO4 and concentrated. The residue is chromatographed on a column of silica H, eluting with a heptane/toluene mixture (50/50; v/v) to give 4.17 g of the expected compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]([NH2:14])[C:5]12[O:12][CH2:11][C:8]([CH3:13])([CH2:9][O:10]1)[CH2:7][O:6]2.[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=O>C1C=CC=CC=1>[CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]([N:14]=[CH:21][C:17]1[S:16][CH:20]=[CH:19][N:18]=1)[C:5]12[O:6][CH2:7][C:8]([CH3:13])([CH2:9][O:10]1)[CH2:11][O:12]2
Reactant: O=Cc1nccs1
Reactant: CC(C)CC(N)C12OCC(C)(CO1)CO2
Solvent: c1ccccc1
Product: CC(C)CC(N=Cc1nccs1)C12OCC(C)(CO1)CO2

Procedure:
A solution of 3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butylamine (1.9 g, 8.8 mmol) and thiazole-2-carboxaldehyde (998 mg, 8.8 mmol) in benzene was refluxed for 3 h using a Dean-Stark trap, during which time water was collected and the remaining residue was evaporated under reduced pressure to get [3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-thiazol-2-ylmethyleneamine as an orange solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH:15][CH:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.CS(C)=O.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:16](=[O:15])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1
Reactant: COc1ccccc1C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a stirring solution of phosphorus pentoxide (0.30 g, 1.10 mmol) in DCM (8 mL) at 0° C. was added a solution of 5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.20 g, 0.54 mmol) in DCM (8 mL) followed by dimethyl sulfoxide (0.20 mL, 2.80 mmol). After stirring for 15 minutes, N,N-diisopropylethylamine (0.28 mL, 1.60 mmol) was added. After 45 minutes, the reaction mixture was cast into cold saturated NaHCO3 and extracted with EtOAc (×2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 175 mg (88%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9])(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccccc1B(O)O
Product: C=CC(=O)Nc1ccccc1B(O)O

Procedure:
2-Acrylamido-phenylboronic acid (“2-APB”) was synthesized by reacting 2-aminophenylboronic acid with an excess of acryloyl chloride in an aqueous alkaline solution. The product was extracted in acetone and dried using a rotary evaporator. The structure of 2-APB was confirmed using NMR. The purity was shown to be greater than 90%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19]O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(CCCCS(C)(=O)=O)Cc1ccccc1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
Cool a mixture of 4-[N-(t-butoxycarbonyl)-N-[(phenyl)methyl]-amino]butan-1-ol (21.8 g, 0.078 mol), methylene chloride (250 mL) and pyridine (9.7 mL). Add mesylchloride (6.65 mL, 0.086 mol) in methylene chloride (6.6 mL) dropwise to the reaction with stirring. After addition is complete, allow the reaction to warm to room temperature and stir for an additional 2 hours. Pour the reaction into methylene chloride (200 mL), rinse with 0.5 N hydrochloric acid (500 mL), saturated sodium bicarbonate (500 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (25% ethyl acetate/hexane, silica gel) to provide 4-[N-(t-butoxycarbonyl)-N-[(phenyl)methyl]-amino]-1-methansulfonyl butane (10.7 g), Rf =0.36 eluting with 25% ethyl acetate/hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([N:21](CC3C=CC(OC)=CC=3OC)[C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[C:13]([F:40])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:50][C:51]1[CH:56]=[CH:55][C:54]([S:57]([OH:60])(=[O:59])=[O:58])=[CH:53][CH:52]=1>O1CCOCC1.CO>[CH3:50][C:51]1[CH:52]=[CH:53][C:54]([S:57]([OH:60])(=[O:59])=[O:58])=[CH:55][CH:56]=1.[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:44]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:42]=[CH:41][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]([F:28])=[CH:26][N:27]=3)(=[O:20])=[O:19])=[C:13]([F:40])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ncc(F)cn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnc(N)c3)cc2F)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(-c2cc(C(F)(F)F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncc(F)cn3)cc2Cl)ccn1
Reaction time: 18 h

Procedure:
4-[2-(2-Aminopyridin-4-yl)-4-(trifluoromethyl)phenoxy]-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 20, 2.24 g, 3.16 mmol) was dissolved in 1,4-dioxane (6.0 mL) and a 4.0 M solution of hydrogen chloride in 1,4-dioxane (4.0 mL, 16 mmol) was added. The reaction mixture was stirred for 18 hours then concentrated in vacuo. The residue was partitioned between water and dichloromethane. A large amount of undissolved solid was present. The aqueous phase was adjusted to pH10 with 1N aqueous sodium hydroxide solution, then back to pH3 with citric acid. The mixture was filtered and the solid was set aside. The organic phase was collected and combined with the solid and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane gradient elution). The resulting residue was then slurried in methanol before 1 equivalent of 4-methylbenzenesulfonic acid was added and the mixture concentrated in vacuo. The residue was dissolved in a minimum amount of hot methanol and filtered while hot. The filtrate was diluted with tert-butyl methyl ether. Crystals formed on standing which were collected by filtration and washed with tert-butyl methyl ether to afford the title compound as a white solid (1.48 g containing 0.5 mol % tert-butyl methyl ether). The solid was dissolved in a minimum amount of boiling methanol, then water was added slowly. Fine crystals formed which were collected by filtration and rinsed with water to afford the title compound as a white powder (1.45 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:29]1([CH2:35][CH2:36][C:37](O)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:37](=[O:38])[CH2:36][CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Dicyclohexylcarbodiimide (4.5 g) was added to a mixture of 3.52 g of 1-benzylpiperazine, 3.5 g of 3-phenylpropionic acid and 20 ml of tetrahydrofuran, and the mixture was stirred overnight at room temperature. The resultant dicyclohexylurea was filtered off, and the mother liquor was concentrated under reduced pressure. Ethyl acetate (100 ml) and 50 ml of water were added to the residue, and the mixture was made alkaline with potassium carbonate and then allowed to undergo phase separation. The ethyl acetate layer was washed in sequence with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6 g of 1-benzyl-4-(3-phenylpropionyl)piperazine.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:13]=[C:5]2[C:6](=[C:10]([O:16][CH3:17])[CH:11]=1)[C:7](=[O:9])[O:8][C:1](=[O:2])[CH2:4]2
Reactant: COc1cc(CC(=O)O)c(C(=O)O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(c(OC)c1)C(=O)OC(=O)C2
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
2-Carboxymethyl-4,6-dimethoxybenzoic acid (60) (3.97 gm) was stirred in toluene (40.0 mL) at ambient temperature in a 100 mL flask with magnetic stirring. Acetic anhydride (1.72 mL) was added and the mixture heated to 110° C. Monitoring by HPLC revealed that the reaction was complete within 2.5 hours. Heat was then removed. Crystallization of 6,8-dimethoxyisochroman-1,3-dione (25) occurred as the solution cooled. The mixture was cooled to 2° C. After a short hold time, yellow crystalline solids were filtered, washed with fresh toluene and then dried on high vacuum. 6,8-Dimethoxyisochroman-1,3-dione (25) (3.05 g) was isolated as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:10]3[N:15]=[C:14]([CH:16]=O)[S:13][C:11]=3[N:12]=2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:10]3[N:15]=[C:14]([CH2:16][N:28]4[CH2:33][CH2:32][CH2:31][CH:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:29]4)[S:13][C:11]=3[N:12]=2)[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1
Reactant: CC(C)(O)C1CCCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)sc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCCC(C(C)(C)O)C3)sc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(2-methylbenzoimidazol-1-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (78 mg, 0.2 mmol), 2-piperidin-3-yl-propan-2-ol (43 mg, 0.3 mmol) trimethyl orthoformate (0.109 mL, 1.0 mmol) and glacial acetic acid (0.017 mL, 0.3 mmol) in 1,2-dichloroethane (2 mL) was stirred at RT under nitrogen atmosphere for 1 h. Sodium triacetoxyborohydride (85 mg, 0.4 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PCC, acetone:cyclohexane: 10:90 to 35:65 by volume). Solvents were reduced in vacuo to afford the title compound as a white solid. The resulting solid was further purified by reverse phase HPLC (MeOH: H2O+0.1% HCCOH, gradient 10:90 to 90:10 over 25 min). The solvent was reduced in vacuo and the aqueous residue freeze dried to afford 362 as a white solid (23 mg, 23%). LCMS (Method G): RT 6.73 min, [M+H]+ 508. 1H NMR (400 MHz, CDCl3): δ 8.18 (1 H, s), 8.04-8.03 (1 H, m), 7.70-7.69 (1 H, m), 7.27-7.26 (2 H, m), 4.38 (4 H, br s), 3.90 (2 H, s), 3.85 (4 H, t, J=4.74 Hz), 3.18 (2 H, m), 2.91 (5 H, m), 2.28-2.15 (2 H, m), 1.81 (2 H, m), 1.75-1.60 (2 H, m), 1.20 (3 H, s), 1.15 (3 H, s)
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][NH2:28])=[O:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30](OC)(OC)OC>>[CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]5[O:26][CH:30]=[N:28][N:27]=5)[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reactant: COC(OC)OC
Agent: Cl
Product: c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)cc(-c2nnco2)n1

Procedure:
A solution of 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide (8 mg, 0.019 mmol, 1.0 eq) and 0.1 mL of 4 M hydrogen chloride in 1 mL trimethyl orthoformate was heated in the microwave at 120° C. for 1200 seconds. The crude product was purified by reverse phase prep HPLC to give the title compound. MH+=392.0
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH:9]=[O:10].[NH4+].[Cl-]>C1COCC1>[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9](=[O:10])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1c(F)cccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(=O)c1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (18 mL of 2 M in Et2O, 35 mmol) is added to a solution of 2-bromo-6-fluoro-benzaldehyde (6.0 g, 30 mmol) in THF (40 mL) at −78° C. and the mixture is stirred for 1 hour at 0° C. The mixture is poured into saturated NH4Cl and extracted with EtOAc. The resulting crude alcohol is oxidized directly by Swern oxidation to yield 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one. 1H NMR (CDCl3) 7.38 (d, 1H), 7.22 (m, 1H), 7.03 (t, 1H), 3.10 (m, 1H), 1.11 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH:5][C:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
To a stirring solution of L-leucine methyl ester (2.0 g, 11.0 mmol) in 1,4-dioxane (20 mL) was added aqueous Na2CO3 solution (12.1 mL, 2M in H2O) followed by benzylchloroformate (1.96 g, 11.5 mmol). The mixture stirred at room temperature for 4 h then partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried (MgSO4), filtered and concentrated to yield the title compound as a colorless oil (3.1 g, 100%). 1HNMR (400 MHz, CDCl3) δ7.34 (m, 5H), 5.27 (d, 1H), 5.12 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 1.65 (m, 3H), 0.96 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:3]1[C:4]2[N:8]=[N:7][NH:6][C:5]=2[CH:9]=[CH:10][C:2]=1[Cl:1])([O-:13])=[O:12]
Reactant: Clc1ccc2[nH]nnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2[nH]nnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
5-Chloro-1H-benzotriazole (3.08 g, 20 mmol) was dissolved in conc. sulphuric acid (40 ml) and cooled to 0° C. on an ice bath. Nitric acid (40 ml, excess) was added drop wise to the cooled solution over a period of 20 minutes. Stirring was continued for 1 hour at 0° C. and then at 60° C. for an additional 1 hour, by which time TLC (A) indicated the conversion of starting material. The solution was cooled to room temperature and poured over ice to precipitate a white solid. The solid was collected by filtration and washed with copious amounts of water until neutral to afford [22] in 83% yield. Rf (A) 0.49 δH(400 MHz; DMSO-d6) 7.75 (1H, d, J8.8, BT) 8.38 (1H, br s, BT); m/z (EI−HR) 197.99383 [(M) calc. for C6H3N4O235Cl 197.99445] and 199.99345 [(M) calc. for C6H3N4O237Cl 199.99150].
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Yield: 58.2 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.6 g, 46.2 mmol), 4-amino-1-Boc-piperidine (10.18 g, 50.8 mmol), diisopropylethylamine (20.9 ml, 120 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 11 h. The mixture was then cooled to 25° C. and was concentrated under reduced pressure. The yellow-orange residue was partitioned between water (150 ml) and CH2Cl2 (2×200 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to afford crude 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (26.4 g, 114%) as a yellow-orange foam. A portion of this material (11.2 g) was used in the next step below. The remaining material was purified by column chromatography on silica gel (gradient: 0 to 70% EtOAc in heptanes) to give the title compound (13.49 g) as a yellow solid. LCMS (Method G, ESI): RT=1.24 min, m+H=502.3; 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 9.08 (s, 1H), 8.19 (d, J=8.0 Hz, 2H), 7.63 (dd, J=8.1, 5.9 Hz, 2H), 7.52 (t, J=7.8 Hz, 2H), 6.70 (d, J=4.2 Hz, 1H), 4.22-4.07 (m, 1H), 4.01 (d, J=13.3 Hz, 2H), 3.12 (t, J=11.3 Hz, 2H), 2.17-2.04 (m, 2H), 1.69-1.58 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[S:22]1[CH:26]=[CH:25][C:24](B(OC(C)C)OC(C)C)=[CH:23]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Fc1ccc(Nc2ncnc3ccc(Br)cc23)cc1Cl
Reactant: CC(C)OB(OC(C)C)c1ccsc1
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-c4ccsc4)cc23)cc1Cl
Yield: 51 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 2 hours, 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 3-thienylboronate to give 4-(3-chloro-4-fluoroanilino)-6-(3-thienyl)quinazoline in 51% yield, m.p. 195-197° C.;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:16]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
(S)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (Omega Chemical Company) (950 mg, 5.55 mmol) was methylated and purified in a similar way to Preparation 67 using 60% sodium hydride dispersion (260 mg, 6.50 mmol) and methyl iodide (0.5 mL, 8.06 mmol) in DMF (15 ml). 1H NMR and Rf were identical to the (R)-enantiomer.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21](C(OC4C=CC=CC=4)=O)[C:22](=O)[O:23]C4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[OH-].[Na+].Cl.[O:43]=[S:44]1(=[O:50])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:47]4[CH2:48][CH2:49][S:44](=[O:50])(=[O:43])[CH2:45][CH2:46]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: O=S1(=O)CCNCC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCS(=O)(=O)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-indol-5-yloxy)-pyridin-2-yl)-N-(phenoxycarbonyl)carbamate (150 mg, 0.278 mmol, Production example 5-2) was dissolved in N,N-dimethylformamide (1.5 ml); 5N aqueous solution of sodium hydroxide (0.29 ml) and 1,1-dioxothiomorpholine hydrochloride (246 mg, 1.44 mmol) were added thereto; and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate). Diethyl ether was added to this to allow to crystallize; and the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound as colorless crystals (100 mg, 0.226 mmol, 78.5%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)(=[O:4])=[O:3].O.[Br:14]Br.[OH-].[Na+]>C(O)(=O)C>[Br:14][C:10]1[CH:9]=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: BrBr
Reactant: COc1cccc(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(S(C)(=O)=O)c1
Reaction time: 15 h
Yield: 45 %

Procedure:
1-Methanesulfonyl-3-methoxy benzene was dissolved in 90 mL glacial acetic acid. 100 mL water was added. A solution of bromine (4.79 g, 30 mmol) in 10 mL acetic acid was added dropwise at 10° C. The stirring was continued at rt for 15 h. The pH of the mixture was adjusted to pH 8 with aqueous NaOH solution, and extracted with EtOAc (3×200 mL) and dried over Na2SO4. The crude compound was purified by column chromatography (SilicaGel 230-400 mesh; 20% EtOAc in hexanes as an eluent) to give 1-bromo-2-methanesulfonyl-4-methoxy benzene (2.4 g, 45%).