Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19](O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].CN(C)C=O.S(Cl)(Cl)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)(=[O:20])=[O:21])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)nc2n(CC)c1=O
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (5.0 g, 0.014 moles) and N,N-dimethylformamide (150 ml) is cooled to 0° and treated with thionyl chloride (3.3 g, 0.027 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry results. To this slurry is added morpholine (20 g, 0.23 moles) in one portion. The resulting slurry is stirred one hour and poured into two liters of water. The resulting suspension is filtered, triturated with ethanol, and dried at 68° to yield 3.29 grams of 4-[[4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)phenyl]sulfonyl]morpholine, mp 354°-355° C.(d).
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29](=O)[CH2:30][O:31][CH2:32][O:33][CH3:34]>CC(C)=O.C(Cl)Cl>[CH3:34][O:33][CH2:32][O:31][CH2:30][C:29]1[CH2:28][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6]
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCC(Cl)(Cl)Cl
Reactant: COCOCC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COCOCC1=C(C(=O)OCC(Cl)(Cl)Cl)N=CSC1
Reaction time: 4 h

Procedure:
A solution of 2,2,2-trichloroethyl α-thioformamidodiethylphosphonoacetate (3.87 g.) in acetone (50 ml.) is treated with powdered potassium carbonate (4.15 g) and 1-chloro-3-methoxymethyloxy-propan-2-one (1.60 g.). The mixture is stirred for 4 hrs. at room temperature under a nitrogen atmosphere, then filtered. Evaporation of the filtrate leaves a residue which is dissolved in methylene chloride. The solution is washed with dilute aqueous dipotassium hydrogen phosphate and water, dried over magnesium sulfate, filtered and evaporated in vacuo affording 2,2,2-trichloroethyl 5-methoxymethyloxymethyl-6H-1,3-thiazine-4-carboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:18]=[C:17]([NH:19]CCO)[C:16]2[C:15]3[CH:23]=[CH:24][N:25]([CH3:26])[C:14]=3[C:13](C3SC=CC=3)=[CH:12][C:11]=2[N:10]=1.[OH-].[Na+].C[I:35].[Cl-].[Na+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[I:35][C:13]1[C:14]2[N:25]([CH3:26])[CH:24]=[CH:23][C:15]=2[C:16]2[C:11]([CH:12]=1)=[N:10][C:9]([NH2:8])=[N:18][C:17]=2[NH2:19]
Reactant: CI
Reactant: Cn1ccc2c3c(NCCO)nc(N)nc3cc(-c3cccs3)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cn1ccc2c3c(N)nc(N)nc3cc(I)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 119.9 %

Procedure:
A solution of 6-iodo-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (prepared as in Example 1, 400 mg, 1.23 mmol) in tetrahydrofuran (20 mL) at 25° C. was treated with sodium hydroxide (98 mg, 2.46 mmol), methyl iodide (0.09 mL, 1.48 mmol), and tetrabutylammonium bromide (198 mg, 0.62 mmol and stirred at 25° C. for 18 h. The resulting mixture was treated with ethyl acetate, water, and a saturated aqueous sodium chloride solution, shaken and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-iodo-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (500 mg) as a yellow solid. The product was taken on into the next reaction without further purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][C@:5]([CH:12]([CH3:14])[CH3:13])([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:12]([C@:5]1([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7][C@@H:3]([NH:2][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:4]1)([CH3:14])[CH3:13]
Reactant: O=C1CCOCC1
Reactant: COC(=O)[C@@]1(C(C)C)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@]1(C(C)C)CC[C@@H](NC2CCOCC2)C1
Reaction time: 0.17 h

Procedure:
Methyl (1S,3R)-3-amino-1-isopropylcyclopentanecarboxylate hydrochloride (prepared in the same way as the intermediate from Step F, Procedure A, INTERMEDIATE 2, except with the modification that the methyl ester was employed instead of the benzyl ester, 1.4 g, 6.1 mmol) was combined with tetrahydro-4H-pyran-4-one (730 mg, 7.3 mmol), and triethylamine (1 mL, 7 mmol) in 50 mL of DCM. After 10 min, 4 Å powdered molecular sieves (1 g), and sodium triacetoxyborohydride (5.1 g, 24 mmol) were added and the resulting mixture was permitted to stir overnight. The reaction mixture was filtered through celite, and the filtrate was washed with saturated NaHCO3 solution twice, then once with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to afford 1 g of methyl (1S,3R)-1-isopropyl-3-(tetrahydro-2H-pyran-4-ylamino)cyclopentanecarboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[CH2:10][CH2:11]Cl.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1>>[CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[CH2:10][CH2:11][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: CC1(C)CCCC(C)(C)N1CCCl
Reactant: CC(=O)Cc1ccc(O)cc1
Product: CC(=O)Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)cc1

Procedure:
Prepared from 2-(2,2,6,6-tetramethylpiperidin-1-yl)ethyl chloride and 4-hydroxyphenylacetone in a similar manner to Example 2 (b).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([CH3:12])[CH2:7]1.Br.Br.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+].[I-].[K+]>C(O)CCC>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]2[O:10][C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2)[CH2:24][CH2:23]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: CN1CC(CCCCCl)OC1=O
Agent: Br
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Product: CN1CC(CCCCN2CCN(c3ccccc3O)CC2)OC1=O
Yield: 34 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-methyl-2-oxazolidinone (5.39 g, 0.0282 mol), 1-(2-hydroxyphenyl)-piperazine dihydrobromide (9.6 g, 0.0282 mol), sodium bicarbonate (9.5 g, 0.113 mol) and potassium iodide (1.0 g) in n-butanol (100 mL) gave an oil which was triturated in light pet ether several times, crystallized from ethyl acetate/isopropyl ether, and dried under high vacuum at 50° C. to give 3.22 g (34% yield), mp 106°-110°.
Reaction SMILES: N1N=CN([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3CCCO)C=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>C1COCC1.C(O)(C)C>[NH:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: OCCCc1c[nH]c2ccc(-n3cnnc3)cc12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 107 %

Procedure:
To a solution of Intermediate 1 (0.20 g, 0.83 mmol) in anhydrous THF (100 ml), at 0° C., was added triethylamine (0.167 g, 1.65 mmol) and methane sulphonyl chloride (0.19 g, 1.65 mmol) and the mixture warmed to room temperature and stirred for 1.5 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and K2CO3 solution (10 ml). The aqueous was separated and extracted further with ethyl acetate (1×50 ml). The combined extracts were dried (MgSO4) and evaporated and used in the next step without further purification. To a solution of the preceding mesylate (0.264 g, 0.825 mmol), in isopropyl alcohol (25 ml), was added powdered K2CO3 (0.114 g, 0.825 mmol), sodium iodide (82 mg, 0.55 mmol) and (±)-1-H-4-(3-hydroxy-2-phenylpropyl)-piperazine (0.11 g, 0.55 mmol), and the mixture stirred at 120° C. for 16 h. The mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between aq. K2CO3 solution (5 ml) and ethyl acetate (×3). The combined extracts were dried (MgSO4) and evaporated, and the residue chromatographed through silica gel eluting with CH2Cl2 /MeOH/NH3 (90:8:1) to give the title-indole (0.104 g, 43%). The 1.6 hydrogen oxalate salt was prepared. mp 137-140° C., (Found: C, 59.62: H, 6.67; N, 13.36. C26H32N6O. 1.6 (C2H2O4). 0.4 (C4H10O) requires C, 59.83; H, 6.39; N, 13.59%), m/e 445 (M+1)+, δ(360 MHz, D6 -DMSO) 1.92-2.06 (2H, m, CH2), 2.56-3.62 (17H, m, 8 of CH2 and CH), 7.18-7.34 (7H, m, Ar-H), 7.50 (1H, d, J=8.6 Hz, Ar-H), 7.79 (1H, s, Ar-H), 9.01 (2H, s, Ar-H), 11.17 (1H, s, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=[CH:38]2>CN(C=O)C>[CH3:45][N:41]1[C:42]2[C:37](=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][N:13]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])=[CH:44][CH:43]=2)[CH:38]=[CH:39][C:40]1=[O:46]
Reactant: Cn1c(=O)ccc2cc(OCCCCCBr)ccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
2-Nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide(308 mg), and potassium carbonate(276 mg) were added to a DMF solution(5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one(348 mg). The mixture was stirred at room temperature for 2 hours. Ice water was poured to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate: methanol=10:1). The purified product was condensed to dryness under reduced pressure to give 5 the title compound(535 mg) as a yellow amorphous solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](N)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:11].N([O-])=O.[Na+]>C(O)(=O)C.O>[Br:11][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=1
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1nnc(Br)s1
Temperature: 65 °C

Procedure:
To a solution of crude 5-tert-butyl-1,3,4-thiadiazol-2-amine (120.8 g) in glacial acetic acid (800 ml) was added aqueous hydrobromic acid (≧40%, 218 ml) at room temperature. The resulting solution was heated to 65° C., and a solution of sodium nitrite (167 g, 2.42 mol) in water (300 ml) was added dropwise such that the internal temperature was maintained at 65˜75° C. After addition was complete, the resulting yellow solution was cooled to room temperature, poured into ice and then extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium carbonate solution until the pH was neutral, dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified via flash column chromatography (ethyl acetate/petroleum ether) to obtain 2-bromo-5-tert-butyl-1,3,4-thiadiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.O.O[N:28]1[C:32]2C=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1.FC(F)(F)C(O)=O>CN(C)C=O.C(Cl)Cl>[ClH:1].[NH2:28][C@@H:32]1[CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 23 h
Yield: 188.6 %

Procedure:
The compound (1.40 g) obtained in Referential Example 61 was dissolved in N,N-dimethylformamide (15 ml), and to the solution 5-chloroindole-2-carboxylic acid (1.64 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g) and 1-hydroxybenzotriazole monohydrate (473 mg) were added. The mixture was stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated solution of sodium hydrogencarbonate were added to the residue to collect precipitates by filtration. The precipitates were washed with ethyl acetate, methylene chloride and methanol. On the other hand, the filtrate was separated to give an organic layer, which was taken out and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (methylene chloride:methanol=19:1) to obtain a pale yellow solid. This pale yellow solid was combined with the precipitates obtained by the filtration and dissolved in methylene chloride (10 ml), and trifluoroacetic acid (10 ml) was added to stir the mixture at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and methylen chloride and 1N aqueous solution of sodium hydroxide were added to the residue to collect precipitate by filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. The precipitates collected by the filtration were added to this solution, and a 4N dioxane solution (20 ml) of hydrochloric acid was further added. The solvent was distilled off under reduced pressure, and methylene chloride (10 ml) and a 4N dioxane solution (10 ml) of hydrochloric acid were added to the residue. The solvent was distilled off again under reduced pressure. Ethyl acetate was added to the residue to collect precipitates formed by filtration, thereby obtaining the title compound (1.83 g).
Reaction SMILES: C([O-])(C)(C)C.[K+].ClC1C=CC(O[CH2:13][C:14]#[N:15])=CC=1.[N+:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)([O-:20])=[O:19].Cl>CN(C)C=O.O>[N+:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:13][C:14]#[N:15])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc2ccccc2c1
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c([N+](=O)[O-])ccc2ccccc12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Prepare a solution of 53.5 g (0.477 mol) of potassium tert.-butanolate in 400 ml of dimethylformamide. Cool the resulting solution to −10° C. and add thereto, over the course of about 1 hour, a solution of 40 g of 4-chlorophenoxyacetonitrile (0.24 mol) and 37 g of 2-nitronaphthalene (0.213 mol) in 200 ml of dimethylformamide. After 2 hours at −5° C., pour the mixture into 4 liters of water containing 1 liter of concentrated hydrochloric acid and extract the aqueous phase with 3×500 ml of dichloromethane. Wash the organic phase with 300 ml of water, dry it over magnesium sulphate, filter and then evaporate off the solvent.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27]C)=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([OH:27])=[O:26])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Temperature: 90 °C

Procedure:
To a solution of (methyl (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)-carboxylate), 5-(4-morpholinylcarbonyl) (25 mg, 0.05 mmol) in MeOH//THF (1:1, 1.6 mL) was added 1 M aqueous NaOH (0.80 mL). The reaction mixture was stirred and heated at 90° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (1 mL), neutralized with 1M aqueous HCl (0.80 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carboxylic acid, 5-(4-morpholinylcarbonyl) (21 mg, 0.05 mmol, 85%) as a light yellow solid. 1HNMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.63 (dd, J=8.4, 1.5 Hz, 1H), 7.60–7.47 (m, 3H), 7.29 (dd, J=7.0, 1.5 Hz, 1H), 4.84 (br s, 2H), 3.98–3.55 (m, 4H), 3.23–3.05 (m, 2H), 2.88–2.69 (m, 5H), 2.12–1.63 (m, 6H), 1.51–1.06 (m, 4H). LCMS: m/e 472 (M−H)−, ret time 1.39 min, column A, 3 minute gradient.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH3:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:10]([CH2:11][CH3:12])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: BrBr
Reactant: CCCCOC(=O)C(=O)CCC
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)C(=O)C(Br)CC
Yield: 98.9 %

Procedure:
The same operation as in Example (106a) was performed using butyl 2-oxopentanoate (described in Cuvigny; C. R. Hebd. Seances Acad. Sci.; 240; 1955; 206, 12g, 69.8 mmol), bromine (3.33 mL, 65 mmol) and chloroform (80 mL), to obtain 16.15 g of the title compound as a colorless liquid (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30](=[O:32])(=[O:31])[NH2:33])=[O:13])=[CH:17][CH:18]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)cc2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (15.2 mmol) of 3-(4-chlorobenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.75 g (16.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 4.70 g (yield: 74.0%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([Cl:24])[CH:7]=[C:8]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:9]=2[CH2:11]O)[NH:4][N:3]=1.S(Cl)(Cl)=O.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:32]([CH2:31][C:30]([F:34])([F:33])[F:29])[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:8]=3[CH:7]=[C:6]([Cl:24])[C:5]=2[NH:4][N:3]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]nc(Cl)c2c1CO)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
(S)-Dimethyl 2-((3,7-dichloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (990 mg, 2.64 mmol) was dissolved in thionyl chloride (2.0 M in dichloromethane) (20 mL, 40.0 mmol). Mixture stirred at room temperature for 3 hours. Mixture was concentrated by roto-vap. Residue was dissolved in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate. Organics were dried MgSO4, filtered and then concentrated to dryness. A portion of the residue (535 mg, 1.359 mmol) was dissolved in acetonitrile (15 mL). 2,2,2-Trifluoroethylamine (600 μl, 7.57 mmol) was added to the mixture followed by potassium carbonate (225 mg, 1.628 mmol). Mixture was warmed to reflux and held with stirring for 1 hour. Mixture was cooled to room temperature and then filtered over celite. Filtrate was concentrated by roto-vap. Residue was dissolved in toluene (15 mL). Acetic acid (500 μl, 8.73 mmol) was added to the mixture. Reaction was warmed to reflux and held with stirring for 14 hours. Mixture was cooled to room temperature and then diluted with ethyl acetate. Material was washed twice with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as off-white solid in 42% yield. MS (M+H)+=423.9, 425.9.
Reaction SMILES: [Cl-].[Li+].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][C:23]1[C:24](OS(C(F)(F)F)(=O)=O)=[C:25]([CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:26]([O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[C:27]2[C:31]=1[CH2:30][O:29][C:28]2=[O:32].[CH3:62][O:63][C:64]1[CH:85]=[CH:84][C:67]([CH2:68][O:69][CH2:70][Sn](CCCC)(CCCC)CCCC)=[CH:66][CH:65]=1.[F-].[K+]>C(OCC)(=O)C.O.CN1CCCC1=O>[CH3:62][O:63][C:64]1[CH:85]=[CH:84][C:67]([CH2:68][O:69][CH2:70][C:24]2[C:23]([CH3:22])=[C:31]3[C:27]([C:28](=[O:32])[O:29][CH2:30]3)=[C:26]([O:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])[C:25]=2[CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[CH:66][CH:65]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCc1ccc(OC)cc1
Reactant: COC(=O)CC/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(C)=C/Cc1c(COCc2ccc(OC)cc2)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
A mixture of lithium chloride (1.6 g), tris (dibenzylideneacetone)dipalladium (O) chloroform adduct (0.22 g), triphenylarsine (0.53 g), methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (8.0 g) and N-methylpyrrolidinone (70 ml) is heated to 55° C. p-Methoxybenzyloxymethyltributyltin (7.5 g) is added. After 3 hours the solution is added to water (200 ml), potassium fluoride (5 g) and ethyl acetate (200 ml). The organic solution is dried, filtered through celite and evaporated, and the residue is chromatographed on silica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6-(1,3-dihydro-6-(p-methoxybenzyloxymethyl)-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.