Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:12][C:13]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I[CH3:32].O>O1CCCC1.CN(C)C=O>[CH3:3][N:4]([CH2:12][C:13]1[CH:17]=[C:16]([N:18]([CH3:32])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CI
Reactant: CN(Cc1cc(Nc2ccccc2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(N(C)c2ccccc2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (16 mg) in tetrahydrofuran (2 mL) and N,N-dimethylformamide (0.5 mL) was added tert-butyl methyl{[1-phenyl-5-(phenylamino)-1H-pyrazol-3-yl]methyl}carbamate (100 mg). After stirring at room temperature for 30 min, iodomethane (75 mg) was added, and the mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→4:1) to give the title compound as a pale-brown oil (yield 67 mg, yield 65%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:16][C:17](=[O:25])[NH:18][C@@H:19]([CH2:23]O)[CH2:20][CH2:21][CH3:22])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[C:12]([O:16][C:17](=[O:25])[NH:18][C@@H:19]([CH2:23][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:20][CH2:21][CH3:22])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC[C@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC[C@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of phthalimide (1.43 g, 9.72 mmol), ((R)-1-hydroxymethyl-butyl)-carbamic acid tert-butyl ester (prepared according to the procedure described in Tetrahedron Letters (1987), 28(48), 6069-72) (1.97 g, 9.69 mmol) and triphenylphosphine (2.55 g, 9.72 mmol) in DCM (25 mL) at 0° C. is added DEAD (1.6 mL, 10.2 mmol) dropwise. The reaction mixture is stirred at RT overnight. The reaction mixture is adsorbed onto silica gel and purification by column chromatography (SiO2, EtOAc/iso-hexane, gradient of 0-15% EtOAc) affords the title compound as white solid. [M+H]+ 233.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)#[N:2].[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[C:1]#[N:2])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: N#Cc1ccccc1C(=O)O
Product: N#Cc1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-cyanobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (25.8% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.97, 7.76-7.72, 7.69-7.66, 7.58-7.55, 7.53-7.43, 6.99, 4.3-3.94, 3.88-3.85, 3.58-3.51, 1.49, 0.78-0.65, 0.48-0.37, 0.16-0.02. 13C NMR (75 MHz, CDCl3) δ166.5, 162.8, 159.9, 145.3, 139.3, 133.3, 133.04, 129.9, 127.6, 127.03, 116.8, 112.4, 109.9, 46.4, 44.7, 44.6, 41.6, 39.6, 34.4, 8.6, 4.1. MS (ES+) m/z 405.2 (M+1).
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][N:6]=1)(=O)=O.[CH3:15][O-:16].[Na+].CO>CO>[CH3:15][O:16][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(C)(=O)=O)cn1
Temperature: 50 °C

Procedure:
A suspension was prepared from 23.5 g of 2,5-bis(methylsulfonyl)pyridine and 200 ml of methanol and this was stirred rapidly under nitrogen while 24 ml of 25% sodium methoxide/methanol was added. This mixture was warmed to 50° C. for 20 minutes to give a homogeneous black solution. The solvent was removed by evaporation under reduced pressure and the resulting slurry was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. The mixture was treated with carbon and filtered through Celite to give a pale yellow filtrate. Concentration of the filtrate under reduced pressure gave a pale yellow oil which solidified on cooling. This was recrystallized from 2-propanol to give 2-methoxy-5-(methylsulfonyl)pyridine as colorless crystals melting at about 85°-86.5° C. Bromination of this compound according to the procedure described in Example 2 gave 3-bromo-2-methoxy-5-(methylsulfonyl)pyridine melting at about 148.5°-150.5° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([O:16][C:17]1[CH:29]=[C:21]2[C:22](O[C:25](=O)[N:26](C)[C:20]2=[CH:19][CH:18]=1)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]([CH3:25])[C:3](=[O:5])[CH:2]3[CH2:6][CH2:7][CH2:8][N:1]3[CH2:22][C:21]=2[CH:29]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2cc(OCc3ccccc3)ccc21
Agent: B
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2cc(OCc3ccccc3)ccc21

Procedure:
The above compound is obtained when 7-benzyloxy- 1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c] [1,4]benzodiazepin- 5,11(10H)-dione (prepared from proline and 5-benzyloxy-N-methylisatoic anhydride by the procedure of Example 1) is treated with 1 M borane in tetrahydrofuran by the procedures of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:26]=[N:25][N:24]([CH:27]([CH3:29])[CH3:28])[C:16]=2[N:17]=[C:18]([NH:20]CC=C)[CH:19]=1)=[O:13].CS(O)(=O)=O>C(O)C.C(Cl)Cl.[Pd]>[NH2:20][C:18]1[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[C:15]2[CH:26]=[N:25][N:24]([CH:27]([CH3:29])[CH3:28])[C:16]=2[N:17]=1
Reactant: C=CCNc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(N)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C

Procedure:
A mixture of 10% Pd/C (0.200 g, 0.188 mmol) and N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-propen-1-ylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.200 g, 0.507 mmol) was suspended in ethanol (10 mL) and stirred. Added next was methanesulfonic acid (0.033 mL, 0.507 mmol), and the stirring contents were heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was diluted with DCM and filtered through Celite. The filter pad was washed with 10% MeOH/DCM. The filtrate was pre-adsorped onto silica gel, and the crude product purified by silica gel chromatography (dry loaded, eluent: gradient of 5-80% Dichloromethane/Chloroform containing 10% 2M Ammonia (in methanol)). The collected product was dried in vacuum oven at 45° C. overnight. The final product was collected as 0.065 g (36%). LCMS E-S (M+H)=355.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.82 Hz, 6H), 2.12 (s, 3H), 2.21 (s, 3H), 4.31 (d, J=5.05 Hz, 2H), 4.85-5.00 (m, 1H), 5.89 (s, 1H), 6.49-6.68 (m, 3H), 7.85 (s, 1H), 8.46 (t, J=5.05 Hz, 1H), 11.54 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:10][CH:9]1[C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1.[IH:26]>O1CCOCC1>[IH:26].[I:26][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1)[CH2:10][NH:8][CH2:7][CH2:6][O:5][C:4]1[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1OCCN1CC1c1ccc(C)c(S(N)(=O)=O)c1
Agent: I
Solvent: C1COCCO1
Product: COc1ccccc1OCCNCC(I)c1ccc(C)c(S(N)(=O)=O)c1
Yield: 70.3 %

Procedure:
In 50 ml of dioxane was dissolved 2.5 g of 5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide and after adding thereto 1 g of concentrated hydroiodic acid, the mixture was stirred overnight. After the reaction was over, the solvent was distilled off under reduced pressure and the residue was washed three with30 ml of water and then three with 200 ml of ether and crystallized by the addition of ethyl acetate. The crystals were recovered by filtration, washed with water, and dried to provide 1.7 g of 5-{1-iodo-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide hydroiodide. The product has the following physicochemical properties.
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][C:4]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[O:15][C:1]=2[CH3:2])[CH:7]=1
Reactant: CC(=O)C(Cc1cccc(Br)c1)NC(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nc(Cc3cccc(Br)c3)c(C)o2)cc1
Yield: 86.2 %

Procedure:
1-[2-Acetyl-2-(p-toluoylamino) ethyl]-3-bromobenzene (13.26 g) was dissolved in 260 ml of toluene, and 6.8 ml of phosphorus oxychloride was added and heated to reflux for 3 hours. The reaction solution was cooled, poured into ice-cold water and extracted with ethyl acetate. The resulting solution was washed with aqueous solution of saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 10.86 g of the objective compound as yellowish crystals. M.p. 74–75° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22]1>C(#N)C>[NH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:22]1
Reactant: NCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of 1.00 g (3.53 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 10 ml of acetonitrile, 0.54 g (3.5 mmole) 1,8-diazobicyclo[5.4.0]undec-7-ene, and 0.37 g (3.7 mmole) of 3-pyrrolidinemethanamine is refluxed one hour, then stirred at room temperature overnight. The reaction mixture is then filtered and the precipitate washed with ethyl ether until dry to yield 1.21 g (94.5%) of the title compound, mp 232°-235° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([NH:41][NH2:42])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)(=[O:21])=[O:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: NNc1ccnc2cc(Cl)ccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1ccnc2cc(Cl)ccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=547.2 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:18]=2[N:17]=1)[CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:24][C:18]=2[N:17]=1)[CH:10]([CH3:15])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-(5-tert-butyl-1H-benzimidazol-2-yl)-2-methylpropanoate (Preparation 33, 7.25 g, 18.65 mmol) and lithium hydroxide (0.67 g, 27.95 mmol) in THF and water (100 mL/10 mL) was stirred at room temperature for 18 hours. The THF was evaporated and the remaining aqueous solution was diluted with water (100 mL). A solution of KHSO4 in water was added resulting in a white precipitate. The solid was filtered and dried to afford the title compound that was taken directly on to the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[N-:17]=[N+:18]=[N-:19].[Li+]>CS(C)=O>[N:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Li+]
Solvent: CS(C)=O
Product: N#Cc1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.97 g (725 mmole) of 4-bromomethyl-2'-cyanobiphenyl (EP 253,310), 445 mg (9.1 mmole) of lithium azide and 5 ml of dry DMSO was stirred at room temperature under nitrogen for one hour and then partitioned between 100 ml of ether and 100 ml of H2O. The organic phase was washed with 3×100 ml of H2O, then dried (MgSO4), filtered, and concentrated in vacuo to give a residual oil which solidified on standing. This solid was triturated with petroleum ether, collected on a filter, washed with petroleum ether and dried overnight to yield the title compound as white crystals, mp 69°-70° C.; mass spectrum (EI) m/e 234 (M+). TLC in 4:1 hexane-EtOAc showed only minor impurities and the material was of sufficient purity to use in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1.O>CC(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:12][S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[O:24])=[CH:18][CH:17]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: O=C=Nc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Br)cc2)cc1
Yield: 91.9 %

Procedure:
To a solution of 9.97 g of 4-methoxybenzenesulfonamide in 54 ml of acetone were added 54 ml of a 1N sodium hydroxide solution. With stirring, a solution of 11.55 g of 4-bromophenylisocyanate in 50 ml of acetone was added. After stirring at room temperature for three days, the reaction mixture was filtered and 55 ml of 1N hydrochloric acid were added to the filtrate providing a fine white precipitate. Two hundred milliliters of water were added, and the solid was recovered by filtration to provide 18.85 g of the desired title product.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[O:6]=[C:7]([CH2:13][C:14](=[O:16])[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)Cl>[Cl:4][CH:13]([C:14](=[O:16])[CH3:15])[C:7](=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)C(Cl)C(C)=O
Reaction time: 3 h
Yield: 101.8 %

Procedure:
A solution of sulfuryl chloride (7.08 g, 52 mmol) in 15 mL of CH2Cl2 was added dropwise to a solution of ethyl 2,4-dioxovalerate (7.91 g, 40 mmol) in 125 ml of CH2Cl2 at room temperature. After three hours TLC analysis indicated that all of the starting material had been consumed. The reaction mixture was washed with H2O (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 7.84 g (81% yield) of the desired product as and orange oil: 1H NMR (CDCl3) δ14.4 (bs, 1H), 5.4 (s, 1H), 4.4-4.3 (m, 4H), 2.5 (s, 3H), 2.4 (s, 3H), 1.4-1.35 (s, 6H) for a 1:1 mixture of tautomers.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:21][C:22]6[O:26][C:25]([C:27]([O:29]C)=[O:28])=[C:24]([C:31](=[O:34])[NH:32][CH3:33])[C:23]=6[CH:35]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.O[Li].O>O1CCOCC1.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:21][C:22]6[O:26][C:25]([C:27]([OH:29])=[O:28])=[C:24]([C:31](=[O:34])[NH:32][CH3:33])[C:23]=6[CH:35]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a suspension of compound methyl 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate (540 mg, 0.93 mmol) in 1,4-dioxane/H2O (6 mL/1 mL) was added LiOH.H2O (196 mg, 4.67 mmol). The mixture was stirred at RT overnight. Then it was concentrated in vacuo, diluted with water, acidized with HCl(aq. 2 M) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated give the product of compound 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (500 mg, yield: 95%). It was used for the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 9.21 (br s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.54˜7.58 (m, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.28˜7.11 (m, 2H), 7.07 (s, 1H), 6.95˜6.88 (m, 1H), 6.25 (s, 2H), 3.28 (s., 3H), 2.95 (s, 3H), 2.83 (d, J=4.4 Hz, 3H). MS (M+H)+: 565.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])=[C:10]([F:25])[CH:9]=[C:8]([Cl:26])[C:6]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([SH:35])[CH3:34].O>CN(C)C=O>[Cl:26][C:8]1[C:6]2[CH:7]=[C:3]([CH2:2][S:35][CH2:33][CH3:34])[O:4][C:5]=2[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:10]([F:25])[CH:9]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(CBr)oc23)c1=O
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
1.5 g (3.3 mmol) of 3-(2-bromomethyl-4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 0.7 g (5.1 mmol) of potassium carbonate were suspended in 20 ml of N,N-dimethylformamide, and 0.21 g (3.4 mmol) of ethylmercaptan was added thereto at room temperature, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.2 g (yield: 83.4%) of the desired product as a yellowish brown glassy substance. Refractive index: 1.5629 (20° C.).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:4]=1[NH:5]2.O1[CH2:21][CH2:20]OC1.CC([O-])(C)C.[K+].C(Br)C.[NH4+].[Cl-]>O>[CH2:20]([N:5]1[C:6]2[C:2](=[CH:1][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:16]3[C:11]([CH2:10][C:4]1=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:21]
Reactant: C1COCO1
Reactant: c1ccc2c(c1)Cc1[nH]c3ccccc3c1-2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCBr
Product: CCn1c2c(c3ccccc31)-c1ccccc1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
15.00 g of 5,6-dihydroindeno[2,1-b]indole (99.8% by G.C., Mw=205.26, 73.1 mmol) were dissolved into 200 mL of 1,3-dioxolane (Aldrich) at room temperature in a 0.5-L flask. 8.28 g of t-BuOK (Fluka, 99%, Mw=112.22, 73.1 mmol) were added and the reaction mixture turned from a green suspension to a brown solution. After 30 min stirring at room temperature, 5.51 mL of EtBr (Fluka, 99%, Mw=108.97, d=1.46, 73.1 mmol) were added, obtaining a brown suspension. Stirring was continued for 2 hours, then the reaction mixture was poured into water containing 8 g of NH4Cl (Carlo Erba RPE, purity 99.5%). After two hours stirring, the green-brown suspension was filtered on a G4 frit, the solid dried in air under moderate vacuum to give a green powder (8.98 g), which was analyzed by 1H NMR. Purity 98.9% wt. by 1H NMR (yield=52.1%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][N:16]4[S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])=[C:12]([C:28]4[NH:32][N:31]=NN=4)[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)(Cl)Cl>[Cl:33][CH2:34][C:35]1[O:36][C:28]([C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3[S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[N:32][N:31]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnn[nH]3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Temperature: 100 °C
Yield: 15.2 %

Procedure:
6-(1H-Indol-4-yl)-1-(phenylsulfonyl)-4-(1H-tetrazol-5-yl)-1H-indazole (1.41 g, 3.19 mmol) was slurried into anhydrous chloroform (20 ml), treated with chloroacetyl chloride (1.023 ml, 12.78 mmol) and heated at 100° C. in a Biotage Initiator microwave for 30 mins, the mixture was split into 4 batches for the microwave reaction. The mixtures were allowed to cool to room temperature and the resultant precipitate collected by filtration to give the title compound as a yellow/brown solid (0.237 g). LCMS (Method A): Rt 1.25 mins, MH+ 490.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:10]([CH3:26])[C:9]2=[O:27])=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:48])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41](O)=[C:40]([CH2:45][CH2:46][CH3:47])[CH:39]=1)([CH3:36])[CH3:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:48])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:9](=[O:27])[N:10]2[CH3:26])=[C:40]([CH2:45][CH2:46][CH3:47])[CH:39]=1)([CH3:35])[CH3:36])[CH3:31]
Reactant: CCCc1cc(OC(C)(C)C(=O)OCC)ccc1O
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Product: CCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCC1CN(Cc2ccc(OC)cc2)C(=O)N1C

Procedure:
The titled compound is prepared, according to the procedure of Example 1, Step A, using toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (0.200 g, 0.478 mmole) and 2-(4-hydroxy-3-propyl-phenoxy)-2-methyl-propionic acid ethyl ester (0.140 g, 0.526 mmole) to produce a colorless oil (0.122 g, 50%). Mass [EI+] 513 (M+H)+.