Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].Cl.[CH3:16][NH:17][CH3:18].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:16][N:17]([CH3:18])[S:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:13])=[O:12]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a solution of 80 g of 2-chloro-5nitrobenzenesulfonyl chloride (Example A-1 above) in 200 ml of methylene chloride heated to reflux, was slowly added a solution of 30 g of dimethylamine hydrochloride in 30 ml of water followed by a dropwise addition of triethylamine. After completion of the addition, the reaction mixture was refluxed for 20 minutes, cooled to room temperature and concentrated by rotatory evaporation. The residue was treated with water and the resulting solid was filtered and recrystallized from ethanol, affording 61 g of the title compound, mp 138°-140° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH:17]([C:22]([O:24][CH3:25])=[O:23])[O:18][C:19](=[O:21])[CH3:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl.C(OCC)(=O)C>[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:11][C:12]=3[CH:17]([C:22]([O:24][CH3:25])=[O:23])[O:18][C:19](=[O:21])[CH3:20])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: COC(=O)C(OC(C)=O)c1cc(CNC(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(OC(C)=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.5 %

Procedure:
A mixture of 4-tert-butoxycarbonylaminomethyl-2-(1-methoxycarbonyl-1-acetoxymethyl)aniline (500 mg, 1 mmol), (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (475 mg, 1.4 mmol), triethylamine (0.55 mL), and Bop-Cl (360 mg, 1.4 mmol) in dichloromethane (15 mL) was stirred for 48 h at room temperature and diluted with ethyl acetate (200 mL). The mixture was washed with 5% potassium hydrogen sulfate, water, 1/15 phosphate buffer (pH 7.5), water, and brine, successively, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 0.3% acetic acid/ethyl acetate to give 340 mg of the title compound (50%).
Reaction SMILES: O[C@H:2]([CH3:22])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 69.6 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3R)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-butanoic acid (0.23 g, 0.74 mmol) in dry CH2Cl2 (23 mL), Et3N (0.31 mL, 2.22 mmol) and subsequently TBTU (0.28 g, 0.88 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the title compound (0.15 g, 69%), as white solid. [α]25D +28.23 (c 0.1, CHCl3). MS (ESI) m/z: 292 [M−H]+; (ESI) m/z: 290 [M−H]−. 1H NMR (DMSO-d6) δ 1.38-1.27 (m, 2H), 1.47 (d, J=6.1 Hz, 3H), 1.64-1.53 (m, 4H), 2.59-2.54 (m, 2H), 3.98 (t, J=6.6 Hz, 2H), 4.77-4.64 (m, 2H), 7.21-7.13 (m, 3H), 7.31-7.24 (m, 2H), 8.04 (d, J=7.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=[O:23].C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C.O>[Br:31][C:5]1[C:4]2[C:3]([CH:22]=[O:23])=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:8]=2[N:7]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(C=O)c(C)cc(C)c32)cc1
Temperature: 60 °C
Reaction time: 18.5 h

Procedure:
To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (2 g, 6.11 mmol) in DMF (10 mL) was added NBS (2.39 g, 13.44 mmol), and then the mixture was stirred at 60° C. for 18.5 h. The reaction mixture was cooled to room temperature. The mixture was diluted with H2O, the layers were separated and the aqueous layer was extracted with EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography to give the title compound. MS (ESI+) m/z 406.0, 408.0 (M+H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:10][O:11][C:12]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:7][CH3:8])=[O:18])=[CH:15][CH:14]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1ccc(C(=O)c2ccccc2OC)cc1
Temperature: 0 °C

Procedure:
To a mixture of anisole (216 g) and terephtalic acid-methyl ester-chloride (99 g) was added aluminium chloride (200 g) at 0° C. in an amount of 1/3 to 1/4 at a time. In that case, temperature was kept to 25° C. or less, and it took from 45 minutes to 1 hour for addition. The temperature returned to room temperature after 30 minutes from termination of addition, and after stirring for 1.5 hours to 2 hours, the pink colored precipitate was obtained by pouring ice-water. The precipitate was separated by filtration, dried with water and washed with methanol. Methanol washings were concentrated under reduced pressure, and washed with a small amount of methanol to give the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]1[NH:11][CH:12]=[CH:13][C:14]=1[C:15]([OH:17])=O.C(Cl)Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CCOC(C)=O>[NH:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:17])[NH:8][CH2:9][C:10]1=2
Reactant: NCc1[nH]ccc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A 5 L round-bottomed flask was charged with 2-(aminomethyl)-1H-pyrrole-3-carboxylic acid TFA salt (1.02 Kg, 2.7 mol), DCM (3.2 L), and DIPEA (2.75 Kg, 21.3 mol). To the reaction mixture was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.55 Kg, 2.97 mol, Accela ChemBio Co. Ltd) and stirred at RT overnight. The solvent was removed in vacuo. The crude material was purified by column chromatography on silica gel (eluting with a gradient of 0% to 5% NH3 (2M in MeOH)/DCM) to give crude product 510 g as sticky oil. The crude product was diluted with EtOAc (4.5 L) and stirred for 1 h. The resulting precipitate was collected by filtration and dried to afford 5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (104 g, 31% yield) as a white solid. The filtrate was concentrated and re-purified by column chromatography on silica gel to give more product 46.5 g (13.6% yield) as a white solid. Overall 5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (150.5 g, 44.6% yield) was obtained. MS (ESI, pos. ion) m/z: 123 (M+1); 1H NMR (400 MHz, MeOD) δ 6.87 (d, J=3.2 Hz, 1H), 6.27 (d, J=3.2 Hz, 1H), 4.27 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:25])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(C)C)cc1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (8.41 g, 61.7 mmol) in diethyl ether (100 ml), sodium borohydride (4.67 g, 123 mmol) was added at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(4-fluorophenyl)-2-(4-isopropylbenzyl)-3-oxopropionate (10.57 g, 30.87 mmol) in diethyl ether (50 ml) at room temperature and the mixture was stirred as it was for 2 hrs. Dilute hydrochloric acid was added to the reaction solution by small portions to decompose excess zinc borohydride. The mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: CO[CH:3]([O:13]C)[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.[CH2:26]([NH2:32])[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C1COCC1.C(Cl)Cl>[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:32][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[O:13])=[CH:12][CH:11]=1)=[O:10]
Reactant: COC(OC)c1ccc(C(=O)O)cc1
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)NCc2ccco2)cc1
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of 4-(dimethoxymethyl)benzoic acid 5 (2.94 g, 15 mmol), EDCI (5.75 g, 30 mmol), furfurylamine (3.5 mL, 37.5 mmol), and DMAP (122 mg, 1 mmol) in THF (200 mL) and CH2Cl2 (50 mL) was stirred at r.t. for 16 h. The solvent was removed by rotary evaporation and the resulting yellow oil was dissolved in CHCl3 and was washed twice with 0.5 M HCl. The organic solution was then vigorously stirred with 1.0 M HCl for 2 h. The layers were separated and the organic phase was washed twice more with 1.0 M HCl and once with brine. The organic phase was dried over Na2SO4 and the solvent was removed by rotary evaporation. The crude product was crystallized from hot EtOAc, yielding the title compound as a pale yellow solid in 2 crops (2.09 g, 58% yield). 1H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H), 7.97 (s, 4H), 7.42 (m, 1H), 6.54 (br s, 1H), 6.39 (dd, J=2.0, 3.3 Hz, 1H), 6.35 (d, J=3.3 Hz, 1H), 4.69 (d, J=5.3 Hz, 2H).
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[C:12]([CH:13]=O)=[C:11]([OH:15])[C:10]([O:16][CH3:17])=[CH:9][CH:8]=1.Cl.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:6][C:7]1[C:12]([CH:13]=[CH2:1])=[C:11]([OH:15])[C:10]([O:16][CH3:17])=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(F)c(C=O)c1O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1c(F)ccc(OC)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 50 g of methyltriphenylphosphonium bromide in 300 ml of toluene there was added dropwise 45 ml of n-butyllithium (2.55 M, hexane solution) at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and allowed to stand. Next, 150 ml of the supernatant was added to a solution of 5 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No. 457628-15-8] in 90 ml of toluene. The mixture was stirred at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 3-fluoro-6-methoxy-2-vinylphenol (4.33 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:13][C:14]3[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=3)=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:32])=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NS(=O)(=O)c2ccc(OC)c(OC)c2)ccc1Oc1cncc(Cl)c1
Yield: 68 %

Procedure:
The title compound was prepared in a manner similar to Example 3, beginning with 0.1 g of the aniline of Example 1 and 3,4-dimethoxybenzenesulfonyl chloride, and adding 0.2 mL of pyridine to the reaction mixture to yield 0.115 g (68%) of the title sulfonamide.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[ClH:45]>CN(C)C=O>[ClH:45].[C:15]([NH:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1CCNCC1)c1ccccc1

Procedure:
A mixture comprising 4-amino-1-(tert-butoxycarbonyl)piperidine (700 mg), benzoic acid (512 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (804 mg), 1-hydroxybenzotriazole (567 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 16 hours to undergo reaction, and the resulting compound was acid-treated with hydrochloric acid to obtain 4-(benzoylamino)piperidine.hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C)C=O>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:20])[CH3:19]
Reactant: OCCc1cccc2cc[nH]c12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCc1cccc2cc[nH]c12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(2-hydroxyethyl)indole (2.86 g, 17.7 mmol) in 25 mL of dry dimethylformamide was added imidazole (2.54 g, 37.3 mmol) followed by triisopropylsilyl chloride (4.35 mL, 19.7 mmol) and the mixture stirred at room temperature under nitrogen for 3 hours. After diluting with hexanes (500 mL) the organic layer was washed with water (2×50 mL) and saturated aqueous sodium chloride (1×50 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to provide 7-(2-(triisopropylsilyloxy)eth-1-yl)indole. This indole was reacted essentially as described in Preparation II to provide the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:28]#[N:29])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>C(#N)C.C(OCC)(=O)C.O>[C:28]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([O:4][CH2:3][CH2:2][N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)=[CH:6][CH:7]=2)[N:11]([CH2:14][CH3:15])[C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=1)#[N:29]
Reactant: CCn1c(-c2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(OCCCl)cc21
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(-c2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(OCCn3ccnc3)cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of cyclopropanecarboxylic acid{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}-amide (102 mg, 0.25 mmol) in 1.5 mL of acetonitrile are added NaI (46 mg, 0.275 mmol), K2CO3 (138 mg, 1 mmol) and imidazole (51 mg, 0.75 mmol) in a sealed tube. Then the mixture is heated to 90° C. and stirred overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2×), dried over anhydrous Na2SO4, filtered and concentrated. The crude compound is purified by preparative HPLC to give 71% of cyclopropanecarboxylic acid{4-[3-cyano-1-ethyl-6-(2-imidazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-amide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([F:16])([F:15])[C:10](OCC)=[O:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].Cl.O>C(O)C>[Cl:1][C:2]1[C:3]([C:9]([F:15])([F:16])[CH2:10][OH:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)c1ncc(Cl)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCC(F)(F)c1ncc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
To a solution of 10 g (37 mmol) of ethyl (3,5-dichloropyridin-2-yl)(difluoro)acetate (Int-7) in 60 mL of ethanol, were added portionwise at 0° C., 1.05 g (27.7 mmol) of sodium borohydride. The reaction mixture was stirred below 10° C. for 2 hours. 30 mL of 1 N HCl were then slowly added followed by 500 mL of water. The aequeous phase was extracted three times by 300 mL of ethyl acetate and the organic phase was successively washed with brine, water and dried over magnesium sulfate. After evaporation of the solvent under vacuum 8.5 g of yellow oil were obtained. After trituration in diisopropyl ether and filtration 6.8 g (80%) of 2-(3,5-dichloropyridin-2-yl)-2,2-difluoroethanol (Int-9) were obtained as a white solid. Mp (melting point)=56° C. (M+1)=228. 19F-NMR (235 MHz, CDCl3) δ (ppm): −105.85 (CF2).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[NH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH2:31]OS(C)(=O)=O)=[N:28][N:27]=2)=[C:22]([C:37]([F:40])([F:39])[F:38])[CH:21]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]2[C:6]=1[N:7]=[CH:8][N:9]([CH2:31][C:29]1[S:30][C:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][C:22]=3[C:37]([F:40])([F:38])[F:39])=[N:27][N:28]=1)[CH:10]=2
Reactant: COc1ccc(-c2nnc(COS(C)(=O)=O)s2)c(C(F)(F)F)c1
Reactant: Fc1ccccc1-c1[nH]c2cncnc2c1Br
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(Cn3cnc4c(Br)c(-c5ccccc5F)nc-4c3)s2)c(C(F)(F)F)c1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
A solution of 7-bromo-6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (152 mg, 0.52 mmol) and methanesulfonic acid 5-(4-methoxy-2-trifluoromethylphenyl)-[1,3,4]thiadiazol-2-ylmethyl ester (211 mg, 0.57 mmol) were stirred in 2 mL DMF at 65° C. for 14 h. The solution was then heated to 85° C. for 4 h and cooled to rt. The resulting solution was filtered and purified by HPLC (10-70% MeCN/H2O with 1% formic acid). Lyophilization of the pure fractions gave 103 mg (0.183 mmol, 35% yield) of the titled compound. 1H NMR (DMSO-d6): 9.15 (s, 1H), 8.96 (s, 1H), 7.72 (d, 1H), 7.64 (t, 1H), 7.55 (q, 1H), 7.43 (s, 1H), 7.32-7.42 (m, 3H), 6.23 (s, 2H), 3.92 (s, 3H). LC-MS calculated for C23H14BrF4N5OS 563.00, found 564.35 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]([CH3:30])[CH:27]([CH3:29])[CH3:28])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]([CH3:30])[CH:27]([CH3:29])[CH3:28])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)N(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a solution of potassium tert-butoxide (5.8 g) in DMF (45 mL) was added dropwise a solution of 2-[benzyl({3-chloro-5-[methyl(1-methylethyl)amino]pyrazin-2-yl}methyl)amino]ethanol (15.1 g) in DMF (30 mL) at 0° C., and the mixture was stirred for 1.5 hr. Water (150 ml) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (eluent: 10% ethyl acetate/hexane) to give the title compound (11 g, 87%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=CC=1.C1(=O)CCCC1>C1(C)C=CC=CC=1>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:20]4([CH2:21][CH2:22][CH2:17][CH2:27]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C1CCCC1
Product: O=C1NC2(CCCC2)Nc2cc(-c3ccncc3)sc21
Yield: 186.6 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (150 mg, 0.68 mmol), p-toluenesulfonic acid monohydrate (50 mg) and cyclopentan-1-one (10 ml) in toluene (20 ml) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the title compound (140 mg, yield 72%) as an orange solid:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:17])[NH:9]2)[C:5]([OH:18])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:25])[CH:23]=O)[CH3:20].S(O)(C)(=O)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:23]([C:22]([O:21][CH2:19][CH3:20])=[O:25])[N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH2:16][CH:8]3[C:6]=2[N:7]=1
Reactant: CCOC(=O)C=O
Reactant: Oc1ccc(Cl)nc1C1Cc2c(F)cccc2N1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1Oc2ccc(Cl)nc2C2Cc3c(F)cccc3N12
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (8.53 g, 32.31 mmol) and glyoxylic acid ethyl ester (6.59 g, 64.59 mmol) in THF (80 mL), MsOH (0.31 g, 3.23 mmol) was added. The mixture was stirred at 50° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE: EtOAc=10:1) to afford ethyl 2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (10.2 g, yield: 90.3%). 1H-NMR (CDCl3, 400 MHz) δ 7.04˜7.13 (m, 3H), 6.63 (d, J=8.0 Hz, 1H), 6.55 (t, J=8.4 Hz, 1H), 6.03 (s, 1H), 5.09 (d, J=8.8 Hz, 1H), 4.22˜4.34 (m, 2H), 3.73 (d, J=16.4 Hz, 1H), 3.44˜3.51 (m, 1H), 1.29 (d, J=7.2 Hz, 3H). MS (M+H)+: 349.