Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][N:65]([C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:20][CH:19]=2)[CH2:64][CH2:63]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.083 g, 0.00031 mol) in DMF (5 mL) was added DIPEA (0.099 g, 0.00077 mol), HOBt (0.041 g, 0.000307 mol) and EDCI.HCl (0.073 g, 0.00038 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.063 g, 0.00026 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.04 g (33%) of N-{2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LCMS: 463.17 (M+1)+, 95.82%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.5 (q, 3H), 7.2 (t, 3H), 7.1 (d, 2H), 6.9 (q, 2H), 6.6 (t, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8 (m, 2H), 2.0 (t, 3H).
Reaction SMILES: [CH:1]1([C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH2:16][CH2:17][CH3:18])[C:8](=[O:19])[CH:7]([NH:20]C(OCC3C=CC=CC=3)=O)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.Br.C(OCC)C>C(O)(=O)C>[NH2:20][CH:7]1[N:6]=[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][CH2:17][CH3:18])[C:8]1=[O:19]
Reactant: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCC2)c2ccccc21
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCN1C(=O)C(N)N=C(C2CCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5-Cyclobutyl-1,3-dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-1-propyl-2H-1,4-benzodiazepin-2-one (1.5 g, 3.7 mmol) was treated with a solution of 30% hydrogen bromide in acetic acid (5 ml), and stirred for 20 min at room temperature. The mixture was then added dropwise onto cold (0° C.) diethyl ether (50 ml). A white solid was precipitated and filtered off. The solid was treated with 10% sodium hydroxide solution (50 ml), then extracted with ethyl acetate (80 ml). The organic layer was separated, dried (Na2SO4) and evaporated to give a colourless oil. This material was then used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH3:11].C(OCC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cccc(Cl)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1cccc(Cl)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6-chloropicolinaldehyde (1.00 g, 7.06 mmol) in 20 mL of THF at −78° C. was added ethylmagnesium bromide, 3.0 M solution in diethyl ether (3.53 mL, 10.60 mmol) slowly. The reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with sat'd NH4Cl aqueous solution, and extracted with ether (3×100 mL). The combined organic layers were dried over Na2SO4 and evaporated to provide the crude product. The crude product was purified by chromatography on silica gel, eluting with 10 to 60% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI) m/z=172 (M+1).
Reaction SMILES: [CH3:1][C:2]([OH:12])([C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:3].ClC1C=C(C2C=CC=CC=2C(OO)=[O:23])C=CC=1>ClCCl>[OH:12][C:2]([CH3:1])([CH3:3])[C:4](=[O:23])[CH:5]=[CH:6][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(O)C#CCN1CCCC1
Reactant: O=C(OO)c1ccccc1-c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(O)C(=O)C=CN1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 2-methyl-5-(pyrrolidin-1-yl)-pent-3-yn-2-ol (0.25 g) in dichloromethane (6 ml) was added in small portions 3-chlorophenylperoxybenzoic acid (0.285 g) over a period of about 2 minutes. After the reaction was stirred at 0° C. for 5 minutes, the mixture was passed over 20 weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and eluted with 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness in vacuo. The resulting residue was dissolved in methanol (20 ml) and heated to reflux temperatures for 7 hours. The solvent was then removed in vacuo and the residue was chromatographed over silica gel (50% ethyl acetate in hexanes was used as the eluant) to provide the desired product as an amber solid. MS(+ES), m/z: 184 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:26])([F:25])[F:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[CH:7][CH:6]=1)(=O)C.C(N)C1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([C:23]([F:24])([F:25])[F:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:12])=[CH:7][CH:6]=1
Reactant: CCOCCCCCC(OC(=O)c1ccc(OC(C)=O)cc1)C(F)(F)F
Solvent: CCO
Solvent: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F
Reaction time: 4 h

Procedure:
The crude product (1.9 g) of the above compound (2) was dissolved in 50 ml of ethanol, and 4 g of benzylamine was added dropwise. Further, after stirring was conducted at room temperature for 4 hours, the mixture was diluted with 500 ml of chloroform, washed with dilute hydrochloric acid and water in this sequence, and dried over magnesium sulfate. After the solvent was evaporated, the residue was isolated and purified by silica gel column chromatography to obtain 1.2 g of a final product (3).
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([S:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28])[C:21](O)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.[BH4-].[Na+].Cl.O>[CH2:10]([S:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28])[CH2:21][OH:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1SCc1ccccc1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(CO)cc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 65.2 %

Procedure:
28 ml of boron trifluoride etherate is added to a suspension of 46 g of crude 3-benzylmercapto-4-carbomethoxy benzoic acid in 750 ml of anhydrous tetrahydrofuran and 7 g of sodium borohydride. The reaction mixture is stirred for 3-4 hours at room temperature, then diluted with about 20 ml of 2N hydrochloric acid and 500 ml of water. The product obtained is extracted with ether and the ether extract is washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Crystallization from ethyl acetate:hexane (1:2) yielded 28.6 g of 3-benzylmercapto-4-carbomethoxy benzyl alcohol having a melting point of 89.5°-92° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:15])[C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[CH3:22][CH2:23][O:24]CC.C(Cl)(=O)C>O>[C:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:15])[C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:24])[CH3:22]
Reactant: CCOCC
Reactant: Cc1csc(N)c1C(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Solvent: O
Product: CC(=O)Nc1scc(C)c1C(=O)c1ccccc1

Procedure:
To a mixture of 4.50 g of 2-amino-3-benzoyl- 4-methylthiophene, 4.5 g of pyridine and 450 ml of anhydrous ether is added dropwise 4.50 g of acetyl chloride. Then the reaction mixture is stirred under reflux for 5 hours. After cooling, the reaction mixture is poured into water. The ether layer is separated and washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give an oily residue, which is crystallized from ether to give 2-acetylamino-3-benzoyl-4-methylthiophene having a melting point of 106° - 107°C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Yield: 95 %

Procedure:
A mixture of 0.30 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine, 75 mg of methyl mercaptan sodium salt and 4 ml of DMF was stirred under ice-cooling for 1 hour. To this mixture was added 37 mg of methyl mercaptan sodium salt, and the mixture was stirred under ice-cooling for further 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.31 g of 3-methylthio-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 11”).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:25])[C:14](=[O:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:25])[C:14](=[O:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28]([O:27][CH3:26])=[O:37])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccccc1CBr
Reactant: COc1ccc(CCN(C)C(=O)CCc2ccc(O)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCC(=O)N(C)CCc2ccc(OC)c(OC)c2)cc1
Yield: 60.6 %

Procedure:
N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(4-hydroxyphenyl)-N-methylpropanamide (198 mg, 0.577 mmol), 2-bromomethyl-benzoic acid methyl ester (139 mg, 0.605 mmol) and potassium carbonate, anhydrous (120 mg, 0.864 mmol) were mixed in acetonitrile (15 ml). The mixture was heated to reflux overnight and then evaporated to dry. Water and ethyl acetate were added and the two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using heptane/DCM (50:50), then DCM and then MeOH/DCM (0.5:99.5) as eluant gave 172 mg the desired product, yield 61%.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:16]=1[CH2:15][C@H:9]1[O:10][CH2:11][CH2:12][N:13]([CH3:14])[C@@H:8]1[CH2:7]2.[CH3:19][S:20][Li]>CN(C=O)C>[CH3:18][O:17][C:5]1[CH:4]=[CH:3][C:2]([S:20][CH3:19])=[C:16]2[C:6]=1[CH2:7][C@H:8]1[N:13]([CH3:14])[CH2:12][CH2:11][O:10][C@@H:9]1[CH2:15]2
Reactant: [Li]SC
Reactant: COc1ccc(I)c2c1C[C@@H]1[C@@H](C2)OCCN1C
Solvent: CN(C)C=O
Product: COc1ccc(SC)c2c1C[C@@H]1[C@@H](C2)OCCN1C
Reaction time: 5 h

Procedure:
0.44 g (1.2 mM) of trans-3,4,4a,5,10,10a-hexahydro-9-iodo-6-methoxy-4-methyl-2H-naphth[2,3-b]-1,4-oxazine (for production see example 1), dissolved in 5 ml of DMF, as well as 2.34 g (16.3 mM) of copper-I-oxide, are added to a suspension of 0.53 g (9.8 mM) of methylthiolithium in 10 ml of dimethylformamide. The reaction mixture is subsequently stirred for 5 hours at 80° under an argon atmosphere. The preparation is then filtered through Hyflo, washed with 20 ml of methylene chloride, and the filtrate is concentrated by evaporation. The residue is taken up in 30 ml of methylene chloride/30 ml of ice water, the organic phase is separated, and the aqueous phase is extracted three times, each with 10 ml of methylene chloride. The combined organic phases are dried and concentrated by evaporation. Trans-3,4,4a,5,10,10a-hexahydro-6-methoxy-4-methyl-9-methylthio-2H-naphth[2,3-b]-1,4-oxazine is obtained as an oil. The oil is purified by chromatography (silica gel, methylene chloride, 5% methanol). 1-H-NMR 90 MHz (CDCl3): δ=2.36 (s; 3H, N--CH3), 2.42 (s; 3H, S--CH3), 3.81 (s; 3H, O--CH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:14][CH2:13][S:10]([CH3:9])(=[O:12])=[O:11])[CH:7]=1
Reactant: C=CS(C)(=O)=O
Reactant: Oc1ccc(Br)cn1
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1cc(Br)ccc1=O
Temperature: 100 °C
Yield: 29 %

Procedure:
5-Bromopyridin-2-ol (4.0 g, 23.0 mmol) and methylsulfonylethene (2.4 g, 2.0 mL, 23.0 mmol) were combined in N,N-dimethylformamide (DMF, 23 mL) and heated to 100° C. The crude reaction mixture was then evaporated to dryness. The crude material was then dissolved in a minimum of dichloromethane. The solution was then washed twice with an aqueous 1 M solution of hydrochloric acid, two times with a saturated aqueous solution of sodium bicarbonate, two times with a saturated aqueous solution of sodium chloride, and finally by two washes of water. The organic layer was dried over sodium sulfate and then evaporated to dryness to yield the product as a pale brown solid (1.87 g, 6.68 mmol, 29%). ESI-MS m/z calc. 279.0. found 280.0 (M+1)+. Retention time 0.34 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]=3[CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][N:27]([CH3:32])[S:28](=[O:31])(=[O:30])[NH2:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]=3[CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:28](=[O:31])(=[O:30])[N:27]([CH3:32])[CH3:26])=[O:8]
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2C1
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(COc2ccc3c(c2)CC(C)(C)CC3)cc1F
Yield: 22.2 %

Procedure:
A solution of 5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), dimethyl(sulfamoyl)amine (326 mg, 0.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.20 mmol) and 4-dimethylaminopyridine (38 mg, 0.20 mmol) in DCM (3 mL) was stirred at room temperature for 16 hrs. The reaction was quenched with water (5 mL), adjusted pH to 5 with HCl (1M) and extracted with DCM (30 mL×3). The combined organic layers were concentrated and purified by reverse phase combiflash (20%-50% MeCN in 0.1% formic acid) to give the desired product (14.6 mg, 19%) as a white solid. LCMS (ESI) Method A: RT=6.47 min, m/z 466.9 [M−H]+; 1H-NMR (500 MHz, MeOD-d4) δ 7.63 (d, J=5.5 Hz, 1H), 7.32 (d, J=11.0 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.66-6.63 (m, 1H), 6.56 (d, J=2.0 Hz, 1H), 5.03 (s, 2H), 2.83 (s, 6H), 2.64 (t, J=13.0 Hz, 2H), 2.40 (s, 2H), 1.46 (t, J=13.5 Hz, 2H), 0.88 (s, 6H).
Reaction SMILES: [C:1]([C:3](=[CH:9][CH:10]([CH3:12])[CH3:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:2].[H][H]>CO>[C:1]([CH:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:2]
Reactant: [H][H]
Reactant: COC(=O)CC(C#N)=CC(C)C
Solvent: CO
Product: COC(=O)CC(C#N)CC(C)C

Procedure:
By following the general procedure of Example 3.1, 200 mg (1.190 mmol) of methyl 3-cyano-5-methyl-hex-3-enoate was dissolved in 3 mL of methanol and reacted with hydrogen gas (60 psi) in the presence of 43 mg (0.06 mmol) of [(R,R)-Et-DuPHOS]Rh(COD)+BF4− to afford 10% conversion to methyl 3-cyano-5-methylhexanoate having 33% e.e. (R).
Reaction SMILES: [CH:1]([CH:3]([CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([O:6]CC)=O)=O.[C:21]([NH:25][S:26]([C:29]1[CH:30]=[N:31][C:32]([NH:35][NH2:36])=[CH:33][CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(NS(C1C=CC(N2C(=O)C(C(C3C=CC=CC=3)C(OC)=O)=CN2)=NC=1)(=O)=O)(C)(C)C>>[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:4](=[O:6])[C:3]([CH:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:1][NH:36]2)=[N:31][CH:30]=1)(=[O:28])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C(C=O)C(C(=O)OCC)c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(NN)nc1
Agent: COC(=O)C(c1ccccc1)c1c[nH]n(-c2ccc(S(=O)(=O)NC(C)(C)C)cn2)c1=O
Product: CCOC(=O)C(c1ccccc1)c1c[nH]n(-c2ccc(S(=O)(=O)NC(C)(C)C)cn2)c1=O

Procedure:
According to the process described in Example 27.2, starting with 2 g (7.19 mmol) of diethyl 2-formyl-3-phenylbutanedioate and 1.75 g (7.19 mmol) of N-tert-butyl-6-hydrazinylpyridine-3-sulfonamide, 3.1 g of methyl {2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}(phenyl)acetate are obtained in the form of a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])[CH:6]=[CH:5][N:4]=1.Cl[C:38]1[CH:39]=[CH:40][C:41]2[O:54][CH2:53][N:44]3[C:45]4[CH:46]=[CH:47][CH:48]=[C:49]([F:52])[C:50]=4[CH:51]=[C:43]3[C:42]=2[N:55]=1.C([O-])([O-])=O.[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:52][C:49]1[C:50]2[CH:51]=[C:43]3[C:42]4[N:55]=[C:38]([C:19]5[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][C:11]6[O:10][C:9]([C:7]7[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=7)=[C:13]([C:14]([NH:16][CH3:17])=[O:15])[C:12]=6[CH:18]=5)[CH:39]=[CH:40][C:41]=4[O:54][CH2:53][N:44]3[C:45]=2[CH:46]=[CH:47][CH:48]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccnc(OC)c2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccnc(OC)c2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a degassed solution of 2-(2-methoxypyridin-4-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (60 mg, 0.12 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (35 mg, 0.13 mmol) and Na2CO3 (25 mg, 0.23 mmol) in dioxane (1.5 mL) and H2O (0.1 mL) was added Pd2(dba)3 (3 mg) and X-Phos (3 mg) under N2. Then the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O and dried over Na2SO4. After concentrated, the residue was purified by prep-HPLC to give the product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(2-methoxypyridin-4-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (35 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 8.29 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.69 (s, 2H), 7.40˜7.49 (m, 1H), 7.30 (s, 1H), 7.19˜7.24 (m, 2H), 7.10˜7.18 (m, 1H), 6.82˜6.87 (m, 1H), 6.11 (s, 1H), 5.99 (s, 2H), 3.99 (s, 3H), 3.36 (s, 3H), 3.04 (d, J=4.8 Hz, 3H), 2.75 (s, 3H). MS (M+H)+: 628.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:17]1=[O:33].[H][H]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:17]1=[O:33]
Reactant: [H][H]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: NCCN
Solvent: CCO
Product: COC(=O)CCC/C=C\CN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A round bottom flask was charged with nickel (II) chloride (68 mg, 0.52 mmol) and sodium borohydride (9.9 mg, 0.26 mmol), then 95% ethanol (1.0 mL) was added. The mixture immediately turned black. After 15 min at rt, ethylene diamine (56 μL, 0.84 mmol) was added. After another 15 min at rt, 7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (40 mg, 0.10 mmol) in 95% ethanol (1.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 18 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the resulting residue by flash column chromatography (CH2Cl2→30% EtOAc/CH2Cl2, gradient) afforded 28 mg (70%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:4]([F:15])[CH:3]=1.C([O-])(=O)C.[Na+].[OH-].[Na+]>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]2[O:10][C:11]([C:12]([OH:14])=[O:13])=[CH:8][C:6]=2[CH:7]=1
Reactant: O=Cc1cc(Br)cc(F)c1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc2cc(Br)cc(F)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of [(4-bromo-2-fluoro-6-formylphenyl)oxy]acetic acid (3.79 mmol) in acetic anhydride (10 mL) was treated with sodium acetate (11.37 mmol). The resulting solution was heated to reflux and stirred overnight. The brown reaction solution was allowed to cool to room temperature, and was diluted with toluene (10 mL). The solution was then treated with 1N aq NaOH (20 mL) and was stirred at room temperature for 30 min. The solution was then further diluted with water (50 mL) and was extracted using hexanes. The aqueous phase was then acidified to pH˜1 using 1N aq HCl, and was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title compound (0.47 g, 48% yield) which was used without further purification. MS(ES)+ m/e 258.5, 260.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.88 (d, J=1.77 Hz, 1H) 7.75 (dd, J=10.36, 1.77 Hz, 1H) 7.69 (d, J=2.53 Hz, 1H).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][N+:4]=1[O-])#N.C[Si](C#N)(C)C>>[N:4]1[CH:3]=[CH:8][CH:7]=[C:6]([CH2:9][CH2:10][OH:11])[CH:5]=1
Reactant: N#Cc1ccc(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c[n+]1[O-]
Agent: C[Si](C)(C)C#N
Product: OCCc1cccnc1
Yield: 116.8 %

Procedure:
2-Cyano-5-(2-triphenylmethyloxyethyl)pyridine N-oxide (8.0 g) and trimethylsilyl cyanide (11.2 ml) were treated as reported in Synthesis, 314 (1983). to give the title compound (2.831 g) as a pale yellow oil (yield: 30.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][O:18]C1N=CC(B(O)O)=CN=1>>[CH3:17][O:18][C:16]1[N:13]=[CH:12][C:11]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])=[CH:15][N:14]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc(C)cc2C(=O)O)cn1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using (2-methoxypyrimidin-5-yl)boronic acid. ESI-MS (m/z): 245 [M+1]+.