Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc2c(Cl)cc(C#N)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
4-Chloro-7-methylquinoline-2-carbonitrile (1-5, 2.47 g, 12.2 mmol, 1.0 equiv.), 4-fluorophenylboronic acid (2.05 g, 14.63 mmol, 1.2 equiv.), Pd(PPh3)4 (0.7 g, 0.61 mmol, 0.05 equiv), and 1M aqueous Na2CO3 (12.2 ml, 2.39 mmol) was added into 1,4-dioxane (40 mL). The mixture was degassed and stirred at 100° C. for 16 hours, until disappearance of the starting material. The mixture was cooled, saturated aqueous sodium hydrogen carbonate (2 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was treated with 50 ml of MeOH, stirred vigorously at rt for 1 h, the mixture was filtered and washed with MeOH. The solid was collected and dried under vacuum. The filtrate was concentrated and retreated with MeOH to get a second crop of white solid that was combined to the first to give 2.75 g of 4-(4-fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6). LRMS m/z (M+H)+ 263.3 found, 263.3 required.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[C:19]([S:23]([N:25]=[CH:26][CH2:27][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([NH:25][S:23]([C:19]([CH3:21])([CH3:20])[CH3:22])=[O:24])[CH2:27][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: Ic1ccccc1-c1ccccc1
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-iodo-1,1′-biphenyl (680 mg; 2.43 mmol) in anh. THF (20 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.52 ml; 2.43 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (600 mg; 2.43 mmol) in anh. THF (5 ml) was added to the cooled reaction mixture, and stirring was continued from −78° C. to 0° C. over 1 h. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 4-([1,1′-biphenyl]-2-yl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate as a mixture of stereoisomers. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 401.79 g/mol and tR=0.94 min.; [M+H]+: 401.80 g/mol.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH2:22][Cl:23].O>CN(C=O)C>[Cl:23][CH2:22][CH2:21][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[CH:9]1
Reactant: ClCCBr
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCn1cnc(-c2ccccc2)c1-c1ccccc1
Temperature: 60 °C
Yield: 17.7 %

Procedure:
Step 1): A solution of 4,5-diphenylimidazole (2.5 g, 11.3 mmol) in dry DMF (20 ml) was added to a suspension of NaH (0.33 g, 13.8 mmol) in dry DMF (5 ml) at 50° C. under nitrogen atmosphere. The reaction mixture was heated at 60° C. for 2 hours. After heating, the mixture was added dropwise to a solution of 1-bromo-2-chloroethane (4.9 g, 33.9 mmol) in dry DMF (30 ml) over 1 hour at 50° C. The reaction mixture was heated continuously at 40° C. for 5 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and concentrated. The precipitates were filtered off. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate and hexane) to give 1-(2-chloroethyl)-4,5-diphenylimidazole (17.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29](=[O:30])[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccc(Cl)cc21)N1CCCCC1

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available 2-chloro-1-piperidin-1-yl-ethanone as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [ClH:1].F[C:3]1[CH:4]=[C:5]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=2)=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].O.Cl>C(O)C>[ClH:1].[C:23]1([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=2)=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)C1=CCCN(CCOC=C(c2cccc(F)c2)c2cccc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1=CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.8 %

Procedure:
1-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-1,2,5,6-tetrahydro3-pyridine carboxylic acid methyl ester (4.33 g, 0.01147 mol) (prepared as described in Method D) was dissolved in ethanol (50 ml) and 10N sodium hydroxide solution (11.5 ml) was introduced, followed by water (5 ml). The solution was stirred at room temperature for 2.5 h and stored at 4° C. for 18 h. 2N hydrochloric acid solution was added until the pH reached ca. 2, and the mixture was extracted with dichloromethane (3×60 ml). The combined extracts were dried (MgSO4) and evaporated to give a foam (4.24 g) which was crystallized from 2-propanol to provide the title compound (2.32 g, 52%) as a white solid, m.p. 173°-176°.
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])(=[O:37])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN([CH:65]=[O:66])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:32][C:31]([F:34])([F:33])[C:65]([OH:66])=[O:37].[CH3:21][C:20]1[CH:19]=[CH:18][C:17]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=2)=[O:23])=[CH:16][C:15]=1[C:11]1[CH:10]=[C:9]2[C:14]([C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]=3[NH:8]2)=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc(Nc2ncccc2Br)c1
Agent: [Pd+2]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Na+]
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncccc12
Product: O=C(O)C(F)(F)F
Yield: 55 %

Procedure:
To a degassed mixture of 3′-[(3-bromopyridin-2-yl)amino]-6-methyl-N-[3-(trifluoromethyl)-phenyl]biphenyl-3-carboxamide (0.085 g, 0.16 mmol) and sodium acetate (20 mg, 0.24 mmol) in DMF (4 mL) was added tri-o-tolylphosphine (9.8 mg, 0.032 mmol) and palladium acetate (3.6 mg, 0.016 mmol). The mixture was degassed again and then was heated to vigorous reflux for 3 hours. The mixture was then cooled, filtered and purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.1% TFA), then lyophilized to afford the product (50 mg, 55%). 1H NMR (400 MHz, d6-DMSO): 12.03 (s, 1H), 10.54 (s, 1H), 8.62 (d, 1H), 8.46 (dd, 1H), 8.28 (d, 1H), 8.25 (s, 1H), 8.08 (d, 1H), 8.01-7.98 (m, 1H), 7.95 (dd, 1H), 7.59 (t, 1H), 7.55-7.49 (m, 2H), 7.45 (d, 1H), 7.33-7.26 (m, 2H), 2.35 (s, 3H); MS (ES) (M+H)=446.1.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)#[N:4].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:3]#[N:4])=[N:6]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.6 %

Procedure:
420 mg of NaH (60% in oil, 10.3 mmol) were added in portions to 1.0 g of 3-cyanoindazole (7.0 mmol) and 1.7 ml of benzyl bromide (14.0 mmol) in 6 ml of THF, and the mixture was stirred at room temperature for 15 hours. The reaction was quenched with 2 drops of water, the mixture was concentrated and the residue was chromatographed (SiO2; petroleum ether:ethyl acetate 3:1). 1.3 g of a solid were obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[C:8]([CH3:11])([O-])[CH3:9].[K+].[CH3:13][C:14](=O)[C:15]#CC>CS(C)=O>[CH2:14]([C:15]1[CH:11]=[C:8]([CH3:9])[NH:6][C:4](=[O:5])[C:3]=1[C:1]#[N:2])[CH3:13]
Reactant: CC#CC(C)=O
Reactant: CC(C)(C)[O-]
Reactant: N#CCC(N)=O
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cc(C)[nH]c(=O)c1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of 2-cyano-acetamide (841 mg, 10.0 mmol) in DMSO (20 mL) and potassium tert-butoxide (1.18 g, 10.5 mmol) was stirred at 23° C. for 30 minutes. The mixture was cooled to 0° C. then pent-3-yn-2-one (1.1 mL, 10 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (3 mL) then diluted with water (10 mL) causing a solid to precipitate out. The suspension was filtered and the solids dried under vacuum to give 4-ethyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd AA, 1.2 g, 71%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:28]([O-])=O)[CH:24]=3)[C:19]2=[O:31])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(OCC)(=O)C.C(Cl)Cl.CCCCCC.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:28])[CH:24]=3)[C:19]2=[O:31])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc(N)cc3C2=O)ccc1OC
Reaction time: 7 h
Yield: 89.8 %

Procedure:
A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-nitro-isoindoline-1,3-dione (600 mg, 1.33 mmol) and Pd/C (100 mg, 10%) in ethyl acetate (40 mL) was shaken under hydrogen (50 psi) for 7 h in Parr type shaker. The mixture was filtered through a pad of celite, and the pad was washed with ethyl acetate (50 mL). The filtrate was concentrated in vacuo to give a solid. The solid was stirred in a mixture of methylene chloride (2 mL) and hexane (10 mL). The resulting suspension was filtered to give 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-aminoisoindoline-1,3-dione as a yellow solid (500 mg, 90% yield): mp, 224.5-227.0° C.; 1H NMR (DMSO-d6); δ 1.32 (t, J=6.8 Hz, 3H, CH3), 2.99 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.00 (q, J=7 Hz, 2H, CH2), 4.03-4.09 (m, 1H, CHH), 4.34 (dd, J=10.3, 14.2 HZ, 1H, CHH), 5.70 (dd, J=3.7, 10.2 Hz, 1H, NCH), 6.52 (br, s, 2H, NH2), 6.79-6.81 (m, 1H, Ar), 6.92 (br s, 3H, Ar), 7.06 (br s, 1H, Ar), 7.48 (d, J=8.2 Hz, 1H, Ar); 13C NMR (DMSO-d6) δ 14.64, 40.99, 46.99, 53.34, 55.46, 63.80, 106.99, 111.78, 112.31, 116.12, 116.80, 118.61, 125.12, 130.33, 134.11, 147.80, 148.74, 155.13, 167.39, 167.86; Anal Calcd for C20H22NO6S: 57.41; H, 5.30; N, 6.69. Found: C, 57.03; H, 5.40; N, 6.33.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[Cl:6][C:7]1[CH:8]=[C:9](CO)[CH:10]=[N:11][C:12]=1[Cl:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N>[Br:5][CH2:1][C:9]1[CH:8]=[C:7]([Cl:6])[C:12]([Cl:13])=[N:11][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Clc1cc(CBr)cnc1Cl
Temperature: 25 °C

Procedure:
CBr4 (497 mg, 1.5 mmol, Aldrich) was added portionwise to a solution of (5,6-dichloro-pyridin-3-yl)-methanol (178 mg, 1.0 mmol, TCI-US) and PPh3 (393 mg, 1.5 mmol, Aldrich) in CH3CN (3 mL) with stirring at room temperature. The mixture was stirred at room temperature for 30 min, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 242 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[C:10]=1[NH2:11])=[O:5])C.[Br:22][C:23]1[CH:38]=[CH:37][C:26]([C:27](Cl)=[N:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O>ClC(Cl)C.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:4](=[O:5])[C:6]3[N:7]=[N:8][N:9]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:13]=4)[C:10]=3[N:11]=2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1nnn(-c2cccc(S(C)(=O)=O)c2)c1N
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)c1cccc(-n2nnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Temperature: 150 °C

Procedure:
A mixture of 5-amino-1-(3-methanesulfonyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (310 mg, 1 mmol), 4-bromo-N-(4-chloro-phenyl)-benzimidoyl chloride (1.2 mmol) and TiCl4 (2 mmol) in anhydrous dichloroethane (5 mL) is heated to 150° C. for 14 h. After cooling down to room temperature, the mixture is diluted with CH2Cl2 (20 mL) and treated with water (30 mL). The solid is collected by filtration and washed with MeOH (5 ml) to provide the crude 5-(4-bromo-phenyl)-6-(4-chloro-phenyl)-3-(3-methanesulfonyl-phenyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one as yellow solid which is used for next step without further purification.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[C:9]([O:13][C:14](=[O:44])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([C:28]2[CH:37]=[C:36]3[C:31]([C:32]([CH3:42])([CH3:41])[CH2:33][C:34](=[O:40])[N:35]3[CH2:38][CH3:39])=[CH:30][C:29]=2[CH3:43])[CH:18]=1)([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[C:9]([O:13][C:14]([CH:15]1[CH2:2][CH:16]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[C:19]([C:28]2[CH:37]=[C:36]3[C:31]([C:32]([CH3:42])([CH3:41])[CH2:33][C:34](=[O:40])[N:35]3[CH2:38][CH3:39])=[CH:30][C:29]=2[CH3:43])[CH:18]=1)=[O:44])([CH3:11])([CH3:10])[CH3:12]
Reactant: C[S+](C)(C)=O
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Temperature: -10 °C
Reaction time: 0.58 h

Procedure:
To a round bottom flask was added trimethylsulfoxonium iodide (2.8 mmol, 0.37 g) and 60% NaH (2.8 mmol, 0.07 g) and the flask was cooled to −10° C. with an ice-water bath. DMSO 92 ML) was then added dropwise. Initially some foamy suspension was observed. The cooling bath was removed and the reaction mixture was allowed to stir at r.t. for 30-40 min till the reaction mixture became a turbid solution. Compound 2B (0.17mmol, 0.085 g) was then dissolved in 1.5 mL DMSO and was added to the reaction mixture. The golden yellow solution was stirred at 50° C. (oil bath) for 2 h. After cooling to r.t., the reaction mixture was poured into 5 mL of ice-water. It was extracted with EtOAc (3×15 mL). The organic layer was washed with water followed by brine and was then dried over Na2SO4. The solvent was filtered and evaporated in vacuo to obtain 2-[3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-phenyl]-cyclopropanecarboxylic acid tert-butyl ester as a colorless oil. It was purified by preparative TLC with 3.5:1 hexanes-EtOAc as the eluting system to obtain 0.04 g of the product as a white foam. The product has the same Rf as the starting material. However, the product does not stain with KMnO4 stain indicating the disappearance of the double bond while the starting material does.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[C:22]3[C:17](=[C:18]([NH:23][C:24]([C:26]4[N:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]5=[N:28][CH:27]=4)=[O:25])[CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:35][CH3:36])=[N:15]2)[N:8]=1)(=O)=O.[B-](F)(F)(F)[CH:40]=[CH2:41].[K+].C(N(CC)CC)C>CC(O)C.C1COCC1>[CH2:35]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[N:28][CH:27]=2)=[O:25])[N:14]([CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH:40]=[CH2:41])[N:8]=2)[N:15]=1)[CH3:36]
Reactant: C=C[B-](F)(F)F
Reactant: CCc1nn(Cc2cccc(OS(=O)(=O)C(F)(F)F)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=Cc1cccc(Cn2nc(CC)c3c(NC(=O)c4cnc5ccccn45)cccc32)n1
Temperature: 80 °C
Yield: 92.6 %

Procedure:
To 6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yl trifluoromethanesulfonate (100 mg, 0.184 mmol) in IPA/THF (3 mL/1 mL) was added potassium trifluoro(vinyl)borate (36.9 mg, 0.275 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (15.0 mg, 0.0184 mmol) and triethylamine (37.2 mg, 0.367 mmol). The reaction mixture was sealed and heated to 80° C. for 16 hours. The mixture was cooled to ambient temperature and concentrated under reduce pressure. The residue was filtered through a plug of silica gel washing with EtOAc. The solution was concentrated to give the product (72 mg).
Reaction SMILES: C(Cl)Cl.[C:4](OC(=O)C)(=[O:6])[CH3:5].[OH:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:4]([O:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:6])[CH3:5]
Reactant: O=C(O)c1cc(-c2cccnc2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2cccnc2)cc1C(=O)O
Temperature: 25 °C

Procedure:
Methylene chloride (5.0 mL), pyridine (0.25 mL), and acetic anhydride (0.19 mL) were sequentially added to the obtained 2-hydroxy-5-(pyridin-3-yl)benzoic acid, followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then pyridine (0.082 mL) and acetic anhydride (0.095 mL) were added thereto, followed by heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 99-93% chloroform/methanol] to obtain 0.035 g of 2-acetoxy-5-(pyridin-3-yl)benzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].[C:17](Cl)(=[O:22])[CH2:18][C:19](Cl)=[O:20].O1CCC[CH2:25]1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([OH:20])=[CH:18][C:17]([O:22][CH3:25])=[N:16]1
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Reactant: O=C(Cl)CC(=O)Cl
Reactant: C1CCOC1
Product: COc1cc(O)n(-c2cc(SCC(F)(F)F)c(C)cc2F)n1

Procedure:
1.5 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 70 mL of tetrahydrofuran, and 0.83 g of malonyl chloride was added under cooling with ice. Stirring was carried out under reflux with heating for 5 hours, and the solvent was distilled off under reduced pressure. To the obtained residue, 20 mL of dichloromethane and 2 mL of methanol were added, and 0.7 mL of a diethyl ether solution (2.0 mol/L) of trimethylsilyldiazomethane was added under cooling with ice, followed by stirring at room temperature for 5 hours. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.14 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-hydroxy-3-methoxypyrazole.
Reaction SMILES: C([O:4][C@H:5]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=O)C>CO.N.C(OCC)C.CCCCCC>[OH:4][C@H:5]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CC(=O)O[C@H](CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: N
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](O)CCc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 86.2 %

Procedure:
8.0 g of tert.butyl 2(R)-acetoxy-4-(4-nitrophenyl)butanoate were dissolved in 200 ml of methanol saturated with ammonia at 0° C. and the mixture was stirred for 16 hours. Evaporation of the mixture in vacuo gave 7 g of an almost colorless oil which was dissolved in an equal volume of diethyl ether/n-hexane (1:1) and eluted through a silica gel column with the same solvent mixture to give 6 g of tert.butyl 2(R)-hydroxy-4-(4-nitrophenyl)butanoate as a colorless crystalline solid having a melting point of 41°-42° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[CH3:8][C:9]1[N:22]=[C:21]([NH2:23])[C:12]2[N:13]=[C:14]3[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[C:10]=1[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH3:8][C:9]1[N:22]=[C:21]([NH2:23])[C:12]2[N:13]=[C:14]3[CH2:20][N:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[C:10]=1[CH3:24]
Reactant: Cc1nc(N)c2nc3n(c2c1C)CCCNC3
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc3n(c2c1C)CCCN(S(C)(=O)=O)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
Methanesulfonyl chloride (198 mg, 1.73 mmol) was added to a solution of 3,4-dimethyl-7,8,9,10-tetrahydro-6H-pyrido[3′,4′:4,5]imidazo[1,2-a][1,4]diazepin-1-amine dihydrochloride (400 mg, 1.31 mmol) and triethylamine (350 mg, 3.46 mmol) in DMF (250 mL) and stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and adsorbed onto silica gel. The material was purified by column chromatography on silica gel, concentrated under reduced pressure, dissolved in dimethyl sulfoxide (DMSO), and purified by reverse phase prep HPLC (eluting with 0.5% formic acid in water/0.5% formic acid in acetonitrile in a 10-minute gradient from 5:95 to 95:5) using a HPLC purification system obtained from Shimadzu corporation (based in Kyoto, Japan) to afford 135 mg of 3,4-dimethyl-9-(methylsulfonyl)-7,8,9,10-tetrahydro-6H-pyrido[3′,4′:4,5]imidazo[1,2-a][1,4]diazepin-1-amine. HRMS (EI) calcd for C13H19N5O2S 310.1338, found 310.1346.