Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21](Cl)=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21]([C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(Cl)cn3)cc2s1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(-c4ccc(F)cc4)cn3)cc2s1
Yield: 24.9 %

Procedure:
Place 5-chloro-pyrazine-2-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (73 mg, 0.187 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), 4-fluorophenyl boronic acid (27 mg, 0.193 mmol), and potassium carbonate (134 mg, 0.97 mmol) in a solution of 1,4-dioxane (5 mL) and water (1 mL): Heat the reaction to reflux overnight. Chromatograph (silica gel, eluting with 7-17% MeOH:DCM) to yield 21 mg (25%) of the title compound. mass spectrum (ion-spray): (m/z)=503.0 (M+1). Retention time=4.51 min.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([O:6][CH3:7])=[O:5].FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=[O:20].[CH3:25][CH:26](O)[CH3:27]>C(OCC)(=O)C>[OH:20][C@@H:2]([CH2:3][O:1][CH:26]([CH3:27])[CH3:25])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)[C@@H]1CO1
Reactant: CC(C)O
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O)COC(C)C
Yield: 302.1 %

Procedure:
(S)-Methyl oxirane-2-carboxylate (2.04 g, 19.98 mmol), magnesium trifluoromethanesulfonate (1.611 g, 5.00 mmol) and propan-2-ol (1.84 mL, 24.0 mmol) in ethyl acetate (10 mL) were heated at reflux for 90 hours. The mixture was diluted with EtOAc (20 mL), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford (S)-methyl 2-hydroxy-3-isopropoxypropanoate (2.45 g, 76%). 1H NMR (400 MHz, CDCl3) δ 1.13 (3H, d), 1.16 (3H, d), 3.00 (1H, d), 3.58-3.64 (1H, m), 3.68-3.74 (2H, m), 3.69-3.73 (1H, m), 3.80 (3H, s), 4.28-4.31 (1H, m)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([OH:30])=O)[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.C1COCC1.[CH3:36][NH:37][CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([N:37]([CH3:38])[CH3:36])=[O:30])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CNC
Reactant: O=C(O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a stirred mixture of 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (65 mg, 0.153 mmol) from Example 81 and TEA (77 mg, 0.767 mmol) in a mixture of anhydrous THF (1.5 mL) and anhydrous DMF (0.5 mL) at rt was added dimethylamine (2 M solution in MeOH, 383 μL, 0.767 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.230 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxamide (33 mg, 48%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.96 (d, J=7.54 Hz, 1H), 7.68 (s, 1H), 7.20-7.33 (m, 2H), 5.50 (s, 2H), 4.73 (d, J=4.90 Hz, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.99 (br. s., 6H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: O[C@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:4][NH:5][CH3:6].Cl.S(Cl)([Cl:26])=O.CCO>ClCCl.O>[Cl:26][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:4][NH:5][CH3:6]
Reactant: CNC[C@@H](c1ccc2ccccc2c1)[C@H](O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CNC[C@@H](c1ccc2ccccc2c1)[C@@H](Cl)c1ccccc1

Procedure:
A mixture of (2R,3S)-3-hydroxy-N-methyl-2-(naphthalen-2-yl)-3-phenylpropan-1-amine.HCl (70 mg, 0.24 mmol) and 1 mL of thionyl chloride in 3 mL of dry dichloromethane (DCM) was stirred at room temperature for 30 minutes under nitrogen. The mass spectrum (MS) of the crude indicated clean and complete conversion. The volatiles were evaporated at reduced pressure. The product MCJ001-C1-RR was washed with dry diethyl ether, and dried under high vacuum. A white solid was obtained (74 mg, 90%) which was judged pure by 1H NMR and MS. 1H NMR (CD3OD) δ 7.84-7.71 (m, 4H), 7.65 (s, 1H), 7.49-7.41 (m, 3H), 7.32-7.10 (m, 4H), 5.37 (d, J=9.4 Hz, 1H), 3.86-3.70 (m, 4H), 2.70 (s, 3H); MS (ESI): m/z 310.30 (M+1)+; [α]D20 −11.0 (c 0.2, 9:1 EtOH:H2O).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.Cl.[CH2:14]([O:21][C:22](=[O:31])[NH:23][C:24]1([C@H:27]([NH2:30])[CH2:28][CH3:29])[CH2:26][CH2:25]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([NH:30][C@@H:27]([C:24]2([NH:23][C:22](=[O:31])[O:21][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:26][CH2:25]2)[CH2:28][CH3:29])[C:8]([F:12])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: CC[C@@H](N)C1(NC(=O)OCc2ccccc2)CC1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC[C@@H](Nc1nc(Cl)c(C#N)cc1F)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Yield: 44.8 %

Procedure:
To a solution of 2,6-dichloro-5-fluoronicotinamide (233 mg, 1.22 mmol) in NMP (5.0 mL) was added (R)-benzyl-1-(1-aminopropyl)cyclopropylcarbamate hydrochloride salt (350 mg, 1.23 mmol) and DIPEA (0.434 mL, 2.44 mmol). After heated at 80° C. for 4 h, the mixture was diluted with EtOAc, organic layer was washed brine, dried and concentrated to give (R)-benzyl 1-(1-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)propyl)cyclopropylcarbamate (220 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][S:16]([CH2:19][CH2:20][CH2:21]O)(=[O:18])=[O:17]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:21][CH2:20][CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Reactant: CS(=O)(=O)CCCO
Product: CS(=O)(=O)CCCOc1cc2nccc(Cl)c2cc1C#N
Yield: 90.3 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 15, (see note a) above), 4-chloro-6-cyano-7-hydroxyquinoline (300 mg, 1.46 mmol), (prepared as described for the starting material in Example 1), was reacted with 3-(methylsulphonyl)-1-propanol (263 mg, 1.9 mmol) and the crude product was purified using a gradient of methylene chloride/ethyl acetate (1/1) to (2/8) to give 4-chloro-6-cyano-7-(3-methylsulphonylpropoxy)quinoline (428 mg, 90%)
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=1)[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]#[C:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=1)[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of benzyl 3-(1-azido-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate (23 g, 49.15 mmol, 1.00 equiv) in tetrahydrofuran (200 mL), water (20 mL), triphenylphosphine (25.7 g, 98.09 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (100:1-50:1). This resulted in 15 g (69%) of benzyl 3-(1-amino-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate as pale-yellow oil.
Reaction SMILES: FC1C=C(C=CC=1F)[C:5](O)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=O)[CH3:27])=[N:17][CH:18]=1>>[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:21]=2[CH2:26][CH2:27][C:5]3=[O:6])=[N:17][CH:18]=1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CC(=O)c1ccccc1Oc1ccc(N)cn1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 3,4-difluorobenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 1-{2-[(5-amino-2-pyridinyl)oxy]phenyl}-1-ethanone obtained in Reference Example 23 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[N:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[N:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][CH:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: N#Cc1cccc(CBr)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C#N)n3)c3ccccc3c2=O)cc1C
Yield: 41.5 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 100 mg (0.341 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-quinolin-4-one, 80.6 mg (0.409 mmol) of 6-bromomethyl-pyridine-2-carbonitrile, 16.4 mg (0.409 mmol, 60% dispersion in oil), and 3.5 mL of N,N-dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane to yield 58 mg of 6-[3-(4-Methoxy-3-methyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridine-2-carbonitrile. LC-MSD, m/z for C25H19N3O3 [M+H]: 410.14 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.3 min.
Reaction SMILES: O[C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5](C=O)=[CH:4][C:3]=1[O:12][CH3:13].C(O)(=O)CC(O)=[O:17].N1[CH2:26][CH2:25]CCC1>C(O)=O>[CH3:11][O:10][C:9]1[CH:8]=[C:5]([OH:17])[CH:4]=[C:3]([O:12][CH3:13])[C:2]=1[CH:25]=[CH2:26]
Reactant: C1CCNCC1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: O=C(O)CC(=O)O
Solvent: O=CO
Product: C=Cc1c(OC)cc(O)cc1OC
Yield: 37 %

Procedure:
A mixture of 4-hydroxy-3,5-dimethoxy benzaldehyde (2.5 g, 0.013 mol), malonic acid (2.80 g, 0.027 mol), piperidine (2–5 mL) and formic acid (10–20 mL) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside the microwave oven and irradiated for 2–8 minutes in parts. The cooled mixture was poured into ice cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4), provided a viscous liquid in 37% yield; 1H NMR (CDCl3) δ 6.73(1H, s, H-3 and H-5), 6.62 (1H, dd, CH═CH2) 5.61 (1H, d, J=18.6 Hz, cis-CH═CH2), 5.16(1H, d, J=10.8, trans-CH═CH2); 13C NMR (CDCl3) δ 147.4 (C-2) and C-6), 137.2 (C-1), 135.1 (CH═CH2), 129.5 (C-4), 112.2 (CH═CH2), 103.3 (C-3 and C-5), 56.0 (2-OMe).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C)C=O.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: Clc1ccccc1Cl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.72 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), dimethylformamide (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 12 to 13 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.72 to 0.75%].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][NH:31][C:32](=[O:36])[C:33](O)=[O:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:33]([C:32]([NH:31][CH3:30])=[O:36])=[O:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: CNC(=O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (51 mg, 0.13 mmol) and 2-(methylamino)-2-oxoacetic acid (13 mg, 0.13 mmol). Yield 34 mg (55%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH3:21][C:22]1([CH3:34])[CH2:26][C:25](=[O:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23]1>C1COCC1>[CH3:21][C:22]1([CH3:34])[CH2:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)([OH:27])[C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23]1
Reactant: CSc1ccc(Br)cc1
Reactant: CC1(C)C=C(c2ccccc2)C(=O)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C2(O)CC(C)(C)C=C2c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-bromothioanisole (2.51 g, 12.3 mmol) in THF (20 mL) at −78° C. was added dropwise a solution of 2.5 M n-butyl lithium in hexane (4.8 mL, 12.0 mmol). The resulting suspension was stirred at this temperature for 1 h and then a solution of 4,4-dimethyl-2-phenyl-2-cyclopenten-1-one from Step 2 (1.25 g, 6.7 mmol) in THF (20 mL) was added slowly via cannula to the cold reaction. The reaction was stirred for 15 min at −78° C. and then for 30 min. at r.t. The reaction was stopped by dilution with NH4OAc buffer 25% w/v and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 10% EtOAc/hexanes to give the title compound as a colorless gum.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].C(Cl)(=O)C(Cl)=O.C(N[N:39](NC(C)C)[SH:40](=[O:42])=[O:41])(C)C.C([N:49]([CH:53]([CH3:55])[CH3:54])[CH:50]([CH3:52])[CH3:51])C.CN(C1C=CC=CN=1)C>CN(C)C=O.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22]([NH:39][S:40](=[O:42])(=[O:41])[N:49]([CH:53]([CH3:55])[CH3:54])[CH:50]([CH3:52])[CH3:51])=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)NN(NC(C)C)[SH](=O)=O
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(C(C)C)S(=O)(=O)NC(=O)C(C)(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12

Procedure:
N,N-dimethylformamide (8 drops) is added to a mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-α,α-dimethyl-1,2-benzisothiazole-3-acetic acid (0.800 g, 0.00194 mol) and methylene chloride. The mixture is cooled on an ice bath and oxalyl chloride (2.0 M in methylene chloride, 2.42 ml, 0.00485 mol) is added. The resultant mixture is stirred one hour on an ice bath and concentrated in vacuo. The residue is taken up in tetrahydrofuran. N,N-Diisopropylaminosulfonamide (0.410 g, 0.00278 mol), ethyldiisopropylamine (0.310 g, 0.00240 mol) and dimethylaminopyridine (0.0100 g) are added and the resultant mixture is stirred overnight at room temperature. The mixture is then filtered and the filtrate is concentrated in vacuo to afford a yellow resin. The resin is filtered through silica gel to afford the title compound as a tan resin (0.500 g, 44.8%).
Reaction SMILES: Cl.[C:2]1([NH:8][C:9](=[O:12])[NH:10][NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13](=[C:15]1[C:23](=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[OH:14]>O.C(O)C>[N:13](=[C:15]1[C:16](=[O:25])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]1=[N:11][NH:10][C:9]([NH:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:12])[OH:14]
Reactant: NNC(=O)Nc1ccccc1
Reactant: O=c1c(=NO)c(=O)c2ccccc12
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(NN=c1c(=NO)c(=O)c2ccccc12)Nc1ccccc1

Procedure:
0.01 mol of 4-phenyl semicarbazide hydrochloride in solution in 10 ml water was added to a solution of 0.01 mol of 2-oximino indan-1,3-dione in 60 ml ethanol. The reaction mixture was refluxed for 1 hour. The precipitate formed was centrifuged when hot, dried and recrystallised from acetonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:8](=[O:10])[C:7]4[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=4)[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: CCOc1ccc(C(=O)O)cn1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A stirred mixture of 6-ethoxy-nicotinic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solvent was removed in vacuo and the crude product was purified by column chromatography (EtOAc hexanes). The product fractions were combined, concentrated and the residue was triturated in Et2O (20 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-6-ethoxy-nicotinamide as a white solid (1.11 g, 85% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.04 min (98.73%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=7.1 Hz, 3H, CH3), 1.96-2.16 (m, 1H, CHH), 2.41-2.69 (m, 2H, CHH, CHH), 2.79-3.00 (m, 1H, CHH), 4.37 (q, J=7.1 Hz, 2H, CH2), 4.65 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 6.88 (dd, J=0.7, 8.8 Hz, 1H, Ar), 7.77-7.94 (m, 3H, Ar), 8.16 (dd, J=2.6, 8.7 Hz, 1H, Ar), 8.71 (dd, J=0.8, 2.5 Hz, 1H, Ar), 9.21 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.41, 21.99, 30.93, 42.51, 49.01, 61.84, 110.27, 121.99, 123.04, 123.55, 129.82, 131.62, 133.44, 138.18, 147.13, 147.48, 164.79, 165.00, 166.97, 167.12, 169.80, 172.72; LCMS: MH=437; Anal Calcd for C22H20N4O6+0.1H2O: C, 60.30; H, 4.65; N, 12.78. Found: C, 60.08; H, 4.62; N, 12.77.
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[N:41]1([C:46]2[C:54]3[C:49](=[N:50][CH:51]=[C:52]([NH2:55])[CH:53]=3)[NH:48][N:47]=2)[CH:45]=[CH:44][N:43]=[CH:42]1>CN(C=O)C>[N:41]1([C:46]2[C:54]3[C:49](=[N:50][CH:51]=[C:52]([NH:55][C:4](=[O:6])[C:3]4[C:7]([F:18])=[CH:8][CH:9]=[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:2]=4[F:1])[CH:53]=3)[NH:48][N:47]=2)[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]nc(-n3ccnc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-n4ccnc4)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
2,6-Difluoro-3-(propylsulfonamido)benzoic acid (140 mg, 0.495 mmol), HOBt.H2O (89 mg, 0.584 mmol), and EDCI (120 mg, 0.674 mmol) was added to 3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine (90 mg, 0.450 mmol) in DMF (10 mL). The mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated, and the residue partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product was purified by column chromatography (10:1 DCM:MeOH), which was followed by trituration with DCM to afford N-(3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (57.7 mg, 28% yield) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.80 (d, 1H), 8.74 (d, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.70-7.64 (m, 1H), 7.27 (s, 1H), 7.17-7.12 (m, 1H), 3.14-3.09 (m, 2H), 1.92-1.82 (m, 2H), 1.06 (t, 3H); m/z (ESI-pos) M+1 462.2.
Reaction SMILES: ICl.C1C(=O)N(Br)C(=O)C1.IC1C2OC=CC=2C=C(S([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])(=O)=O)C=1>>[CH3:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([NH2:24])[CH:30]=1
Reactant: COc1ccc(C)cc1NS(=O)(=O)c1cc(I)c2occc2c1
Agent: ClI
Agent: O=C1CCC(=O)N1Br
Product: COc1ccc(C)cc1N

Procedure:
7-iodo-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide is produced starting from 2,3-dihydrobensofuran. Treatment with chlorosulfonic acid gives the corresponding sulfonyl chloride, which is iodinated using iodine monochloride. Aromatization is done using NBS, resulting in 7-iodo-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide after treatment with cresidine.