Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu].C(OCC)(=O)C.O>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][C:6]2[C:7](=[O:8])[C:2]([NH:1][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][O:4][C:5]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: Brc1ccccc1
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc2occ(Nc3ccccc3)c(=O)c2cc1Oc1ccccc1
Yield: 10.2 %

Procedure:
3.46 g of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 35 ml of N,N-dimethylformamide. Thereto were added 7 ml of bromobenzene, 1.66 g of potassium iodide, 1.38 g of potassium carbonate and 0.64 g of a copper powder. The mixture was refluxed for 6 hours. The reaction mixture was introduced into a mixture consisting of 300 ml of water and 200 ml of ethyl acetate. The insolubles were removed by filtration, and the filtrate was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 20:1 mixture of toluene and ethyl acetate) and then recrystallized from acetonitrile to obtain 430 mg (yield: 10.2%) of 7-methylsulfonylamino-3-phenylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 212°-213° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].O1CCCC1.O>CO>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CO)c1
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Sodium borohydride (1.18 g) was added to a solution of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (18.3 g) in methanol (50 ml)-tetrahydrofuran (100 ml) in portions at 0° C. After stirring for 30 minutes, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (15.5 g, yield 84%) as colorless crystals. m.p. 101-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([NH:13][C:14](=[NH:16])[CH3:15])[NH:11][N:12]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[N:13]=[C:14]([CH3:15])[NH:16][C:17](=[O:18])[N:11]2[N:12]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=N)Nc1cc(-c2ccccc2Cl)n[nH]1
Agent: Cl
Solvent: CS(C)=O
Product: Cc1nc2cc(-c3ccccc3Cl)nn2c(=O)[nH]1
Reaction time: 0.02 h

Procedure:
To a pale yellow solution of N-[5-(2-chlorophenyl)-2H-pyrazol-3-yl]-acetamidine (I-1A-1b; 2.04 g, 8.69 mmol) in DMSO (17 mL) was added 1,1′-carbonyldiimidazole (1.53 g, 9.44 mmol), portionwise over 1 minute at room temperature. After stirring for one hour, the reaction was added to stirred 1 M aqueous HCl (17 ml) over 5 minutes. The colorless precipitate that formed was stirred for 2.5 hours and then collected on a course sintered funnel. The solids were washed with water (50 ml) and then dried on the frit under a stream of air using low vacuum to afford I-1A-1c as a colorless solid (2.29 g, quantitative): +APcI MS (M+1) 261.3.
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=CC(SC)=C([C:17]([F:20])([F:19])[F:18])C=2)O1.[CH2:22]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:38](C)=[C:37]([N+]([O-])=O)[CH:36]=[CH:35][C:34]=2[O:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:29][CH:28]=1)(=O)=O)C>>[CH3:22][S:24][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[C:37]([C:17]([F:20])([F:19])[F:18])[CH:36]=[CH:35][C:34]=2[O:43][CH2:44][C:45]([O:47][C:30]([CH3:33])([CH3:31])[CH3:29])=[O:46])=[C:31]([C:17]([F:18])([F:19])[F:20])[CH:32]=1
Reactant: CSc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(-c2c(OCC(=O)O)ccc([N+](=O)[O-])c2C)cc1
Product: CSc1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)OC(C)(C)C)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of example 1 step (ii) using the products from steps (ii) and (iii). Yield 0.564 g. Carried forward to step (v) without characterisation.
Reaction SMILES: O.[OH-].[Li+].O.C[O:6][C:7](=[O:39])[CH2:8][CH2:9][CH:10]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]3)[C:20]=2[C:24]([F:27])([F:26])[F:25])[CH:15]=1)[N+:11]([O-:13])=[O:12].CO.O1CCCC1>>[C:35]([C@H:32]1[CH2:31][CH2:30][C@H:29]([O:28][C:19]2[C:20]([C:24]([F:25])([F:26])[F:27])=[C:21]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([CH:10]([N+:11]([O-:13])=[O:12])[CH2:9][CH2:8][C:7]([OH:39])=[O:6])[CH:23]=[CH:22]3)[CH2:34][CH2:33]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)CCC(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(CCC(=O)O)[N+](=O)[O-])ccc3c2C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
A 2 M solution of lithium hydroxide, monohydrate in water (1.00 mL, 2.00 mmol) was added to a solution of 4-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-nitro-butyric acid methyl ester (0.114 g, 0.230 mmol) in methanol (1.00 mL, 24.7 mmol) and tetrahydrofuran (1.00 mL, 12.3 mmol). The mixture was stirred at room temperate. After 2 h, HPLC analysis showed that the reaction was complete. The mixture was concentrated to dryness under reduced pressure then dissolved in methylene chloride and partitioned between 1N HCl aqueous solution. The organic phase was then dried over MgSO4, filtered, concentrated and purified by flash chromatography (0-5% MeOH in methylene chloride) to give 81.2 mg of the title compound (73% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]3[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:17](=[O:20])[NH:18][CH2:19][C:9]=23)[CH:7]=1.[S:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:35]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[O:36])[CH:3]=[CH:4][C:5]=3[CH3:29])[C:9]=2[CH2:19][NH:18][C:17]1=[O:20]
Reactant: CSc1nc(-c2cc(N)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: O=C(O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compounds 5-(5-amino-2-methylphenyl)-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.205 g, 0.5 mmol), 3-thiophenecarboxylic acid (0.0647 g, 0.5 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g, 0.55 mmol), 4-(dimethylamino)pyridine (0.002 g, 0.016 mmol), and triethylamine (0.14 mL, 1 mmol), were dissolved in chloroform (10 mL) and stirred under argon at room temperature for 16 h. The reaction was not complete. An additional 3-thiophenecarboxylic acid (0.13 g, 1.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g, 0.55 mmol) were dded and heated to 40° C. for 17 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water (3×), brine (1×), dried over anhydrous Na2SO4, filtered and evaporated. The crude product was flash chromatographed on silica gel (10 g) eluted with 0-5% MeOH/CH2Cl2 to give the title compound as a solid. LC-MS m/z 524 (M+H)+, 2.2 min (ret. time).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[C:3](=[NH:7])[O:4]CC.C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26]>O1CCCC1>[F:17][C:14]([F:15])([F:16])[C:10]1[CH:9]=[C:8]([CH:2]2[O:1][C:25](=[O:26])[NH:4][C:3]2=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cccc(C(F)(F)F)c2)O1
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Ethyl 1-hydroxy-1-(3-trifluoromethylphenyl)methane carboximidate (9.5 g., 0.038 mole) was dissolved in 500 ml. of tetrahydrofuran and cooled to 0°-5° C. Triethylamine (7.68 g., 0.076 mole) was added and the solution perfused with phosgene for 35 minutes at 0°-5° C. After stirring for 1.5 hours, isolation and recrystallization according to Example 3 gave 5-(3-trifluoromethylphenyl)-oxazolidine-2,4-dione (6.4 g., 69%, m.p. 93°-96° C.). A second recrystallization from toluene gave purified product (4.9 g., 53% over-all; m.p. 97°-99° C., m/e 245).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]3)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].[C:33](=O)([O:41]C1C=CC([N+]([O-])=O)=CC=1)[O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)CC)(C)C>>[CH3:38][Si:37]([CH3:40])([CH3:39])[CH2:36][CH2:35][O:34][C:33]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[CH2:23][CH2:22][O:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:30]([O-:32])=[O:31])[CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:41]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.5 %

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-6-nitro-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one (200 mg in 5 mL dicloroethane) was added 136 mg of 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate followed by 0.092 mL diisopropylethylamine and the mixture heated to reflux. After 20 hours, the reaction was cooled to room temperature, concentrated in vacuo and purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:1) to give the title compound (183 mg.)
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[Cl:10])=[O:4].[OH-].[Na+]>C(O)C>[C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[Cl:10])([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)c(C(=O)O)s1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 2-methoxycarbonyl-3-chloro-5-methylthiophene (1.3 g, 6.8 mmol) in ethanol (16 mL) was added aqueous sodium hydroxide (1 N, 16 mL, 16 mmol) and the mixture stirred at ambient temperature. After 3 hours the mixture was concentrated of all volatiles in vacuo. The residual solid was dissolved in water (60 mL), acidified with 1 N HCl and the solid collected by filtration to afford 1.2 g (95% yield) of 2-carboxy-3-chloro-5-methylthiophene as a white solid; NMR (CDCl3) 6.8 (s, 1), 2.5 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:48][CH2:49]3)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:27]=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1ccc(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccc(S(C)(=O)=O)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methanesulfonyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% of 1:1 ethanol/acetonitrile in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C35H43N4O6S2Cl2 [(M+H)+] 749.1996, observed 749.1991.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].CCN=C=[N:13][CH2:14][CH2:15][CH2:16]N(C)C.Cl.C(N)C#C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([NH:4][CH2:5][C:6]([NH:13][CH2:14][C:15]#[CH:16])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: C#CCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CCNC(=O)CNC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of N-acetylglycine (200 mg, 1.71 mmol), DMAP (11 mg, 0.09 mmol) and EDC hydrochloride (360 mg, 1.88 mmol) in DCM (10 mL) was added propargylamine (109 μL, 1.71 mmol). The reaction mixture was stirred at RT overnight and then evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0 to 5% methanol in DCM, to afford the title compound (12) (218 mg, 83%) as a white solid: 1H NMR (500 MHz, CDCl3) δ: 2.07 (3H, s), 2.25 (1H, t), 3.95 (2H, d), 4.07 (2H, dd), 6.34 (1H, br s), 6.49 (1H, b s).
Reaction SMILES: C(S([O:8][N+:9]([O-])=[O:10])(=O)=O)(F)(F)F.[CH2:12]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[C@H:20]([N:28]([CH2:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:19][C@@H:18]1[CH3:48])=[O:16])[CH3:13].O>ClCCl>[CH2:12]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][C:25]=2[N+:9]([O-:10])=[O:8])[C@H:20]([N:28]([CH2:33][C:34]2[CH:35]=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:19][C@@H:18]1[CH3:48])=[O:16])[CH3:13]
Reactant: O=[N+]([O-])OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)N1c2ccc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1c2c(cc(Cl)cc2[N+](=O)[O-])[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
To a pre-dried flask under nitrogen atmosphere was prepared a slurry of F3CSO3NO2 (2.6 mmol) in 9 mL of dichloromethane [ref. J. Org. Chem. 1973, 38 (25), 4243]. The solution was cooled to -78° C. and a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 32) (0.72 g, 1.3 mmol) in anhydrous dichloromethane (5 mL) was added. The reaction was stirred at -78° C. for 1.5 h, then warmed to 0° C. and stirred for 1 h and 40 min. Water (30 mL) was then added, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title product (0.75 g, 96%). MS m/z 598 (M+ +H); 1H NMR (CDCl3) δ 7.85 (bs, 1H), 7.8 (bs, 1H), 7.7 (bs, 1H), 7.65 (bs, 1H), 7.1 (bs, 1H), 3.80 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[CH:18]=[O:19].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][C:10]=1[CH:18]=[O:19]
Reactant: O=Cc1cc(B(O)O)ccc1F
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1cc(-c2ccccn2)ccc1F
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-bromopyridine (300 mg; 1.89 mmol), 4-fluoro-3-formylphenylboronic acid (318 mg; 1.89 mmol), Cs2CO3 (1.546 g; 4.74 mmol), Xantphos (82 mg; 0.14 mmol), and Pd2(dba)3 (43 mg; 0.04 mmol) in dioxane (4.5 ml) was heated to 80° C., under nitrogen, for 17 h. After cooling to rt, the mixture was filtered over celite, and the separated solids were washed with AcOEt. The filtrate was then washed with water, and the separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded 2-fluoro-5-(pyridin-2-yl)benzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.46 min.; [M+H]+: 202.02 g/mol.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:29]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][C:10]([CH:7]1[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]1)=[O:12]
Reactant: NCC(=O)c1ccccc1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)NCC(=O)c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
A suspension of 1-acetyl-4-piperidine carboxylic acid (93 g, 542 mmol) in CH2Cl2 (700 mL) is treated portionwise at 23° C. with carbonyldiimidazole (80 g, 542 mmol). The solution is allowed to stir at 23° C. under N2 for 1.5 h, then treated with 2-aminoacetophenone hydrochloride (93 g, 542 mmol) and diisopropylethylamine (113 mL, 650 mmol). The orange solution is stirred for 15 h, then washed with 2 N NaOH (2×200 mL), 2 N HCl (2×200 mL), and brine (1×300 mL), dried (MgSO) and concentrated to a red solid. The solid is dissolved in hot MeOH, and addition of hexane gave a pale orange solid which is obtained by filtration. The mother liquid is concentrated, the residue taken up in hot MeOH, and another crop of product is obtained by addition of hexane, to give a combined yield of 122 g of 1-Acetyl-piperidine-4-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide as a pale orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC.Cl>CN(C=O)C.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]>[OH:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:5]4=[N:6][CH:7]=[C:2]([C:34](=[O:36])[CH3:35])[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 17.4 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.109 mmol) from Example 29, tributyl(1-ethoxyvinyl)tin (79 mg, 0.218 mmol) and TEA (22 mg, 0.218 mmol) in anhydrous DMF (1 mL) at rt was flushed with a stream of argon for 15 min. To the resulting mixture was added tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.0165 mmol). The reaction vessel was sealed and the mixture was heated with stirring at 110° C. for 1.5 h. After cooling to rt, aq 2 M HCl (500 μL) was added and the mixture was stirred for 1 h. The reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone (8 mg, 17%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J=1.5 Hz, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.20-7.32 (m, 2H), 5.53 (s, 2H), 4.76 (br s, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.68 (s, 3H), 2.04 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 422 (M+H)+.
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])(=[O:8])[CH3:7].[CH2:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O.C(Cl)(Cl)Cl>[CH2:22]([S:26]([NH:29][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1)(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCCCS(N)(=O)=O
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)NC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
N,N′-carbonyldiimidazole (9.40 g) is added to an N,N-dimethylformamide (300 ml) solution of 4-acetylamino-3-nitro-benzoic acid (10.0 g), and the solution is stirred for 1 hour at room temperature. Then, 1-butanesulfonamide (7.92 g) and diazabicycloundecene (8.83 g) are added into the solution, and the solution is stirred for 72 hours at 100° C. After chloroform and water are added into the solution and the solution is separated into layers, the residue, which is obtained by concentrating the organic layer, is purified using silica gel column chromatography (eluate: ethyl acetate/methanol=4/1), and thus, N-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide (10.75 g) is obtained. 1H-NMR (DMSO-d6, δ): 0.87 (3H, t, J=7.4 Hz), 1.37-1.44 (2H, m), 1.64-1.71 (2H, m), 2.12 (3H, s), 3.52 (2H, t, J=7.7 Hz), 7.83 (1H, d, J=8.6 Hz), 8.21 (1H, dd, J=8.6 and 2.1 Hz), 8.54 (1H, d, J=2.2 Hz), 10.56 (1H, s), 12.32 (1H, s).