Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N:21]1([CH:26]2[CH2:31][CH2:30][CH2:29][N:28](Cl)[CH2:27]2)[CH:25]=[CH:24][N:23]=[N:22]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH2:31][CH:26]([N:21]5[CH:25]=[CH:24][N:23]=[N:22]5)[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: ClN1CCCC(n2ccnn2)C1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCCC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 66.9 %

Procedure:
To a suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.18 mmol) and 3-(1,2,3-triazol-1-yl)piperidine-1-yl hydrochloride (83 mg, 0.44 mmol) in 3 ml of acetonitrile was added 67 mg (0.44 mmol) of DBU. The solution was heated at reflux under nitrogen for 16 hrs. The suspension was cooled and the solid collected, washed with water, dried to yield 50 mg of the title product, m.p. 239°-240° C. 1H NMR (TFA) δ: 9.35 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 8.16 (d, J=10.6Hz, 1H), 5.45-5.15 (m, 1H), 4.7-3.55 (m, 5H), 2.85-2.05 (m, 4H), 1.8-1.3 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][O:6][CH:7]=1)[CH3:2].[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]>>[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25]([C:5]2[O:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: CCc1cocn1
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(CC)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-ethyl-oxazole (47 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (74 mg) as a yellow gum.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([S:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([S:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)(=[O:36])=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(S(=O)C4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(S(=O)(=O)C4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(1-isopropylpiperidine-4-sulfinyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 242 (38 mg, 0.078 mmol) in DCM (4 mL) was added TFA (30 μL, 0.39 mmol) followed by a solution of m-CPBA (18 mg, 0.101 mmol) in DCM (1 mL). The resulting mixture was stirred for 3 h at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 3-15% MeOH in DCM) affording 244 as a white solid (31 mg, 81%). LCMS: RT 2.77 min [M+H]+ 499.1. 1H NMR (CD3OD, 400 MHz): δ 8.73 (1H, d, J=8.46 Hz), 7.84 (1H, s), 7.60 (1H, dd, J=8.47, 1.85 Hz), 7.55 (1H, d, J=1.82 Hz), 5.95-5.82 (1H, m), 4.65-4.57 (4H, m), 3.22-3.11 (1H, m), 2.99 (2H, bd, J=11.61 Hz), 2.77-2.64 (1H, m), 2.37 (3H, s), 2.20 (2H, t, J=11.89 Hz), 2.01 (2H, d, J=12.72 Hz), 1.73 (2H, td, J=12.41, 3.93 Hz), 1.55 (6H, d, J=6.65 Hz), 1.03 (6H, d, J=6.56 Hz)
Reaction SMILES: O[C@@H:2]([C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 38.3 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3S*)-3-hydroxy-4,4-dimethyl-2-(5-phenyl-pentoxy-carbonylamino)-pentanoic acid (0.346 g, 0.98 mmol) in dry CH2Cl2 (45 mL), at 0° C., Et3N (0.41 mL, 2.95 mmol) and subsequently TBTU (0.38 g, 1.20 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 70:30) to afford the pure title compound (0.125 g, 38%), as white solid. MS (ESI) m/z: 351 [M−NH4]+; (ESI) m/z: 332 [M−H]−. 1H NMR (DMSO-d6) δ 0.93 (s, 9H), 1.34 (h, J=6.37, 7.16 Hz, 2H), 1.53-1.65 (m, 4H), 2.57 (t, J=7.69 Hz, 2H), 4.02 (q, J=6.25 Hz, 2H), 4.36 (d, J=6.24 Hz, 1H), 5.56 (dd, J=6.32, 8.47 Hz, 1H), 7.07-7.34 (m, 5H), 8.38 (d, J=8.48 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(NS(C)(=O)=O)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(NS(C)(=O)=O)cc2)CC(C)(C)C1
Temperature: -2.5 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of N-{4-[(4-methoxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-methanesulfonamide (180) (0.25 g, 0.585 mmol) in dry dichloromethane (20 mL) was slowly added BBr3 (1 N in dichloromethane) (1.75 mL, 1.75 mmol) at −5 to 0° C. The reaction mixture was stirred at −5 to 0° C. under nitrogen for 3 h. The reaction mixture was poured onto ice and stirred for several minutes. The quenched reaction mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc and the organic extracts were combined, washed with brine, dried over MgSO4, filtered, and concentrated to give an off white solid. The solid was triturated with hexanes followed by dichloromethane. The product was filtered, washed with methanol, and dried to give 0.174 g (72%) of compound 181 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 12 H), 1.23 (s, 2 H), 1.86 (s, 2 H), 1.89 (s, 2 H), 2.94 (s, 3 H), 6.64 (d, J=8.6 Hz, 2 H), 6.90 (d, J=8.5 Hz, 2 H), 7.06 (s, 2 H), 7.07 (s, 2 H), 9.25 (s, 1 H), 9.64 (s, 1 H). HRMS (ESI) calcd for C24H30NO3S: 412.1946 (M−H)−. Found: 412.1942.
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[OH-].[Na+:37]>C(#N)C.O>[OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O-:10])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1.[Na+:37]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)[O-])C(C)(C)C3)s2)c1
Temperature: 35 °C

Procedure:
(1S,4R)-4-Hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (9.8 mg, 0.019 mmol) was dissolved in acetonitrile (20 μL) and water (20 μL). Sodium hydroxide (19 μL, 0.019 mmol) was added, and the mixture was heated to 35° C. for 10 min. The mixture was allowed to cool to rt, diluted with water, froze to a solid, and lyophilized to dryness to afford sodium (1S,4R)-4-hydroxy-2,2-dim ethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxylate.
Reaction SMILES: [CH:1]1[N:10]2[C:4]([CH2:5][CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:9]=32)=[N:3][CH:2]=1.[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=1)=[O:19]>>[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][C:4]4[N:10]([CH:1]=[CH:2][N:3]=4)[C:9]=3[CH:11]=2)[N:27]=1)=[O:19]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)-n1ccnc1CCC2
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)-n2ccnc2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-3,10b-diaza-benzo[e]azulen-9-ylamine and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide were converted to 3-[5-chloro-2-(5,6-dihydro-4H-3,10b-diaza-benzo[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide. HCl salt: 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1H), 8.08 (d, 1H), 7.85 (s, 1H), 7.81 (d, 1H), 7.68 (d, 1H), 7.65 (s, 2H), 7.51 (d, 1H), 3.07 (t, 2H), 2.91 (s, 3H), 2.80 (t, 2H), 2.50 (pent, 2H); MS (m/e) 466 (M+1).
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[CH:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=O>C1COCC1.CCCCCCC>[C:19]([C:18]1[CH:17]=[C:16](/[CH:14]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: N#Cc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)/C=C/c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Methyl 2-(dimethoxyphosphoryl)acetate (20.83 g, 114.39 mmol) was dissolved in THF (500 mL). Sodium hydride (4.58 g, 114.39 mmol) was added in small portions. 3-formylbenzonitrile (10 g, 76.26 mmol) was added dissolved in 50 mL of THF and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with heptane, washed with H2O, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated in heptane, filtered, washed with heptane and dried under vacuum, giving 13.26 g title compound (93%) as a white powder. 1H NMR (400 MHz, CDCl3) δ ppm 3.83 (s, 3H) 6.50 (d, J=16.02 Hz, 1H) 7.52 (t, J=7.81 Hz, 1H) 7.61-7.84 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([OH:26])[C:18]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26][CH2:2][CH2:3][OH:4])[C:18]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.2 %

Procedure:
A solution of 2-bromoethanol (0.034 g) in DMF (1 ml) was added to a stirred mixture of ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 36, 0.1 g) and cesium carbonate (0.127 g) in DMF (1 ml). The resultant mixture was stirred at room temperature for 3 hours. Further 2-bromoethanol (0.017 g) was added and the mixture was stirred at room temperature for a further 3 days. Cesium carbonate (0.085 g) and 2-bromoethanol (0.024 g) were added and the mixture was stirred for 1 hour. 2-Bromoethanol (0.015 g) was added and the mixture was stirred for a further 1 hour. The resultant mixture was partitioned between ethyl acetate and water and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 30-50%. The product was again purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 25-30% to give ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-(2-hydroxyethoxy)benzoate (0.037 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH2:3]1
Reactant: CC1(C)CNc2ccccc21
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: ClCCl
Product: CC1(C)CN(c2ccccc2[N+](=O)[O-])c2ccccc21
Temperature: 175 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To 2c (317 mg, 2.12 mmol) was added 1-fluoro-2-nitrobenzene (200 mg, 1.42 mmol). The reaction mixture was stirred at 175° C. for 8 h. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl and dried over Na2SO4. The solvent was evaporated under reduced pressure and purified by column chromatography using 0 to 10% EtOAc in hexane over 30 min as eluting solvent to afford 2d (360 mg, 95%) as an oil. MS (ES) m/z 269 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.5 %

Procedure:
3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). 1-Bromobutane (3.17 mL, 29.5 mmol) was added to this suspension and stirred for 19 hours at room temperature. This mixture was partitioned into ethyl acetate and water. This organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.23 g).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1ccc(F)cc1F
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(F)cc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2,4-difluorophenol:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C:25]([CH3:35])([CH3:34])[CH2:26][NH:27][C:28]1[CH2:32][S:31][C:30](=[O:33])[N:29]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:26][C:25]([OH:24])([CH3:35])[CH3:34])=[N:29][C:30](=[O:33])[S:31]/2)[CH2:8][CH2:7]1
Reactant: CC(C)(O)CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (25.2 g) and 4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one (7.00 g) in 2-propanol (200 mL) was added piperidinium acetate (10.8 g). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give a solid. The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (11.5 g).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[NH3:18]>>[S:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:13]2)(=[O:16])(=[O:15])[NH2:18]
Reactant: N
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Cl)cc2C1
Product: CC(=O)NC1Cc2ccc(S(N)(=O)=O)cc2C1

Procedure:
was prepared from 2-Acetylamino-indan-5-sulfonyl chloride and an excess of ammonia.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:26])(O)O>>[F:12][C:8]1[C:7]([OH:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:26])=[N:3]2
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Reactant: Oc1ccc2nc(Cl)ccc2c1F
Product: Cc1cc(C(=O)O)ccc1-c1ccc2c(F)c(O)ccc2n1

Procedure:
Followed the procedure described for Example 70, starting from 2-chloro-5-fluoroquinolin-6-ol (Intermediate 16) and 4-borono-3-methylbenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.03 (b, 1H), 10.47 (b, 1H), 8.43 (d, 1H), 7.93 (s, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.52 (t, 1H), 2.43 (s, 3H). MS (ESI): m/z=296.38 [M−1]−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[C:8]([CH3:13])=[C:7]2[Cl:14].C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1>[Cl:14][C:7]1[C:6]2[C:11](=[C:2]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:11][N:10]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:20][N:21]=2)[C:8]=1[CH3:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2c(Br)cccc2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(-c3ccccn3)cccc2c1Cl

Procedure:
The chlorides were prepared according to Procedure E using 8-bromo-2,4-dichloro-3-methylquinoline (0.32 g, 1.11 mmol), 2-(tributylstannyl)pyridine (0.45 mL, 1.23 mmol) and palladium tetrakistriphenylphosphine (0.13 g, 0.11 mmol) in toluene (2.2 mL) to give 8-bromo-4-chloro-3-methyl-2-(pyridin-2-yl)quinoline and further elution gave 4-chloro-3-methyl-2,8-di(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=332.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cs1
Solvent: CCCCO
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cs1
Temperature: 160 °C
Reaction time: 18 h

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide (200 mg, 0.563 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (338 mg, 1.69 mmol) in n-BuOH was stirred at 160° C. in a sealed tube. After 18 hours, additional (R)-tert-butyl piperidin-3-ylcarbamate (113 mg, 0.563 mmol) was added to the mixture and heating at 160° C. was continued for a further 18 hours. The mixture was concentrated in vacuo and purified by C-18 reverse phase column chromatography (Biotage Flash 25 M+ column) on Biotage SP4 unit eluting with a gradient of 10-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-methylthiazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. This material was dissolved in neat TFA (3 mL), stirred at room temperature for 30 minutes and concentrated in vacuo. The oily residue was dissolved in a few drops of methanol and treated with 2M HCl in ether. The resulting precipitate was concentrated under reduced pressure, and the residue was dissolved in a few drops of methanol and CH3CN was added. The precipitate formed was filtered and dried under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide hydrochloride (25 mg, 10% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.87 (s, 1H), 10.64 (s, 1H), 8.34 (br s, 3H), 8.31 (s, 1H), 8.28 (s, 1H), 8.09 (d, 1H), 3.85-3.24 (m, 1H), 3.70-3.57 (m, 2H), 3.35-3.28 (m, 1H), 3.09-3.02 (m, 1H), 2.81 (s, 3H), 2.36-2.27 (m, 2H), 1.94-1.86 (m, 1H), 1.63-1.51 (m, 1H); LCMS (APCI+) m/z 435.0, 437.0 (M+H)+, Retention time=2.54 minutes (Method 2).
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:5][C:6]1[C:15]([Br:2])=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([O:17][CH3:18])=[N:13]2)=[N:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc2ncc(Br)c(O)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Br)c(Br)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
Phosphorus tribromide (140 mg, 0.53 mmol, 1.3 eq) is added at 0° C. to a stirred suspension of 3-bromo-6-methoxy-[1,5]naphthyridin-4-ol (100 mg, 0.39 mmol, 1.0 eq) in N,N-dimethylformamide (1 mL). After 2 hours stirring at room temperature, the reaction mixture is poured into saturated sodium carbonate aqueous solution (50 mL). The resulting suspension is filtered and the cake is washed with water and methanol to afford 7,8-dibromo-2-methoxy-[1,5]naphthyridine as a white solid (100 mg, 80% yield).