Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][C@@H:4]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C@@H:3]12.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:5]1[CH2:6][CH2:7][O:2][C@@H:3]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][C@@H:4]12)=[O:27]
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCO[C@@H]2c3ccccc3OCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.21 g of trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, prepared according to the procedure of Example 2, and 1.65 ml of triethylamine in 25 ml of methylene chloride is treated dropwise with a solution of 0.70 ml of chloroacetyl chloride dissolved in 10 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, washed with a dilute solution of hydrochloric acid, followed by a water wash, a wash of dilute sodium hydroxide solution and finally by a wash of a saturated solution of sodium chloride. The reaction mixture is dried over anhydrous magnesium sulfate and evaporated to dryness to obtain 1.44 g of trans-N-chloroacetyl-3,4,4a,5,6,11b-hexahydro-2H-[1]-benzoxepino[5,4-b]-1,4-oxazine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>N1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Oc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccccc3F)cn2)CC1
Temperature: 0 °C
Yield: 6.7 %

Procedure:
A mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (684 mg, 2.0 mmol), 2-fluorophenol (1.1 g, 10.0 mmol), copper (650 mg, 10.0 mmol) and cesium carbonate (6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120 0° C. in a sealed tube overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and then filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 20:1) to give tert-butyl 4-(5-(2-fluorophenoxyl)pyrimidin-2-yl)piperazine-1-carboxylate (50 mg, 6%) as a yellow solid. MS (ES+) C19H23FN4O3 requires: 374, found: 397 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[C:36]1([CH2:42][CH2:43]CO)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH2:43][CH2:42][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: OCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 56.4 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-phenyl-1-propanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (42 mg, yield 49%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:29][CH3:30])[C:5]([N:8](COCCO[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](CO)[CH:32]=1.[H-].[Na+].CN1CCC[C:43]1=[O:47]>>[ClH:1].[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:29][CH3:30])=[N:3][C:2]([O:47][CH2:43][C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: COc1nc(Cl)cnc1N(COCCO[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: OCc1cccnc1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OCc2ccccn2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Product: Cl

Procedure:
Procedure as for Example 115 using N-(5-chloro-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.5 g), pyridine-3-methanol (0.11 g) and sodium hydride (0.05 g of a 60% dispersion in oil) in N-methylpyrrolidinone (5 mL). Yield 0.23 g.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].N#N.[CH:28]1([C:31]#[CH:32])[CH2:30][CH2:29]1.C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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>[CH:28]1([C:31]#[C:32][C:2]2[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][N:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][C:3]=2[O:24][CH3:25])[CH2:30][CH2:29]1
Reactant: COc1ccc(CON=C(c2ccccc2)c2nnnn2C)nc1Br
Reactant: C#CC1CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CON=C(c2ccccc2)c2nnnn2C)nc1C#CC1CC1
Reaction time: 0.33 h
Yield: 57.4 %

Procedure:
To a stirred solution of N-[(6-bromo-5-methoxypyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.150 g, 0.372 mmol, 1 eq.) in 2 ml dry THF “degassed” with N2, was added cyclopropylacetylene (0.073 g, 1.11 mmol, 3 eq.) followed by N-ethyldiisopropylamine (0.191 g, 1.48 mmol, 4 eq.), Copper Iodide (0.010 g, 0.056 mmol, 0.15 eq.) and Tetrakis(triphenylphosphine)palladium (0.042 g, 0.037 mmol, 0.1 eq.). The reaction was microwaved 120° C./normal/fixed hold/pre stir 100 s for 1200 s. The reaction was diluted with EtOAc and filtered through a “celite” plug. The solvent was evaporated and the residue purified by chromatography on silica gel to give N-{[6-(cyclopropylethynyl)-5-methoxypyridin-2-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.083 g, 57% yield) as a yellow viscous oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[K+].[CH2:22]([SH:24])[CH3:23]>CN(C)C=O.C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([S:24][CH2:22][CH3:23])[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCS
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCSc1nc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
A solution of 3.40 g (12 mmol) 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 60 ml N,N-dimethylformamide heated to 60° C. was treated with a solution of 3.36 g (60 mmol) potassium hydroxide and 6 ml (81 mmol) ethanethiol in 30 ml absolute ethanol. After stirring 15 minutes at 60° C. the mixture was poured into 240 ml ice cold 0.5 N hydrochloric acid, and the precipitate was filtered, washed with water and crystallized from acetic acid--water to give 3.10 g, mp 242°-244° C. of the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:8]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:7]2[C:6]=1[OH:25])=[O:4].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>>[Cl:24][C:22]1[CH:23]=[C:7]2[C:6]([OH:25])=[C:5]([C:3]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:8]2[CH:21]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(OC)cc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Cn2c(=O)c(C(=O)N[C@@H](C)C(=O)O)c(O)c3cc(Cl)cn32)cc1

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-methoxy-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 420 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:9]=O)=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([BH3-])#N.[Na+].O>CO>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Reaction time: 18 h
Yield: 11.1 %

Procedure:
To a solution of bis-(4-chloro-phenyl)-acetaldehyde (3.74 mmol) in methanol under a nitrogen atmosphere, N-BOC-piperazine (1.05 g, 5.61 mmol) was added ???, the reaction mixture was stirred for 1 hour before addition of sodium cyanoborohydride (0.28 g, 4.49 mmol). The reaction mixture was stirred for 18 hours, water added (3 ml) and the solvent removed under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer was separated, dried (MgSO4), filtered and concentrated. Purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (3:7) to yield the title compound (0.18 g, 11% yield for steps 30A and 30B combined). LC/MS: (PS-A2) Rt 2.66 E[M−BOC+H]+ 335.02.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml), and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 97%).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li+].CC([N-]C(C)C)C.[O:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:19]2([OH:22])[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[CH:5][C:6]=1[CH3:7]
Reactant: O=C1CCOCC1
Reactant: Cc1ccsc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2(O)CCOCC2)sc1Br
Temperature: 25 °C
Yield: 46.8 %

Procedure:
To a −78° C. solution of 2-bromo-3-methyl-thiophene (2.0 g, 17.75 mmol) and THF (30 mL) is added 2.0 M LDA (9.32 mL, 18.63 mmol). After 30 minutes at −78° C. tetrahydro-pyran-4-one (2.3 mL, 23.07 mmol) is added and the solution is warmed to ambient temperature. The solution is washed with sat. NH4Cl (30 mL). The aqueous phases is extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (30%-100% EtOAc/hexane gradient) furnish the title compound (2.3 g, 8.30 mmol, 47%). 1H NMR (CDCl3), δ 1.82 (m, 2H), 2.00 (s, 3H), 2.06-2.15 (m, 3H), 2.16 (s, 3H), 3.77-3.84 (m, 2H), 3.87 dt, J=11.3, 2.2 Hz, 2H), 6.67 (s, 1H). LC/MS (m/z): calcd. for C10H13BrO2S (M+H)+: 277.0; found: 260.9.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.COCCC[N:36](C)[CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[C:44](OC(N1CCC(NC)CC1)=O)(C)(C)[CH3:45].COCCCOS(C1C=CC(C)=CC=1)(=O)=O>>[NH:36]1[C:37]2[C:38](=[C:44]([C:2]3[N:3]=[C:4]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:41][CH:42]=2)[CH:39]=[N:40]1
Reactant: COCCCN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COCCCN(C)C1CCNCC1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: COCCCOS(=O)(=O)c1ccc(C)cc1
Product: COCCCN(C)C1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Via [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-(3-methoxy-propyl)-methyl-amine, prepared from (3-methoxy-propyl)-methyl-piperidin-4-yl-amine. The amine, (3-methoxy-propyl)-methyl-piperidin-4-yl-amine, was prepared from 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester and toluene-4-sulfonic acid 3-methoxy-propyl ester (produced from 3-methoxy-1-propanol using standard conditions) in a similar manner to 128.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[O:29][C:19]3=[C:20]4[C:25](=[CH:26][CH:27]=[C:18]3[O:17][CH2:16]2)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]4)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C.C(OCC)C.CO>[CH3:28][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]3[O:17][CH2:16][CH:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[O:29][C:19]3=2)[N:24]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)O3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCNCC1)O3
Temperature: 35 °C

Procedure:
To an ice-cold solution of (2S)-4-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazine 1 carboxylic acid tert-butyl ester of Step A′ (0.550 g, 1.37 mmol) in ethyl acetate (8 mL) is added dropwise 1 M hydrochloric acid in diethyl ether (15 mL). The mixture is allowed to come to room temperature, diluted with methanol (10–15 mL) and warmed at 35° C. until the reaction is complete by TLC. The solvents are removed in vacuo and the residue is slurried in diethyl ether. The solid is collected and dried in vacuo. The free base is prepared by basifying an aqueous solution of the hydrochloride salt with concentrated aqueous sodium hydroxide, followed by extraction with dichloromethane. The title compound is obtained as a thick oil (quantitative yield).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[N:19][CH:20]=1>C(Cl)Cl>[F:24][C:14]([F:13])([F:23])[C:15]1[CH:16]=[C:17]2[NH:22][C:1](=[O:2])[NH:21][C:18]2=[N:19][CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(F)(F)F)cnc1N
Solvent: ClCCl
Product: O=c1[nH]c2cc(C(F)(F)F)cnc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add 1,1′-carbonyldiimidazole (1.0 g, 6.17 mmol)to a solution of 5-trifluoromethyl-pyridine-2,3 diamine (0.90 g, 5.08 mmol) in CH2Cl2 (10 mL) and stir at room temperature for 18 hours. Heat the solution to reflux for 2 hours and filter the precipitate to obtain 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](I)=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[F:45].C([O-])([O-])=O.[K+].[K+].C(#N)C>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>[F:38][C:39]1[CH:40]=[C:41]([C:15]2[C:9]3[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]4[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:2]=4[F:1])[CH:8]=3)[NH:13][CH:14]=2)[CH:42]=[CH:43][C:44]=1[F:45]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Reactant: OB(O)c1ccc(F)c(F)c1
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: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(-c4ccc(F)c(F)c4)c3c2)c1F
Temperature: 160 °C
Yield: 44.2 %

Procedure:
2,6-Difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.025 g, 0.038 mmol), 3,4-difluorophenylboronic acid (0.0090 g, 0.057 mmol), K2CO3 (0.026 g, 0.19 mmol), and Pd(PPh3)4 (0.0022 g, 0.0019 mmol) were taken up in 4:1 acetonitrile (“ACN”)/water (1.5 mL) and degassed with argon for 10 minutes. The reaction mixture was heated to 160° C. for 10 minutes under microwave irradiation. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil. DCM was added to the oil, and a solid precipitated out, which was collected by filtration giving N-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (8.5 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 12.08 (br s, 1H), 10.97 (s, 1H), 9.80 (br s, 1H), 8.66 (br s, 1H), 8.52 (br s, 1H), 7.99 (br s, 1H), 7.69-7.75 (m, 1H), 7.51-7.59 (m, 3H), 7.25-7.30 (m, 1H), 3.11-3.15 (m, 2H), 1.74-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=505.2.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:53]=[CH:52][C:51]2[CH2:50][CH:49]([C:54](O)=[O:55])[CH2:48][CH2:47][C:46]=2[N:45]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:54]([CH:49]1[CH2:48][CH2:47][C:46]2[N:45]=[C:44]([C:43]([F:58])([F:42])[F:57])[CH:53]=[CH:52][C:51]=2[CH2:50]1)=[O:55])[CH3:4]
Reactant: O=C(O)C1CCc2nc(C(F)(F)F)ccc2C1
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 73.9 %

Procedure:
A 2 mL vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (14 mg, 0.049 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (17 mg, 0.044 mmol). A solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (6.0 mg, 0.024 mmol) and N,N-diisopropylethylamine (21 uL, 0.12 mmol) in N-methylpyrrolidinone (0.4 mL, 4 mmol) was added, and the mixture stirred to dissolution. After 40 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (8.4 mg, 72%). 1H NMR (400 MHz, CD3OD) δ 7.73 (app t, J=8.3 Hz, 1H), 7.53 (dd, J=3.8, 8.0 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.14 (dd, J=1.4, 11.7 Hz, 1H), 5.19 (app pentet, J=7.0 Hz, 1H), 3.17-2.94 (m, 4H), 2.98 (s, 3H), 2.82-2.71 (m, 1H), 2.32 (s, 3H), 2.23-2.12 (m, 1H), 2.07-1.89 (m, 1H), 1.47 (d, J=7.0 Hz, 3H); m/z=474.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].[C:20]1(S(N)(=O)=O)[CH:25]=CC=C[CH:21]=1.ClC1C=CC=CC=1C(Cl)=O.[H-].[Na+].C(Br)C=C>O1CCCC1>[CH2:25]([N:6]([C:4](=[O:5])[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:20]=[CH2:21]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccccc1Cl
Agent: O=C(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCN(C(=O)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
3.0 g (0.01 mole) of N-2-chlorobenzoyl benzenesulfonamide prepared from benzenesulfonamide and 2-chlorobenzoyl chloride was added to 0.58 g (0.012 mole) of 50% sodium hydride in 15 ml of dry tetrahydrofuran. After stirring for 30 minutes at room temperature, 1.48 g (0.012 mole) of allyl bromide was added. Then the mixture was reacted for 2 hours under the same conditions. The tetrahydrofuran was distilled off under reduced pressure, and cold water was added. The resulting oil layer was extracted with benzene. The benzene layer was separated, dried over anhydrous magnesium sulfate, and concentrated to afford a white solid. Recrystallization from methanol afforded compound No. 27 in Table 2 in a yield of 35%.
Reaction SMILES: C(Cl)Cl.Br[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:16]=[C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])[NH:14][N:13]=2)[C:8]([Cl:21])=[CH:7][N:6]=1.[C:22]([NH:26][S:27]([C:30]1[S:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([NH:26][S:27]([C:30]1[S:34][C:33]([C:5]2[N:10]=[C:9]([NH:11][C:12]3[CH:16]=[C:15]([C@@H:17]4[CH2:19][C@H:18]4[CH3:20])[NH:14][N:13]=3)[C:8]([Cl:21])=[CH:7][N:6]=2)=[CH:32][CH:31]=1)(=[O:28])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)s1
Reactant: C[C@@H]1C[C@H]1c1cc(Nc2nc(Br)ncc2Cl)n[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]1c1cc(Nc2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)ncc2Cl)n[nH]1
Temperature: 90 °C
Yield: 63.2 %

Procedure:
The mixture of Pd(dppf)Cl2.CH2Cl2 (74 mg, 0.09 mmol, 0.15 eq.), 2-bromo-5-chloro-N-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.61 mmol, 1.0 eq), 5-(N-tert-butylsulfamoyl)thiophen-2-ylboronic acid (192 mg, 0.73 mmol, 1.2 equiv.) and saturate Ka2CO3 (5 mL) in dioxane (10 mL) was heated to 90° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to rt, and extracted with THF. The combined layers were purified by silica gel chromatography (EtOAc/Petroleum ether from 10:1 to 2:1) to afford compound N-tert-butyl-5-(5-chloro-4-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (180 mg, 63%).