Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:34]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:33])[N:22]=[CH:23][C:24]=4[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl.O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[N:34]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:33])[N:22]=[CH:23][C:24]=4[C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[O:26])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCOCC5)cnn4C)ccn3n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(O)c3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (Example 75) (2.7 g, 5.86 mmol) in DCM (50 ml) was added a solution of boron tribromide in DCM (1 M solution; 15 ml, 14.6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 4 h under nitrogen atmosphere. The mixture was diluted with water (100 ml) and stirred for 15 min. The resultant precipitated solid was filtered, washed thoroughly with water and dried azeotropically with toluene (3×100 ml) to give 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide as off-white solid (2.5 g, 96%). LC-MS: m/z=448.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[C:25]([C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]#[C:25][C:27]4[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=4)=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: C#Cc1cnc(C)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#Cc3cnc(C)nc3)cc2c1=O
Temperature: 150 °C
Yield: 54 %

Procedure:
Compound D (50 mg, 0.13 mmol, 1.0 eq), 5-ethynyl-2-methyl-pyrimidine (30 mg, 0.26 mmol, 2.0 eq), copper(I) iodide (2.5 mg, 0.013 mmol, 0.010 eq), bis(triphenylphosphine)palladium(II) dichloride (4.5 mg, 0.0064 mmol, 0.050 eq) and triethylamine (53.6 μL, 0.38 mmol, 3.0 eq) were dissolved in DMF (1.3 mL) in a microwave vial and heated in a microwave reactor at 150° C. for 15 minutes. The reaction was purified directly using reverse phase chromatography to afford 30 mg (55%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.47 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.81-7.76 (m, 3H), 7.53 (t, J=8.7 Hz, 2H), 7.02 (d, J=8.80 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 2.66 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 428.2.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:14][CH2:13]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 4-(4-nitro-phenoxy)-piperidine (7.80 g, 35.1 mmol) and triethylamine (7.77 mL, 56.2 mmol) in DCM (100 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (3.26 mL, 42.1 mmol) and stirred cold for 1 hour. The mixture was diluted with DCM, washed with 1M HCl, a saturated NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated under vacuum to leave the title compound (9.10 g, 86% yield) as a yellow/orange solid. 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 4.68 (m, 1H), 3.39 (m, 4H), 2.84 (s, 3H), 2.05 (m, 4H). LCMS (m/z, Method A) ES+ 301.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1
Reactant: CCCCCCI
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCSc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 4-bromobenzenethiol (10.1 g), and to the solution was added at room temperature potassium carbonate (9.6 g). To the mixture was added dropwise 1-iodohexane (9.5 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 1-bromo-4-(hexylthio)benzene (14.2 g). In THF (127 ml) was dissolved 1-bromo-4-(hexylthio)benzene (14.1 g), and to the solution was added dropwise at −78° C. 1.6M n-butyllithium/hexane (35.5 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (16.1 g) in THF (32 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (70.5 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(hexylthio)phenyl borate (6.6 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[N:11]2)=[CH:6][CH:5]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2ccc(OC(F)(F)F)cc2)n1
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 2-(4-(trifluoromethoxy)phenyl)-2H-1,2,3-triazole-4-carboxylate (127 mg, 422 μmol, Eq: 1.00) in THF (5 ml) and MeOH (1.00 ml) was added LiOH 1M (843 μl, 843 μmol, Eq: 2). The mixture was stirred overnight. To the residue was added water and 1 N HCl (pH:1), this aqueous phase was extracted two times with ethyl acetate, the resulting organic layers were combined and washed with brine, then dried over MgSO4, filtered and concentrated to give the desired compound (94 mg, 81.6%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]1[C:37]([O:39][CH3:40])=[O:38])(=O)=O.Cl>CN(C)C=O.C(OCC)(=O)C.O>[C:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[N:7]([CH2:21][CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:26][CH:25]3[C:37]([O:39][CH3:40])=[O:38])[C:6]=2[CH:8]=1)#[N:13]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCOS(C)(=O)=O
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCN1C(=O)COc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (265 mg, 1.53 mmol) in dry dimethylformamide (DMF) (5 mL) was treated at 0° C. with sodium hydride (105 mg, 60% in oil, 2.63 mmol) and then stirred for 30 minutes at room temperature. A solution of 1-tert-butyl 3-methyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1,3-dicarboxylate in DMF (Intermediate 132, 0.31 mmol/mL, 5 mL, 1.53 mmol) was then added and the resulting mixture was stirred at room temperature for 96 hours. The reaction was diluted with ethyl acetate and water. The aqueous layer was adjusted to pH3 with 1N HCl. The layers were separated. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed four times with water, dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica gel with (10-35%) acetone in hexanes gave 445 mg (64%) of the product as a white semi-solid (as a mixture of diastereomers).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:11]2[C:19]3[NH:18][C:17](=[O:20])[NH:16][C:15]=3[CH:14]=[C:13]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:12]=2)[C:5]([CH:8]2[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[Cu][C:39]#[N:40].[C-]#N.[Na+]>O>[CH:8]1([C:5]2[C:4]([C:11]3[C:19]4[NH:18][C:17](=[O:20])[NH:16][C:15]=4[CH:14]=[C:13]([C:21]4[C:22]([CH3:27])=[N:23][O:24][C:25]=4[CH3:26])[CH:12]=3)=[CH:3][C:2]([C:39]#[N:40])=[CH:7][N:6]=2)[CH2:10][CH2:9]1
Reactant: Cc1noc(C)c1-c1cc(-c2cc(N)cnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: Cc1noc(C)c1-c1cc(-c2cc(C#N)cnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 5.6 %

Procedure:
4-(5-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (21 mg, 0.058 mmol) was suspended in a mixture of water (1 mL) and con. HCl (1 mL), cooled suspension to 0° C., a solution of sodium nitrite (4 mg, 0.058 mmol) in water was added slowly. After 5 mins, the reaction mixture was neutralised by the addition of NaHCO3 solution. Then the resultant suspension was added in aliquots to a solution of copper (I) cyanide (5 mg, 0.058 mmol) and sodium cyanide (6 mg, 0.11 mmol) in water at room temperature. Heated to 70° C. for 30 mins. Extracted with EtOAc, evaporated organic solvent, the residue was purified with Prep HPLC. (0-100% CH3CN/H2O) to afford 1.2 mg of 6-cyclopropyl-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)nicotinonitrile.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[C:23]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>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].CN(C=O)C>[ClH:1].[C:23]([C:26]1[S:30][C:29]([C:21]2[C:15]3[S:14][C:13]([C:11]([NH:10][C@@H:4]4[CH:5]5[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]5)[CH2:3]4)=[O:12])=[CH:17][C:16]=3[CH:18]=[CH:19][CH:20]=2)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)s1
Temperature: 85 °C
Reaction time: 14 h

Procedure:
100 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 42.3 mg (0.25 mmol) of 5-acetyl-2-thienylboronic acid are introduced into 1.5 ml of DMF. Addition of 0.37 ml of 2 M sodium carbonate solution and 9.11 mg (0.01 mmol) of PdCl2(dppf) is followed by heating to 85° C. After 14 h, the reaction mixture is filtered through kieselguhr and purified by preparative HPLC. The product fractions are concentrated, taken up in a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 52 mg (46% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:19][C:20]([CH3:29])([CH2:27][CH3:28])[CH2:21][CH2:22][C:23](OC)=[O:24]>C1COCC1.O.C(O)(=O)C>[CH3:19][C:20]([CH3:29])([CH2:27][CH3:28])[CH2:21][CH2:22][C:23](=[O:24])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCC(C)(C)CCC(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CCC(C)(C)CCC(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
Dimethyl methylphosphonate (5.89 g, 47.5 mmol) was dissolved in anhydrous THF (80 ml). To the resulting solution cooled to -78° C. under argon atomosphere, a solution of n-butyl lithium in hexane (1.63N, 29.1 ml, 47.5 mmol) was added and the mixture was stirred for 30 minutes. A solution of methyl 4,4-dimethylhexanoate (3.00 g, 19.0 mmol) in anhydrous THF (15 ml) was then added to the reaction mxiture at -78° C. and the mixture was stirred for 30 minutes. After warming the mixture to room temperature, acetic acid was added to neutralize the solution and a small quantity of water was then added, and concentrated. After ethyl acetate was added to the residue, the ethyl acetate layer was washed with water and with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to give oily product, dimethyl 5,5-dimethyl-2-oxoheptylphosphonate (3.38 g, 13.5 mmol, 71.1%, b.p.: 120°-122° C./0.18 mmHg). The structure was confirmed by the following data.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(OC)c(OC)cc4nc3OC)CC2)c1
Yield: 68 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 68%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.29 (m, 4H), 3.75-3.79 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 4.13 (s, 3H), 6.07-6.11 (m, 3H), 7.14 (s, 1H), 7.27-7.28 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH2:14][NH2:15])[CH:16]=[CH:17][CH:18]=2)[N:9]=[C:8]([C:19]([F:21])([F:20])[F:22])[CH:7]=1
Reactant: N#Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 53 (3 g, 9.89 mmol) in THF (50 mL) at 0° C. was added lithium aluminium hydride (0.939 g, 24.73 mmol). The resulting suspension was allowed to stir for 0.5 h. The reaction mixture was then warmed to room temperature and stirred for another 1 h. The following was added sequentially: 0.9 mL of water, 0.9 mL of 15% NaOH and 1.8 mL of water. The white solid was removed by filtration and the filtrate evaporated under vacuum. The title product 54 (3.04 g, 100% yield) was isolated as a pale yellow oil. Crude was used without any further purification. LRMS (ESI): calc. 307.3; found 308.4 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[S:20][C:21]([F:24])([F:23])[F:22])[NH2:16]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([S:20][C:21]([F:24])([F:22])[F:23])=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(SC(F)(F)F)c(F)c1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and 3-fluoro-4-trifluoromethylsulfanyl-aniline to afford a white crystalline solid. HPLC (Condition 4) tR=6.71 min, UPLC-MS (Condition 3) tR1.34 min, m/z=429 [M−H]−.
Reaction SMILES: [C:1]([C@@H:3]([NH:21][C:22]([C:24]1([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[NH:16][C:15]=3[CH:20]=2)=[CH:7][CH:6]=1)#[N:2].N>C(O)=O.O>[NH2:30][C:24]1([C:22]([NH:21][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:18][C:17](=[O:19])[NH:16][C:15]=4[CH:20]=3)=[CH:9][CH:10]=2)=[O:23])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4oc(=O)[nH]c4c3)cc2)CCOCC1
Agent: N
Solvent: O
Solvent: O=CO
Product: N#C[C@H](Cc1ccc(-c2ccc3oc(=O)[nH]c3c2)cc1)NC(=O)C1(N)CCOCC1

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 33, step (ii), 160 mg) was heated at 50° C. in formic acid (0.5 mL) for 10 min. The cooled solution was diluted with water (50 mL) and basified with ‘880’ ammonia and the resulting precipitate extracted into ethyl acetate (200 mL). The dried extract was concentrated to dryness and purified purified by reversed phase HPLC (using a SunFire column) eluting with methanol/0.1% aqueous trifluoroacetic acid. The pure fractions were freeze dried to afford the titled compound as a trifluoroacetatic acid salt (36 mg) TFA salt as a colourless solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11]C(C)([O-])C.[Na+].CI>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10]
Reactant: N#CCc1ccccc1I
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C#N)c1ccccc1I
Reaction time: 3 h

Procedure:
2-(2-Iodophenyl)acetonitrile (3.0 g, 12 mmol) and sodium tert-butoxide (3.6 g, 37 mmol) were stirred in 20 mL of DMF, and MeI (0.77 mL, 12 mmol) was added dropwise. The reaction was then stirred for 3 hours. The solvent was removed under vacuum. The crude residue was purified by silica flash chromatography 0-15% EtOAc/hexanes.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=3[N:23]=2)[CH2:9]1)=[O:7].Cl>CO>[O:13]=[C:11]1[N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=3[N:23]=2)[CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:12]1
Reactant: COC(=O)C1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1COc2ccc(N3CC(C(=O)O)CC3=O)nc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
An aqueous solution (0.1 ml) of lithium hydroxide monohydrate (8.62 mg, 0.206 mmol) was added to a solution of 5-oxo-1-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pyrrolidin-3-carboxylic acid methyl ester (40 mg, 0.137 mmol) in methanol (0.8 ml) and the mixture was stirred overnight at room temperature. The reaction solution was neutralized by adding 1N hydrochloric acid (0.206 ml), methanol was removed under reduced pressure, the obtained residue was triturated with water and the insoluble material was collected by filtration and dried to yield 32.9 mg (87%) of the title compound in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([C:18]([OH:20])=O)[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[NH2:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([C:18]([NH:26][C:22]4[S:21][CH:25]=[CH:24][N:23]=4)=[O:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccc2ccc(-c3ccnc(Cl)c3)nc12
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nccs1)c1cccc2ccc(-c3ccnc(Cl)c3)nc12
Temperature: 50 °C
Reaction time: 10 h
Yield: 79.1 %

Procedure:
A mixture of 2-(2-chloropyridin-4-yl)quinoline-8-carboxylic acid (285 mg, 1.0 mmol), thiazol-2-amine (100 mg, 1.0 mmol), HATU (760 mg, 2.0 mmol) and DIPEA (258 mg, 2.0 mmol) in DMF (10 mL) was stirred at 50° C. for 10 hours. The mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (3×25 mL), and the organic layer was dried over anhydrous Na2SO4, concentrated in vacuo and purified by chromatography on silica gel (5% Methanol in CH2Cl2) to give 2-(2-chloropyridin-4-yl)-N-(thiazol-2-yl)quinoline-8-carboxamide (290 mg, 79% yield).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][SnH:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.CC(C)=O>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Sn:18]([CH3:20])([CH3:19])[CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C=CCCCCS(=O)(=O)c1ccc(C)cc1
Reactant: C[SnH](C)C
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)CCCCCC[Sn](C)(C)C)cc1

Procedure:
The procedure described in Example 5 was employed except that 10.1 g (42.5 mmoles) of 5-hexenyl p-tolyl sulfone and 14.0 g (85 mmoles) of trimethyltin hydride were the reactants. The reaction mixture was irradiated for 232 hours. The excess trimethyltin hydride was allowed to evaporate from the reaction mixture under a flow of nitrogen. The unreacted 5-hexenyl p-tolyl sulfone was removed from the reaction mixture by distillation at 1×10-3 mm Hg leaving 3.25 g of crude product. Column chromatography of the distillation residue over silica gel, employing toluene and 1% acetone in toluene as eluents, afforded an oil, 6-(p-tolylsulfonyl)hexyltrimethylstannane. The presence of both the sulfonyl and trimethyltin moieties was indicated by the strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1285 cm-1 and 1140 cm-1 (--SO2 --) and 760 cm-1 [(CH3)3Sn--]. NMR showed the following:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16](I)[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.C[CH2:31][N:32](C(C)C)C(C)C.CN.C(Cl)Cl>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16]([NH:32][CH3:31])[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)c(I)c1C#N)c1ccc(F)cc1
Agent: CN
Solvent: ClCCl
Solvent: CCCCO
Product: CNc1c(F)c(Nc2cc(C3CC3)[nH]n2)nc(N[C@@H](C)c2ccc(F)cc2)c1C#N
Temperature: 185 °C
Yield: 51.4 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile (Example 134, 0.10 g, 0.19 mmol) and DIEA (0.03 g, 0.25 mol) in n-BuOH (1.5 ml) was added methylamine (2.0 M in THF, 1.9 mmol). The reaction was then heated to 185° C. under microwave conditions (1 hour×2 cycles). The reaction was then cooled to room temperature, DCM (10 ml) was added, and washed with 10% aqueous Na2S2O3. The organic layer was then dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.04 g, 49%). 1H NMR (400 MHz, CD3OD) δ 7.35 (br s, 2H), 7.04-7.00 (m, 2H), 5.95 (br s, 1H), 5.14 (br s, 1H), 3.15 (d, J=2.7 Hz, 3H), 1.87-1.82 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.95-0.94 (m, 2H), 0.65-0.63 (m, 2H). MS: Calcd.: 409; Found: [M+H]+ 410.