Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[CH:9]([CH3:11])[CH3:10].[Br:16][CH2:17][CH2:18][CH2:19]Br.[Cl-].[NH4+]>O1CCCC1>[Br:16][CH2:17][CH2:18][CH2:19][C:9]([CH3:11])([CH3:10])[C:8]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCBr
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 28.7 ml of diisopropylamine in 150 ml of tetrahydrofuran was added 126 ml of 1.6M n-butyllithium-hexane with stirring at -5° to 0° C. and the mixture was further stirred for 30 minutes. This reaction mixture was cooled to -78° C. and 26.7 ml of ethyl isobutyrate was added dropwise. The mixture was stirred for 1 hour, after which 41.8 g of 1,3-dibromopropane was added dropwise. The reaction mixture was stirred at -78° C. for 1 hour and then at room temperature for 2 hours. The mixture was then poured in aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was then distilled off and the residue was subjected to vacuum distillation to provide 40.3 g of the title compound as colorless oil. b.p. 76°-78° C./0.27 mmHg
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:65]1[CH2:69][CH2:68][C@H:67]([OH:70])[CH2:66]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([N:65]5[CH2:69][CH2:68][C@H:67]([OH:70])[CH2:66]5)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.8 %

Procedure:
To a solution of (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (0.10 g, 0.22 mmol) in DMF (2 mL) was added HATU (0.17 g, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.66 mmol) and the reaction was stirred for 20 minutes at ambient temperature. (S)-Pyrrolidin-3-ol (0.058 g, 0.66 mmol) was added, and the reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with EtOAc (30 mL) and washed with HCl (1 N, 10 mL), NaOH (1 N, 10 mL), water (10 mL), and brine (10 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by reverse preparative HPLC. The combined fractions were diluted with EtOAc (50 mL) and washed with 1N NaOH (10 mL), water (10 mL), and brine (10 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum to give (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((S)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.0353 g, 0.0678 mmol, 30.6% yield). Mass spectrum (apci) m/z=521.0 (M+H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[F:11][C:12]([F:21])([F:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16].[CH3:22]I.[OH-].[Li+].Cl>O1CCCC1.CO>[CH3:22][CH:14]([CH2:13][C:12]([F:21])([F:20])[F:11])[C:15]([OH:17])=[O:16]
Reactant: CI
Reactant: CCOC(=O)CCC(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CC(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
To sodium hexamethyldisilazane (0.945 M in tetrahydrofuran) (667 mL, 0.63 mol) in tetrahydrofuran (0.9 L) at -78° C., under nitrogen, was added a solution of ethyl 4,4,4-trifluorobutyrate (90.6 mL) in tetrahydrofuran (100 mL). After stirring for 1.5 hour, to the vigorously stirred mixture was added methyl iodide (112 mL) as fast as possible. The reaction was warmed with a 0° C. bath for 2 hours. Methanol (1 L) and 1N lithium hydroxide (1.2 L) were added and stirring continued for 48 hours. The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic phase was washed (brine), dried (MgSO4), and evaporated at 30° C. After combination with product from separate conversions of ethyl 4,4,4-trifluorobutyrate (97.79 g), distillation afforded 2-methyl-4,4,4-trifluorobutyric acid (173.24 g, 96%) as a brown solid-liquid contaminated with 4,4,4-trifluorobutyric acid and 2,2-dimethyl-4,4,4-trifluorobutyric acid; bp 48.0°-108° C. (9,900 Pa); GLC: tR =6.1 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19]5[N:20]([N:29]=[CH:30][N:31]=5)[C:21]([C:24]5[CH:25]=[N:26][NH:27][CH:28]=5)=[CH:22][N:23]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3]C1.BrC1N2N=CN=C2C(NC2C=CC(N3CCN(C4CC4)CC3)=CC=2)=NC=1>>[CH:4]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[C:19]5[N:20]([N:29]=[CH:30][N:31]=5)[C:21]([C:24]5[CH:25]=[N:26][NH:27][CH:28]=5)=[CH:22][N:23]=4)=[CH:15][CH:16]=3)[CH2:9][CH2:10]2)[CH2:1][CH2:3]1
Reactant: c1nc2c(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)ncc(-c3cn[nH]c3)n2n1
Agent: Brc1cnc(Nc2ccc(N3CCN(C4CC4)CC3)cc2)c2ncnn12
Product: c1nc2c(Nc3ccc(N4CCN(C5CC5)CC4)cc3)ncc(-c3cn[nH]c3)n2n1

Procedure:
This compound may be prepared using methods as described for Compound 46, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-(4-cyclopropylpiperazin-1-yl)-phenyl]amine. LCMS: Rt=0.84 (95%), m/z (ESI) 402 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5](OC)=[O:6].[CH3:12][N:13]1[CH:18]=[CH:17][C:16](=O)[O:15]C1=O>CN(C)C=O>[OH:15][C:16]1[CH:17]=[CH:18][N:13]([CH3:12])[C:5](=[O:6])[C:4]=1[C:3]([O:10][CH3:11])=[O:9]
Reactant: Cn1ccc(=O)oc1=O
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)ccn(C)c1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 39.9 %

Procedure:
Under ice cooling, 568 mg of sodium hydride (60%) was added to a mixture of 181 mg of dimethyl malonate and 70 ml of N,N-dimethylformamide, and the mixture was stirred for 20 minutes. After the mixture was heated to 80° C., 1.50 g of 3-methyl-2H-1,3-oxazine-2,6(3H)-dione was added to the mixture, followed by further stirring at 120° C. for 7 hours. The reaction mixture was concentrated under reduced pressure, 2 mol/L hydrochloric acid was added to the residue, and the mixture was stirred at 60° C. for 15 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 100 mg of methyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate represented by the formula:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:43])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:18]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:17][C:16]=2[N:15]([CH3:42])[C:13]1=[O:14])([O-])=O.O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:43])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:18]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:17][C:16]=2[N:15]([CH3:42])[C:13]1=[O:14]
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1N)c(=O)n2C

Procedure:
Prepared by treating 1-[2-(2-nitrophenyl)-2-oxoethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert-butyloxycarbonylamino)piperidin-1-yl]xanthine with powdered iron in a mixture of ethanol, water, and glacial acetic acid (150:50:14) at 90° C. Mass spectrum (ESI+): m/z=566 [M+H]+.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[O:20]=[S:21]1(=[O:46])[C:27]2[CH:28]=[C:29]([OH:33])[C:30]([Br:32])=[CH:31][C:26]=2[N:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:24][C:23]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:40][CH3:41])[CH2:22]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:46]=[S:21]1(=[O:20])[C:27]2[CH:28]=[C:29]([O:33][CH:2]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:30]([Br:32])=[CH:31][C:26]=2[N:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:24][C:23]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:40][CH3:41])[CH2:22]1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(O)cc2S(=O)(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C(=O)OCC)c3ccccc3)cc2S(=O)(=O)C1
Yield: 94.2 %

Procedure:
Ethyl α-bromophenylacetate (0.139 g), Na2CO3 (0.200 g) and tetrabutylammonium bromide (0.034 g) were added to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 96/16051; 0.200 g, 0.442 mmol) in MeCN (6 ml). The suspension was heated under reflux overnight before the solvent was removed under reduced pressure. The crude product was extracted (DCM/H2O) and purified by flash chromatography (Hex:EtOAc-5:1) to give the title compound 0.256 g (94%) as a white solid. NMR 0.65–0.85 (m, 6H), 0.95–1.65 (m, 8H), 3.00–3.15 (m, 2H), 3.50–3.80 (m, 2H), 3.70–3.80 (2s, 3H), 5.60 (s, 1H), 5.65 (d, 1H) 7.00–7.60 (m, 17H), 8.05–8.20 (2d, 1H).
Reaction SMILES: [Cl-].[Li+].O.[Cl:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]3[CH:25]([C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)C(OC)=O)=[N:12]2)=[CH:7][CH:6]=1>CS(C)=O>[Cl:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:16]([CH2:25][C:30](=[O:38])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:23]3=[O:24])=[N:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(C(=O)Cc1ccccc1)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cc1ccccc1)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
Lithium chloride (4.2 g) and water (1.8 cc) are added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of methyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-3-oxo-4-phenylbutanoate (3 g) in dimethyl sulphoxide (230 cc), and the reaction mixture is heated to reflux for 45 minute$. After the mixture is cooled to a temperature in the region of 40° C., ice-cold water (1500 cc) is added. After 15 minutes.varies. stirring, the solid which precipitates is separated by filtration, washed with distilled water (5×25 cc) and dried in the air. The solid obtained is purified by chromatography on silica gel (140 g) contained in a column 3.4 cm in diameter (eluent: dichloromethane/methanol (98:2 by volume)]. Elution is first performed with 200 cc of solvent: the corresponding eluate is discarded. Elution is then performed with 900 cc of solvent: the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa), at 40° C. After recrystallization in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(3-phenyl-2-oxopropyl)-1-isoindolinone (1.2 g), m.p. 182° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Br[CH:19]1[CH2:21][CH2:20]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH:19]1[CH2:21][CH2:20]1
Reactant: Oc1cc(F)ccc1Br
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OC2CC2)c1
Temperature: 220 °C
Yield: 94.2 %

Procedure:
To a stirred solution of 2-bromo-5-fluorophenol (1.0 g) in DMF (15 mL) in a microwave tube was added cesium carbonate (5.0 g), potassium iodide (130 mg) and bromocyclopropane (1.82 g). The mixture was heated in a microwave oven to 180° C. for 1 h, to 200° C. for 1 h and to 220° C. for 1 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.14 g of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][NH2:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:29]=1[O:30][CH2:31][C:32](Cl)=[O:33]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][NH:10][C:32]([CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:28]=2[Cl:27])=[O:33])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: CC1(C)CON(Cc2ccc(NN)cc2Cl)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NNC(=O)COc3ccc(Cl)cc3Cl)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 2-[(2-chloro-4-hydrazinophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone hydrochloride (1.5 g, 0.0049 mole) and triethylamine (1.4 ml) in tetrahydrofuran (100 ml) was cooled to 10° C. and 2,4-dichlorophenoxyacetyl chloride (0.80 g, 0.0067 mole) was added in one portion. The reaction mixture was stirred overnight at ambient temperature. Triethylamine hydrochloride was removed by filtration, and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 60:40 ethyl acetate:heptane. Appropriate fractions were combined and concentrated under reduced pressure. The residual solid was recrystallized from ethyl acetate:heptane to yield 2-[[2-chloro-4-[(2,4-dichlorophenoxy)methylcarbonylhydrazo]phenyl]methyl]-4,4-dimethyl-3-isoxaolidinone as a yellow solid; m.p. 149°-150° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:34]=[CH:33][C:9]([O:10][C:11]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=O)[C:18]([N+:30]([O-])=O)=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].O.O.[Sn](Cl)Cl.Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.CO.C(OCC)(=O)C>[CH2:1]([S:3]([C:6]1[CH:34]=[CH:33][C:9]([O:10][C:11]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][C:18]3[NH:30][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:21][C:19]=3[CH:20]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(NC(=O)c3ccccn3)c([N+](=O)[O-])cc2C(=O)OC)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C(=O)OC)cc1
Temperature: 80 °C

Procedure:
Methyl 2-[4-(ethylsulfonyl)phenoxy]-5-nitro-4-[(2-pyridinylcarbonyl)amino]benzoate (7.46 g) was suspended in dimethylformamide (37 ml) and methanol (37 ml), and tin(II) chloride dihydrate (17.3 g) and concentrated hydrochloric acid (15 ml) were added to it, and stirred under heat at 80° C. for 40 minutes. The reaction liquid was restored to room temperature, and gradually added to an aqueous sodium hydrogencarbonate solution and neutralized. Ethyl acetate was added to it, and stirred at room temperature for 30 minutes, and the formed salt was taken out through filtration. The filtrate was washed with water and saturated saline water. After dried, the solvent was evaporated away to obtain the entitled compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25](B(O)O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=4[N:7]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3ccc4[nH]ccc4c3)nc2N2CCOCC2)O1
Temperature: 120 °C
Yield: 16.7 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 5-indolylboronic acid (42 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated to 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 115 as a white solid (11 mg, 17%). LCMS: RT=4.37 min, [M+H]+=367. 1H NMR (400 MHz, CDCl3): δ 8.67 (1H, s), 8.28-8.20 (2H, m), 7.39 (1H, d, J=8.6 Hz), 7.23-7.19 (1H, m), 6.61 (1H, broad s), 3.91 (2H, s), 3.90-3.82 (8H, m), 1.48 (6H, s)
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(4-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.34 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.24 g, 34%). MS (ISN) 478.0 [(M−H)−]; mp 225° C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C@H:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8]1)=[O:6].CO.O1CCCC1>O>[C:22]([O:21][C:19]([N:9]1[CH2:10][C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[C@H:7]([C:5]([OH:6])=[O:4])[CH2:8]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Add lithium hydroxide (0.50 g, 12 mmol) to a solution of trans-4-(3-bromo-phenyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.80 g, 2.08 mmol) in a 1:2:1 mixture of MeOH:tetrahydrofuran:water (8 mL). Stir the mixture at room temperature for 3 h then concentrate under reduced pressure to remove volatile organics. Wash the concentrated aqueous mixture with EtOAc and then acidify to pH 5 using a 0.5 M solution of citric acid. Extract the mixture with EtOAc, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to provide 0.53 g of trans-4-(3-bromo-phenyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:23])[C:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2F)=[S:12])=[CH:6][CH:5]=1.CN(C=O)C>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:11]2[S:12][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:22])[N:13]=2)[CH3:23])=[CH:6][CH:5]=1
Reactant: CN(C(=S)NC(=O)c1ccncc1F)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)cc1)c1nc(=O)c2ccncc2s1
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
In an atmosphere of argon, a suspension of 167 mg of sodium hydride (60% oil suspension) in 1 ml of THF was added to a mixture of 1.230 g (3.80 mmol) of 1-(4-chlorophenyl)-3-(3-fluoroisonicotinoyl)-1-methylthiourea and 10 ml of DMF while being cooled over a water bath. The mixture was stirred for 10 minutes, and then stirred over a 110° C. oil bath for 5 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. The resulting residue was then poured into ice-water. The resulting precipitate was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was then recrystallized from ethanol to obtain 802 mg of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[4,3-e]-1,3-thiazin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Temperature: 135 °C
Yield: 26.6 %

Procedure:
A stirred mixture of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (220 mg, 0.67 mmol) from the previous step, (1R,2R)-2-amino-cyclohexanol (152 mg, 1 mmol), and DIEA (259 mg, 2.01 mmol) in DMA (5 mL) was heated at 135° C. for 2 h. The reaction mixture was cooled to rt, poured into water (30 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed sequentially with water and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified directly by preparative reverse-phase HPLC to afford (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (68 mg, 27%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.41 (m, 1H), 8.06 (m, 1H), 7.79 (m, 1H), 7.39 (s, 1H), 7.13-7.15 (m, 2H), 5.48 (s, 2H), 4.67 (d, J=3.9 Hz, 1H), 3.30-3.35 (m, 2H), 1.86-1.95 (m, 2H), 1.60-1.65 (m, 2H), 1.15-1.35 (m, 4H); LCMS (ESI) m/z 382 (M+H)+.