Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)[NH2:6].Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH:20]=[C:19]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1([CH2:24][NH:23][C:21]2[CH:20]=[C:19]([CH2:28][O:29][CH2:30][C:31]([F:33])([F:34])[F:32])[N:18]=[C:17]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:22]=2)[CH2:27][CH2:26]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: FC(F)(F)COCc1cc(NCC2CC2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(NCC3CC3)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C

Procedure:
A mixture of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (99 mg, 0.49 mmol), 2-chloro-N-(cyclopropylmethyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (72 mg, 0.24 mmol), cesium carbonate (159 mg, 0.49 mmol), palladium(II) acetate (8.20 mg, 0.04 mmol) and 2-(dicyclohexylphosphino)biphenyl (12.80 mg, 0.04 mmol) in dioxane (1.5 mL) was heated at 120° C. by microwave irradiation under nitrogen atmosphere for 90 minutes. The mixture was filtered through diatomeous earth, the pad was eluted with methanol. The eluate was concentrated and the residue was purified by preparative chromatography to give the title compound as a dry film, 65 mg (58%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(=O)N1c2ccccc2[C@@H](O)C[C@@H]1C
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc(F)cc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
50 mg of trans-1-acetyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline, 112 mg of 4-fluorophenol, 126 mg of 1,1-azodicarbonyldipiperidine, and 125 mg of tributylphosphine were dissolved in 2 mL of toluene, and the solution was stirred for 2 hours at 50° C. The reaction liquid was filtered to remove any insoluble materials, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (diethyl ether), and thus 26 mg (yield 36%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](O)=[O:9])=[CH:4][N:3]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1
Reactant: Cc1ncc(C(=O)O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc(CO)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of 2-methylpyrimidine-5-carboxylic acid (150 mg, 1.23 mm01) in ethanol (5 mL) was added sodium borohydride (93 mg, 2.46 mmol). The mixture was stirred at room temperature for 3 h. It was quenched with aqueous HCl (2 N, 2 mL), extracted with DCM, dried over sodium sulfate, filtered and concentrated give the yellow oil product (2-methylpyrimidin-5-yl)methanol (95 mg, 62.6%). LCMS MH+ 125.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2[N:25]=[C:26]([NH2:29])[S:27][CH:28]=2)[CH:21]=[C:20]([Cl:30])[N:19]=1>C(#N)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2[N:25]=[C:26]([NH:29][C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:15])([F:1])[F:16])(=[O:11])=[O:10])=[O:14])[S:27][CH:28]=2)[CH:21]=[C:20]([Cl:30])[N:19]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1
Solvent: CC#N
Product: O=C(Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1)NS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 93.8 %

Procedure:
7.53 g (0.03 mol) of 2-trifluoromethylphenylsulphonyl isocyanate are added to a solution of 7.38 g (0.03 mol) of [4-(2,6-dichloropyridin-4-yl)-thiazol-2-yl]-amine in 180 ml of acetonitrile at 75° C. in the course of 5 minutes, while stirring. The reaction mixture is stirred at 75° C. for a further 3 hours and then cooled to room temperature, and the solid which has precipitated out is filtered off with suction, washed twice with 10 ml of acetonitrile each time and dried at 45° C. under reduced pressure. 14 g (93.9% of theory) of N-[4-(2,6-dichloro-pyridin4-yl)-thiazol-2-yl]-N'-(2-trifluoromethyl-phenylsulphonyl)-urea are obtained in this manner in the form of a solid substance with a melting point of >280° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:12]([O:14]CC)=O.[C:17]([O:20][C:21](=O)[CH3:22])(=[O:19])[CH3:18].Cl>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:12](=[O:14])[CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1c(F)cccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1c(F)cccc1Cl
Yield: 35.8 %

Procedure:
Into a mixture of 9.6 g of sodium hydride (60% in oil) and 200 ml of tetrahydrofuran, 21.7 g of ethyl 2-chloro-6-fluorophenylacetate were added dropwise under reflux. Then, a solution of 12.3 g of acetic anhydride in 40 ml tetrahydrofuran was added thereto and refluxed under heating for 10 hours. The reaction mixture was cooled, poured into iced dil. hydrochloric acid and extracted with t-butyl methyl ether. The organic layer was washed with dil. hydrochloric acid, aqueous saturated sodium bicarbonate solution, dil. hydrochloric acid and water, subsequently, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 9.27 g of ethyl (2-chloro-6-fluorophenyl)acetoacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[OH:12].[Br:13]N1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[Br:13][C:4]1[C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:12]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc([N+](=O)[O-])c(C)c(Br)c1O
Yield: 72.8 %

Procedure:
Into a magnetically stirred suspension of 2,5-dimethyl-4-nitrophenol (12.70 grams, 75.98 mmol) in CH2Cl2 (150 milliliters) at room temperature was added portionwise N-bromosuccinimide (14.88 grams, 83.58 mmol). The mixture rapidly became homogeneous and after one hour thin layer chromatography (3:1 hexane:ethyl acetate) indicated complete consumption of the starting material and formation of a single major product. Saturated Na2SO3 solution (15 milliliters) was added and the solvent was removed under reduced pressure. Ethyl acetate was then added and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford 2-bromo-3,6-dimethyl-4-nitrophenol (13.6 grams, 55.3 mmol, 73%) as a rust colored solid. H'-NMR (CDCl3) 9.26 (brS, 1H), 7.71 (S, 1H), 2.60 (S, 3H), 2.31 (S, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14](=[O:34])[CH2:15][CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH2:18][CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C1C=C(C(C)C)C(S([N:50]=[N+:51]=[N-:52])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14](=[O:34])[CH:15]([N:50]=[N+:51]=[N-:52])[CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][Si:24]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:33])[CH3:32])[CH2:18][CH2:17]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[Si](OCC1CCC(CC(=O)N2C(=O)OCC2Cc2ccccc2)CC1)(C(C)C)C(C)C
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)[Si](OCC1CCC(C(N=[N+]=[N-])C(=O)N2C(=O)OCC2Cc2ccccc2)CC1)(C(C)C)C(C)C
Yield: 52 %

Procedure:
Acyl oxazolidinone (1.28 g, 2.62 mmol) from Step G in 30 mL of THF at −78° C. was treated with 5.8 mL (2.89 mmol) of a 1.5 M solution of potassium hexamethyldisilylamide in toluene followed by 973 mg (3.14 mmol) of trisyl azide in 6 mL of THF and quenched by the addition of 634 mg (10.5 mmol) of acetic acid according to the procedure of D. A. Evans et al., J. Amer. Chem. Soc. 1990, 10, 4011. Purification by Biotage chromatography on silica gel (25% ether/hexane) provided 720 mg (52%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.39–7.24 9 (m, 5H), 5.12 (d, 0.3H, J=8.7 Hz), 4.97 (d, 0.7H, J=7.5 Hz), 4.72 (m, 1H), 4.25 (m, 2H), 3.61 (d, 0.6H, J=7 Hz), 3.51 (d, 1.4H, J=5.9 Hz), 3.33 (dd, 1H, J=3 and 4 Hz), 2.87 (dt, 1H, J=3 and 10 Hz), 2.0–1.4 (m, 8H), 1.07–0.9 (m and d, 24H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=1.CCCCCCC>CCO.C(Cl)Cl.[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:1])=[N:3][N:4]2[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:9][CH:8]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCO
Product: Cc1nn(C(=O)OC(C)(C)C)c2cc(N)ccc12
Reaction time: 6 h
Yield: 69.2 %

Procedure:
tert-Butyl 3-methyl-6-nitro-1H-indazole-1-carboxylate (7.40 g, 26.7 mmol) was dissolved in EtOH (534 mL). To the solution was added Pd/C (10 wt %, 1.42 g, 1.33 mmol). The mixture was flushed with H2, and placed under an atmosphere of H2 at atmospheric pressure at rt for about 6 h. The mixture was filtered through Celite® and washed through with MeOH. The solvents were removed under reduced pressure. The residue was purified by column chromatography (120 g silica gel) eluting with 20-80% EtOAc/heptane to give a solid. The solid redissolved in DCM (20 mL) and heptane (50 mL) was added. The mixture was concentrated to remove the DCM. The resulting precipitate was collected by vacuum filtration and washed with heptane (20 mL) to provide tert-butyl 6-amino-3-methyl-1H-indazole-1-carboxylate (4.57 g, 69%): LCMS (Table 2, Method c) Rt=1.81 min.; MS m/z: 248 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J=8.5 Hz, 1H), 7.14 (d, J=1.7 Hz, 1H), 6.59 (dd, J=8.5, 1.9 Hz, 1H), 5.71 (d, J=19.5 Hz, 2H), 2.33 (s, 3H), 1.58 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH:14]([CH3:15])[C:5]=3[C:4]=2[CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH:14]([CH3:15])[C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CC1c2c([nH]c3ccc(Cl)cc23)CCN1C
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC1c2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)CCN1C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-1,2-dimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:32]([C:35]1[C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37][C:36]=1[O:43][C:44]1[CH:45]=[C:46]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:47]#[N:48])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:37]2[C:36]([O:43][C:44]3[CH:45]=[C:46]([CH:49]=[C:50]([CH3:52])[CH:51]=3)[C:47]#[N:48])=[C:35]([CH:32]([CH3:33])[CH3:34])[C:40](=[O:41])[NH:39][C:38]2=[O:42])[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1ccc(CNc2cc(CO)cc(F)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Yield: 47.8 %

Procedure:
[2-Fluoro-6-(4-methoxy-benzylamino)-pyridin-4-yl]-methanol (262 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with 3-(5-Isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzonitrile (285 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:1)) to afford 253 mg (47%) of a colorless syrup. 1H NMR (200 MHz, CDCl3/CD3OD) δ 1.09 (6H, d, J=6.8 Hz), 2.32 (3H, s), 2.62 (1H, m), 3.80 (3H, s), 4.32 (2H, s), 4.70 (2H, s), 5.97 (1H, s), 6.24 (1H, s), 6.74-6.92 (3H, m), 7.18-7.32 (4H, m).
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([F:35])[CH:29]=1.[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([CH2:36][CH2:37][CH3:38])=[CH:40][CH:41]=2)=[S:49])=[C:30]([F:35])[CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: CCCc1ccc(C(=O)Cl)cc1
Agent: CCCc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-Propyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-propyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-propyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, 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 (74 mg, yield 90%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11]C(=O)OCC)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=4)=[C:20]([O:39][CH3:40])[CH:19]=3)[C:5]2=[N:6][CH:7]=1.[CH3:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1>CN(C)C=O.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-].[Cl-].[Fe+2].[Pd+2]>[CH3:40][O:39][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:38])([F:37])[C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=1)[CH2:17][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:45]3[CH:44]=[N:43][N:42]([CH3:41])[CH:46]=3)[CH:3]=[C:4]2[N:10]=[C:9]1[NH2:11]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(C(F)(F)C(F)(F)F)cc2)c(OC)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(Cn2c(N)nc3cc(-c4cnn(C)c4)cnc32)ccc1OCc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 13.8 %

Procedure:
To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.090 g, 0.13 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.054 g, 0.26 mmol) in N,N-dimethylformamide (3 mL) and 2M aqueous sodium carbonate solution (150 μL) was added (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.050 g, 0.06 mmol). The resulting mixture was heated to 80° C. under a nitrogen atmosphere. After 4 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to afford 0.010 g (14%) of the product as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 2H), 7.84 (s, 1H), 7.72-7.70 (m, 2H), 7.66-7.64 (m, 2H), 7.58 (d, J=1.6 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 6.95-6.89 (m, s 3H), 6.72 (d, J=6.8 Hz, 1H), 5.19 (s, 2H), 5.15 (s, 2H), 3.85 (s, 3H), 3.73 (s, 3H) ppm; (M+1)=559.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12](O)=[O:13])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27]>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][NH:27][C:12]([C:11]1[C:2](=[O:1])[NH:3][C:4]2[C:9]([C:10]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:13]
Reactant: O=C(O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(-c2ccccc2)c2ccccc2[nH]c1=O

Procedure:
1,2-Dihydro-2-oxo-4-phenyl-3-quinolinecarboxylic acid was reacted with 3,5-bis(trifluoromethyl)benzylamine by a method similar to Example 101 (amidation) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][O:22]C4CCCCO4)[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[N:11]=[C:10]2[O:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=2)=[N:6][CH:7]=1.C(Cl)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][OH:22])[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[N:11]=[C:10]2[O:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:43])[F:44])[CH:36]=2)=[N:6][CH:7]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cn1
Solvent: CCO
Solvent: CC(=O)Cl
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a solution of 7-((5-chloropyridin-2-yl)methyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (80 mg, 0.14 mmol) in ethanol (5 mL) was added acetyl chloride (0.2 mL) at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give crude product which was purified by preparative HPLC to give 7-((5-chloropyridin-2-yl)methyl)-1-(3-hydroxypropyl)-3-methyl-8-(2-(3-(trifluoromethoxy)phenoxy)ethoxy)-1H-purine-2,6(3H,7H)-dione (15 mg, 19.0% yield) as white solid. 1H-NMR (CD3OD) δ 8.33(d, 1H), 7.70(dd, 1H), 7.35(t, 1H), 7.26(d, 1H), 6.87(dd, 1H), 6.76(s, 1H), 5.43(s, 2H), 4.86-4.87(m, 2H), 4.33-4.35(m, 2H), 4.04(t, 2H), 3.56(t, 2H), 3.54(s, 3H), 1.80-1.85(m, 2H). LCMS retention time 2.606 min; LCMS MH+ 570.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24](C(OC(C)(C)C)=O)[CH2:25][C:18]=2[C:17]=1[F:34])=O)(C)(C)C.C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[C:42]2[N:47]([CH:48]=1)[CH2:46][CH2:45][O:44][CH2:43]2)CCC.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]>C1(C)C=CC=CC=1.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>[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[CH:41]=[C:42]3[N:47]([CH:48]=2)[CH2:46][CH2:45][O:44][CH2:43]3)[C:19]2[C:23](=[O:33])[NH:24][CH2:25][C:18]=2[C:17]=1[F:34]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2n(c1)CCOC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3n(c2)CCOC3)c2c(c1F)CNC2=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 7-(tributylstannyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (124 mg, 0.301 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. Following work-up, the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, was purified by preparative HPLC eluting with a gradient of 55-95% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined and the solvent stripped by rotary evaporation to give a solid intermediate. The intermediate was subsequently dissolved in TFA (3 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 20-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (7.3 mg, 6.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=7.33 Hz, 2H), 1.59 (br s, 1H), 1.63-1.92 (m, 4H), 3.98 (d, J=1.77 Hz, 3H), 4.26-4.46 (m, 3H), 4.74 (s, 2H), 6.54-6.71 (m, 2H), 7.74 (br s, 3H), 8.17-8.36 (m, 2H). ESI-MS m/z [M+H]+ calc'd for C20H24FN5O2, 386. found, 386.