Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CS([O-])=O.[Na+].C1OCCOCCOCCOCCOCCOC1>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:20]([CH3:19])(=[O:22])=[O:21])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: CS(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CS(=O)[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Cc1ccc(Br)cn1
Reaction time: 1 h
Yield: 80 %

Procedure:
Commercially available (5-bromopyridin-2-yl)methanol (2000 mg, 10.6 mmol) in CH2Cl2 (20 mL) is treated with di-isopropylethylamine (2.8 mL, 16 mmol) and methane sulfonylchloride (1.0 mL, 12.8 mmol) stirred for 1 hour and the solvent removed under reduced pressure. The crude solid is dissolved in dimethylformamide (10 mL) and treated with sodium methanesulfinate (4.39 g, 42.5 mmol), 18-crown-6 (580 mg, 2.13 mmol) and the mixture stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate (20 mL), washed with water (20 mL) and brine(20 mL), dried over MgSO4, filtered, concentrated, and the crude material purified by column chromatography on silica gel eluting with a gradient of ethyl acetate/heptane to afford the title compound (2.12 g): m/z (Cl) 251 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:18][O:19]C)[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11]>Br>[Cl:1][C:2]1[N:3]=[C:4]([CH2:18][OH:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: COCc1nc(Cl)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Agent: Br
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(CO)nc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.4, 380 mg, 1.29 mmol, 1.00 equiv) in HBr (40% in AcOH) (10 mL). The solution was stirred overnight at 80° C., then cooled and concentrated under reduced pressure. The crude residue was purified by prep-HPLC (WATER WITH 0.05% TFA and CH3CN (0% CH3CN in 3 min, then up to 100% for 5 min, down to 0% in 1 min); Detector, 254 & 220 nm. The fractions containing clean product were combined and lyophilized to yield 171 mg (50%) of the title compound as yellow crude oil.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[C:32]([F:35])([F:34])[F:33])=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:18][CH:19]=2)=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:27]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(F)cc3C(F)(F)F)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(F)cc3C(F)(F)F)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 76A. mp 125-127° C.; IR (KBr) cm−1: 3132, 3032, 1742, 1708, 1244, 1110; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.71-7.81 (m, 1H), 7.65 (dd, 1H, J=9.3, 2.6 Hz), 7.51-7.61 (m, 1H), 7.01-7.19 (m, 3H), 6.81-6.91 (m, 2H), 6.57 (d, 1H, J=8.5 Hz), 5.11 (s, 2H), 4.61 (s, 2H), 3.95 (s, 2H), 2.75 (t, 2H, J=7.4 Hz), 2.66 (t, 2H, J=7.4 Hz), 1.89 (pentet, 2H); MS m/z 502 (M−1). Anal. Calc'd for C26H22F4O4S: C, 61.65; H, 4.38. found: C, 61.28; H, 4.12.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=O)(C)(C)C.[ClH:34]>ClCCl.C(O)C>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1.[ClH:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reaction time: 1 h

Procedure:
3-(4-((3S)-3-t-Butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (2.1 g, 4.54 mmol) was suspended by stirring in dichloromethane (10 ml) under nitrogen and treated with a solution of hydrogen chloride in ethanol (4M, 50 ml) at ambient temperature. The mixture was stirred 1 hour, evaporated to a small volume, and treated with a mixture of dichloromethane (30 ml) and diethyl ether (30 ml). The precipitate was filtered and washed with diethyl ether to give the title compound as its hydrochloride (2.0 g).
Reaction SMILES: C([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH2:19][CH2:20][OH:21])[C:12]([CH3:23])([CH3:22])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[K+]>>[OH:9][CH:10]1[CH2:15][C:14]([CH3:16])([CH3:17])[N:13]([O:18][CH2:19][CH2:20][OH:21])[C:12]([CH3:23])([CH3:22])[CH2:11]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OCCO
Agent: [K+]
Agent: [OH-]
Product: CC1(C)CC(O)CC(C)(C)N1OCCO

Procedure:
The title compound is prepared by heating a methanolic solution of the compound obtained in Example 69 with potassium hydroxide.
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])[CH:2]=[CH2:3].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH2:16][CH2:15][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OCC)OCC)C(=O)CCl
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCN(CC1OCCCO1)C(=O)CCl

Procedure:
N-Allyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), propandiol-1,3 (3 ml) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-allyl-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide.
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1.[C:17]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:16][C:2]1([F:1])[C:7](=[O:8])[N:6]([CH3:17])[C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2OC1(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(F)(F)Oc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
To a stirred suspension of 2,2-difluoro-7-nitro-4H-1,4-benzoxazin-3-one (WO 99/40094,2.16 g, 9.38 mmol) in DMF (10 mL) is added K2CO3 (1.94 g, 14.07 mmol) followed by addition of Mel (0.87 mL, 14.07 mmol). The resulting solution is stirred over night at room temperature. To this reaction mixture is added water (50 mL), and the resulting solution is extracted with EtOAc (50 mL×3). The combined organic phases are washed with water (50 mL) and saline (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound that is purified by passing through a short silica gel column with EtOAc (1.3 g, 57%), 1H NMR (300 MHz, DMSO) δ 8.25-8.17 (m, 2H), 7.62 (d, 1H), 3.47 (s, 3H).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15](O)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O.Cl>C(OCC)(=O)C>[Cl:26][C:15]1[N:14]=[CH:13][N:12]=[C:11]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:16]=1
Reactant: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-hydroxypyrimidin-4-yl)propanoate (1.00 g) and DMF (66 μL) in ethyl acetate (11 mL) was added oxalyl dichloride (1.11 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. A small amount of 1N hydrochloric acid was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (929 mg) as a colorless oil.
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2C=CC=C[C:9]=2[C:14]2C(OC)=CC=CC=2OC)CCCCC1.[CH2:30]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39](I)[C:40]=1[O:41]COC)[CH:36]=[O:37])[CH3:31].C1(B(O)O)CC1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.O.C1(C)C=CC=CC=1>[CH:14]1([C:39]2[CH:38]=[C:35]([CH:34]=[C:33]([O:32][CH2:30][CH3:31])[C:40]=2[OH:41])[CH:36]=[O:37])[CH2:9][CH2:8]1
Reactant: CCOc1cc(C=O)cc(I)c1OCOC
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOc1cc(C=O)cc(C2CC2)c1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 594.5 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (2.30 g) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (2.21 g) were added to a mixture of 3-ethoxy-5-iodo-4-(methoxymethoxy)benzaldehyde (12.1 g), cyclopropylboronic acid (9.25 g), a 2 M aqueous sodium carbonate solution (53.9 mL), and toluene (60 mL), and the resultant mixture was stirred at 100° C. for 2 hours in an argon atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a purified product. 6 M hydrochloric acid (50 mL) was added to a methanol (100 mL) solution of the obtained purified product, and the mixture was stirred at 70° C. for 3 hours, and then, the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (6.60 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29]>N1CCCCC1.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=[C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20][C:21]2=[O:29])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)OC)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)c(CCC(=O)OC)c1C
Temperature: 10 °C
Yield: 75.1 %

Procedure:
5-Formyl-4-(2-methoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (80.2 g), 2-oxindole (37.9 g) and ethanol (300 mL) were warmed to 70° C. in a 500 mL, 3-neck round bottom flask equipped with mechanical stirring and a reflux condenser. Piperidine (1.3 g) was added and the mixture was refluxed for 4 hours. The mixture was cooled to 10° C. and the orange precipitate collected by vacuum filtration and washed with 30 mL of ethanol. The solid was slurry-washed in 150 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 81.7 g (75%) of 4-(2-Methoxycarbonylethyl)-3-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as an orange solid.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[CH3:16]N(C)C=O.[OH-].[Na+].CI>O>[CH3:16][N:2]1[C:3](=[O:15])[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1]1
Reactant: CN(C)C=O
Reactant: O=c1[nH]nc2n1C=Cc1ccccc1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: Cn1nc2n(c1=O)C=Cc1ccccc1C2

Procedure:
To a solution of 8 parts of 2,11-dihydro-3H-s-triazolo-[3,4-b][3]benzazepin-3-one in 80 volume parts of dimethylformamide is added 9 volume parts of 5N aqueous sodium hydroxide solution and then 3 volume parts of methyl iodide is added dropwise under stirring. After stirring for 1 hour, the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and the solvent is distilled off. The precipitate is collected by filtration to give 2,11-dihydro-2-methyl-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from isopropyl ether gives light-brown needles melting at 123° -124° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH2:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:56]>C(Cl)Cl.CCOC(C)=O.CO>[CH3:60][C:59]([CH3:62])([CH3:61])[CH2:58][O:57][C:55](=[O:56])[NH:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:43][CH2:44]3)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: CC(C)(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)COC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a mixture of cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl]-amide bis hydrochloride (50 mg, 0.075 mmol) in 2 mL of DCM was added 44 μL (0.25 mmol) of DIPEA and 15 mg (0.1 mmol) of neopentyl chloroformate. The mixture was stirred at rt for 2 h. It was then diluted with EtOAc and washed with pH 4 buffer (2×) and brine (1×). The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. The resulting oil was dissolved in methanol and purified by preparative HPLC (YMC XTERRA, S5, 30×50 mm, gradient: 65% B to 100% B, 15 min, hold 2 min, flow rate 40 mL/min) to isolate the product as a white powder (42 mg, 79%): LC-MS (Method A, retention time: 3.58 min), MS m/z 710 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)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:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Reactant: COc1ccc(B(O)O)cn1
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)cn1
Yield: 59.8 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 6-methoxypyridin-3-ylboronic acid (66 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in hexanes) to yield the product (72 mg, 62%). ESI-MS m/z calc. 401.17. found 402.5 (M+1)+. Retention time 1.86 minutes.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)=[N:9][C:10]([C:13]2[S:14][C:15]([S:18](=[O:25])(=[O:24])[NH:19]C(C)(C)C)=[CH:16][CH:17]=2)=[N:11][CH:12]=1)(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)=[N:9][C:10]([C:13]2[S:14][C:15]([S:18](=[O:24])(=[O:25])[NH2:19])=[CH:16][CH:17]=2)=[N:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCc1cnc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
The solution of 2-(2-(5-(N-tert-butylsulfamoyl)thiophen-2-yl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-5-yl)ethyl acetate (300 mg, 0.6 mmol) in CF3COOH (5 mL) was stirred at 60° C. After 1 h, the solution was evaporated to afford 2-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-(5-sulfamoylthiophen-2-yl)pyrimidin-5-yl)ethyl acetate (Compound 313) (250 mg, 93%). LC-MS (m/z)=449 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.76 (m, 2H), 0.98-0.99 (m, 2H), 1.94 (m, 1H), 1.99 (s, 3H), 2.98 (s, 2H), 4.20 (s, 2H), 6.47 (s, 1H), 7.59 (s, 1H), 7.76 (d, J=2.8 Hz, 1H), 7.81 (s, 2H), 8.16 (s, 1H), 9.44 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=4)=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A mixture of 301.6 mg of 3,5-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred in 2 ml of methylene chloride while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. The reaction mixture is stirred at room temperature for 2 hours and 100 mg of 3,5-dichlorobenzoyl chloride added. The reactants are heated at reflux for 36 hours. The cooled reaction mixture layer washed with 1N HCl, water, 1N NaOH, water and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 242 mg of the desired product as a crystalline solid, m.p. 263°-265° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:16]=1[N:26]1[C:30]([CH2:31][CH3:32])=[C:29]([CH2:33]O)[C:28]([CH2:35][CH3:36])=[N:27]1.C(N(CC)CC)C.CS(Cl)(=O)=O>CCOCC>[CH2:35]([C:28]1[C:29]([CH2:33][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]=2[OH:11])=[C:30]([CH2:31][CH3:32])[N:26]([C:16]2[C:15]([Cl:14])=[CH:20][C:19]([C:21]([F:22])([F:24])[F:23])=[CH:18][C:17]=2[Cl:25])[N:27]=1)[CH3:36]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CO
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1Cc1c(O)ccc2ccccc12
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of 303 mg (2.1 mmol) of 2-naphthol in 5 mL of dry ether was treated with 50 mg (2.1 mmol) of sodium hydride and the mixture was stirred for 15 minutes. A solution of 368 mg (1.0 mmol) of the compound of step C in 5 mL of dry ether and 126 mg (0.174 mL, 1.22 mmol) of triethylamine was cooled to 0° C. and treated with 114 mg (0.077 mL, 1.0 mmol) of methanesulfonyl chloride. Triethylamine hydrochloride was removed by filtration and the filtrate was added to the above suspension of sodium 2-naphthoxide and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then partitioned between water and ether and the organic extracts were dried and evaporated to give the desired product in 29% yield. 1H-NMR (CDCl3) δ 1.00 (3H, t, J=7),1.20 (3H, t, J=7), 2.44 (2H, q, J=7), 2.72 (2H, q J=7), 4.58 (2H, s), 6.96-7.84 (8H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:26])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10](=[O:24])[C:9](Br)=[CH:8]2)=[O:4].[C:27]1([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:26])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10](=[O:24])[C:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccc(OC)cc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccc(OC)cc2)c1O
Temperature: 120 °C
Yield: 78.2 %

Procedure:
A mixture of 3-bromo-5-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (180 mg, 0.43 mmol), PhSnBu3 (0.17 mL, 0.52 mmol), and PdCl2(PPh3)2 (60 mg, 0.086 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (20 mL) were added. 0.1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 140 mg of the title compound as a light yellow solid. MS: (+) m/z 417.30 (M+1).