Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([NH:18][CH:19]([CH3:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([NH:18][CH:19]([CH3:20])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:27])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3ccccc3c2n1NC(C)C
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1NC(C)C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (334 mg, 1.18 mmol) in 10 mL of CH2Cl2 was treated with 3-chloroperoxybenzoic acid (MCPBA) (77% max., 334 mg, 1.45 mmol). After stirring for 3 h, the reaction was quenched with saturated NaHCO3 solution and extracted into CH2Cl2. The organic portion was washed with saturated NaHCO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (338 mg) as a light brown solid.
Reaction SMILES: C(OC(=O)C(C1C=CC(/C=C/C(=O)NC2C=CC=CC=2NC(OC(C)(C)C)=O)=CC=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])C.[Br:42]CCO.[Si](Cl)(C(C)(C)C)(C)C>>[Br:42][CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCCBr
Reactant: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OCCBr

Procedure:
Key building block (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (II) can be prepared according to Scheme 6. Starting with commercially available 2-bromo-ethanol (XXIX), silylation with tert-butyldimethylsilyl chloride provides (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (XXX). Alkylation of the potassium enolate of (4-bromo-phenyl)-acetic acid ethyl ester with XXX furnishes 2-(4-bromo-phenyl)-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (XXXI). Heck reaction of XXXI with (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester gives key building block 2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-hydroxy-butyric acid ethyl ester (II).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)([O:19][CH2:20][O:21][CH3:22])[CH3:18])[N:14]=[C:13]([NH2:30])[N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]([C:17]([C:15]2[CH:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:35]5[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=5)[N:3]=4)[NH:8][CH:9]=3)[N:12]=[C:13]([NH2:30])[N:14]=2)([O:19][CH2:20][O:21][CH3:22])[CH3:18])[CH:28]=[CH:27][CH:26]=1
Reactant: COCOC(C)(c1cccc(F)c1)c1cc(-c2c[nH]c3ncc(Br)nc23)nc(N)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: CN(C)C=O
Product: COCOC(C)(c1cccc(F)c1)c1cc(-c2c[nH]c3ncc(-c4cnn(C)c4)nc23)nc(N)n1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-6-[1-(3-fluorophenyl)-1-methoxymethoxyethyl]pyrimidin-2-ylamine (0.249 g, 0.395 mmol) is dissolved in DMF (7 ml), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.164 g, 0.790 mmol) and Pd[PPh3]4 (0.046 mg, 0.040 mmol) are added, the reaction solution is flushed with nitrogen for 5 min, 2N Na2CO3 solution (1.5 ml) is subsequently added. The mixture is stirred at 130° C. for 1 h. The mixture is cooled to room temperature, ethyl acetate is added, and the organic phase is extracted three times with water, the aqueous phase is separated off, and the organic phase is dried over sodium sulfate. The solid is filtered off, and the residue is evaporated in vacuo. The residue is purified by RP-HPLC, giving 4-[1-(3-fluorophenyl)-1-methoxymethoxyethyl]-6-[2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]pyrimidin-2-ylamine (“A2”), (HPLC/MS Rt=1.72 min, [M+H] 475); 1H-NMR [DMSO-d6]: δ [ppm]=12.72 (br, 1H), 8.72 (s, 1H), 8.49 (m, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.43 (m, 1H), 7.32 (m, 2H), 7.13 (m, 1H), 4.79 (s, 2H), 3.95 (s, 3H), 3.37 (s, 3H), 1.98 (s, 3H);
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH:30]4[CH2:32][CH2:31]4)=[O:28])=[C:22]([CH3:33])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:34]#[N:35])C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[C:34]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH:30]2[CH2:32][CH2:31]2)=[O:28])=[C:22]([CH3:33])[CH:21]=1)#[N:35]
Reactant: Cc1cc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)ccc1NC(=O)NC1CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccnc3cc(O)c(C#N)cc23)ccc1NC(=O)NC1CC1
Yield: 77.5 %

Procedure:
In the same manner as Production Example 301-2, 1-[4-(7-benzyloxy-6-cyano-quinolin-4-yloxy)-2-methyl-phenyl]-3-cyclopropyl-urea (0.8 g) was debenzylated in tetrahydrofuran using palladium-carbon, to obtain the title compound (0.5 g) as a solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])[CH2:36][CH2:37][CH3:38].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:14](=[O:15])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[C:29]3[C:34]2=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:44][CH2:43]1)=[O:41])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 3 h

Procedure:
To a solution of 500 mg (S)-6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid in 7 ml DMF were added at 0° C. 172 mg piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate, 0.14 ml N-ethylmorpholine and 357 mg TOTU. After stirring for 3 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 650 mg.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1NCc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
4-Fluorobenzylamine (5.88 ml, 51.4 mmol) was added to a solution of 2-chloro-3-nitropyridine (8.16 g, 51.4 mmol) and sodium carbonate (8.72 g, 82,3 mmol) in anhydrous N,N-dimethylformamide (100 ml). The reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then filtered to discard an insoluble solid. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a saturated sodium chloride solution (100 ml) four times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give 11.5 g of the titled compound as yellow solid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].I[CH2:45][CH3:46]>C1COCC1.CN(C=O)C>[F:41][C:2]([F:40])([F:1])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[CH:25]([O:26][CH2:45][CH3:46])[CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCOCC2)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of (2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol (20.4 mg, 0.034 mmo) in THF (0.15 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 4.1 mg, 0.10 mmol). The mixture was stirred at room temperature for 30 minutes, recooled to 0° C. and DMF (5 drops) was added followed by iodoethane (8 μL, 0.10 mmol). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford the title compound (11.5 mg, 54%). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (m, 1H) 1.1 (t, J=7.1 Hz, 3H) 1.4(m, 2H) 1.7(m, 1H) 1.8(d, J=13.3 Hz, 1H) 3.2 (m, 4H) 3.9 (dd, J=11.6, 3.3 Hz, 1H) 4.0 (dd, J=11.4, 3.9 Hz, 1H) 4.2 (s, 3H) 4.2 (d, J=7.1 Hz, 1H) 4.7 (d, J=13.3 Hz, 1H) 4.7 (s, 2H) 4.9 (d, J=15.8 Hz, 1H) 7.3 (s, 1H) 7.6 (m, 2H) 7.6 (s, 2H) 7.8 (s, 1H). MS (ES+) Calc: 625.2, Found: 626.4 (M+1) According to the procedure described in example 33 and using the appropriate secondary alcohol and alkylating reagent, examples 34-40 were prepared.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([C:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:16])[CH:10]=[CH:11][C:12]=4[C:13]=3[N:14]=2)[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3n2)CC1
Temperature: 180 °C
Yield: 78.5 %

Procedure:
A 0.5 ml microwave vial was loaded with 2-bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamide (8 mg, 0.019 mmol), 1-Methylpiperazine (0.25 ml, 2.246 mmol) and NMP (0.25 ml), sealed and heated to 180° C. for 2 hours. Purification by prep HPLC, followed by filtration of the product containing fractions through gave a Waters MCX cartridge, washing with MeOH and elution with 2M NH3 in MeOH and drying gave 6.3 mg 2-(4-methylpiperazin-1-yl)-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamid. MS (ESI) m/e+=423, m/e−=421 consistent with [M+H]+ and [M−H]−. HPLC retention time 5.42 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (CD3OD) δ ppm 8.25 (d, 1H, J=8.3), 7.67 (b, 1H), 7.42 (s, 1H), 7.26 (dd, 1H, J=8.0, 1.2), 3.90-3.50 (m, 12H), 2.74-2.66 (m, 4H), 2.41 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([N:33]1[CH2:32][CH2:31][CH:30]([C:23]2[CH:22]=[C:21]3[C:26]([CH2:27][CH:28]([CH3:29])[N:19]([C:17]4[CH:18]=[C:13]([N:10]5[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]5)[N:14]=[C:15]([NH2:36])[N:16]=4)[CH2:20]3)=[CH:25][CH:24]=2)[CH2:35][CH2:34]1)(=[O:39])[CH3:38]
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and acetyl chloride. LCMS (M+H)+: m/z=464.4.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][CH2:13][C@H:14]([CH3:70])[NH:15][C:16](=[O:69])[C@@H:17]([NH:51]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:18][S:19][CH2:20][C@H:21]([O:37][C:38](=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:22][O:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>N1CCCCC1.C1COCC1.C(OC)(C)(C)C.C(OCC)(=O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][CH2:13][C@H:14]([CH3:70])[NH:15][C:16](=[O:69])[C@@H:17]([NH2:51])[CH2:18][S:19][CH2:20][C@H:21]([O:37][C:38](=[O:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:22][O:23][C:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)COCCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Solvent: C1CCNCC1
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)N[C@@H](C)COCCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(6S,9R,13R)-9-(((9H-fluoren-9-yl)methoxy)carbonylamino)-13-(dodecanoyloxy)-6-methyl-8,16-dioxo-4,15-dioxa-11-thia-7-azaheptacosylphosphonic acid diethyl ester (1 eq, from the previous step) in was dissolved in 20% piperidine in THF (0.1 M) and stirred at room temperature for 2 hours. The viscous reaction mixture was diluted in methyl tert-butyl ether and ethyl acetate. The organic layer was washed with 1:1 saturated aqueous NH4Cl/water (2×), brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-5% methanol in DCM to give the product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[Na+].[CH3:11][S:12]([O-:14])=[O:13]>O.C1COCC1.CN(C=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(Cl)nnc1Cl

Procedure:
3,4,6-Trichloropyridazine (2.5 g; 13.6 mmol) and methanesulfinic acid sodium salt (2.78 g, 27.26 mmol) were stirred in 20 ml of a solvent mixture of water/THF/DMF (5:10:5) at RT for 30 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic phase was removed and concentrated, and the crude product was purified by flash chromatography (dichloromethane:methanol). Yield: 1.4 g
Reaction SMILES: [CH3:1][CH:2]([C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Li]CCCC.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1C(OC)=O.[NH4+].[Cl-]>C1COCC1>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:6]1[O:5][C:3](=[O:4])[C:2]([CH3:1])=[C:7]([OH:14])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)c1cc2ccccc2o1
Reactant: CCCCCCC(=O)C(C)C(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 2-methyl-3-oxononanoate (3.06 g) in THF (5 ml) was added to a suspension of 60% NaH (608 mg) in THF (30 ml) while cooling on ice, and the mixture was stirred at 0° C. for 10 minutes and then at room temperature for 30 minutes. The reaction solution was cooled to −78° C., 1.66 M n-BuLi (9.2 ml) was added, and the mixture was stirred at −78° C. for 30 minutes to prepare a dienolate. A solution of methyl 2-benzofurancarboxylate (1.25 g) in THF (5 ml) was added to the dienolate, and the mixture was stirred at −78° C. for 30 minutes. The reaction solution was brought to 0° C., an NH4Cl aqueous solution was added for quenching, and extraction was performed with AcOEt. The organic layer was rinsed with water and saturated saline in that order, and then dried with Na2SO4, filtered and concentrated. The residue was dissolved in MeOH (50 ml), and after adding 2N-LiOH (30 ml) and stirring at room temperature for 2 hours, 1N-HCl was added at 0° C. to acidity of approximately pH 3, and extraction was performed with AcOEt. The organic layer was rinsed with water and saturated saline in that order, and then dried with Na2SO4, filtered and concentrated. Pyridine (20 ml) and Ac2O (20 ml) were added to the residue, and after stirring the mixture at room temperature for 5 hours it was concentrated under reduced pressure. The residue was dissolved in MeOH (20 ml), imidazole (483 mg) was added at 0° C., and after stirring the mixture at 0° C. for 10 minutes and then at room temperature for 30 minutes, it was concentrated under reduced pressure. AcOEt was added to the residue, and the precipitated crystals were filtered off. The crystals were recrystallized from EtOH to obtain 6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-n-pentyl-2H-pyran-2-one.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]2)[CH2:3][CH2:2]1.I[C:14]1[N:32]=[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=3)[N:16]2[N:15]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[CH3:31][S:28]([C:24]1[CH:23]=[C:22]([C:21]2[N:16]3[N:15]=[C:14]([NH:12][C:10]4[CH:9]=[N:8][N:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:11]=4)[N:32]=[C:17]3[CH:18]=[CH:19][CH:20]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(I)nn23)c1
Reactant: Nc1cnn(C2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4cnn(C5CCOCC5)c4)nn23)c1
Temperature: 160 °C
Yield: 10.5 %

Procedure:
A suspension of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (50.0 mg, 0.299 mmol, 1.2 equiv), 2-iodo-5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.100 g, 0.249 mmol, 1 equiv), tris(dibenzylideneacetone)dipalladium (0) (17.0 mg, 0.019 mmol, 0.075 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21.6 mg, 0.037 mmol, 0.150 equiv), and sodium tert-butoxide in dioxane (2 mL) was heated at 160° C. for 15 min under microwave radiation. The reaction mixture was partitioned between half saturated aqueous sodium chloride solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC provided product (11.5 mg, 11% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.28 (s, 1H), 8.79 (s, 1H), 8.35 (d, J=7.9 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.87 (dd, J=16.6, 8.8 Hz, 2H), 7.66 (dd, J=8.7, 7.3 Hz, 1H), 7.55 (m, 1H), 7.40 (m, 1H), 7.21 (m, 1H), 4.31 (m, 1H), 3.95 (d, J=11.1 Hz, 2H), 3.52-3.39 (m, 2H), 2.07 (s, 3H), 1.89 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=[O:21].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C@:38](OS(C)(=O)=O)([CH2:44][CH2:45][CH2:46][CH3:47])C(OCC)=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:44][CH2:45][CH2:46][C@H:47]([NH:1][C@@H:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:3]2=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCC[C@](OS(C)(=O)=O)(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H]1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 49.1 %

Procedure:
A mixture of 0.32 g of tert-butyl (RS)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 0.2 g of ethyl (R)-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate is heated at 90° C. for 30 minutes. After cooled, the mixture is separated and purified by silicagel column chromatography (hexane: ethyl acetate=2:1) to give 0.14 g of tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as colorless oil from the first fraction.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([CH3:18])[NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[Li+].[OH-]>O1CCOCC1.O>[N+:14]([C:10]1[CH:9]=[C:8]([CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:19])=[O:2])[CH3:18])=[O:17])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: COC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reaction time: 4 h

Procedure:
The title compound was prepared by dissolving 9.27 g (0.0348 mols) of the N-(3-nitrophenylacetyl)-L-alanine methyl ester in 60 mL of dioxane and 15 mL of H2O and adding LiOH (3.06 g, 0.0731 mol) that has been dissolved in 15 mL of H2O. After stirring for 4 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4×100 ml), the combined organics were dried over Na2SO4 and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/isooctane giving 7.5 g (85 %). C11H12N2O5 requires C, 52.38 H, 4.80 N, 11.11. Anal found C, 52.54 H, 4.85 N, 11.08. [α]23=−29.9@589 nm.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[NH2:15][C:16]([NH2:18])=[NH:17]>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:15]=[C:16]([NH2:18])[N:17]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)N
Product: Cc1nc(C)c(-c2ccnc(N)n2)s1

Procedure:
This compound was prepared by heating equimolar amounts of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and guanidine in refluxing 2-methoxethanol. 1H-NMR (300 MHz, CDCl3) δ2.67 (s, 3H, CH3), 2.68 (s, 3H, CH3), 5.14 (br, 2H, NH2), 6.83 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 8.30 (d, 1H, J=5.3 Hz, pyrimidinyl-H).