Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]([C:8]2[N:16]=[CH:15][C:14]3[NH:13][C:12]4[N:17]=[CH:18][C:19](Br)=[CH:20][C:11]=4[C:10]=3[CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](#[N:24])[CH3:23]>C(=O)([O-])[O-].[Na+].[Na+].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>[N:1]1([C:6]([C:8]2[N:16]=[CH:15][C:14]3[NH:13][C:12]4[N:17]=[CH:18][C:19]([C:9]5[CH:10]=[CH:14][C:22]([N:24]6[CH2:4][CH2:5][N:1]([CH3:6])[CH2:2][CH2:3]6)=[CH:23][CH:8]=5)=[CH:20][C:11]=4[C:10]=3[CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc2c(cn1)[nH]c1ncc(Br)cc12)N1CCCC1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(C(=O)N6CCCC6)cc5c4c3)cc2)CC1
Temperature: 120 °C
Yield: 5 %

Procedure:
A degassed mixture of 6-(pyrrolidinylcarbonyl)-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (158 mg, 0.457 mmol), 4-(4-methylpiperizin-1-yl)-phenyl-1-boronic acid, pinacol ester (597 mg, 1.98 mmol), and bis(triphenylphosphine)palladium(II) chloride (69.0 mg, 99.0 μmol, 5.0 mol %) in acetonitrile (2.5 mL) and 1.0M aqueous sodium carbonate (2.5 mL) was heated under microwave irradiation at 120° C. for 10 minutes, allowed to cool, and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate filtered and concentrated in vacuo. The resultant residue was purified by preparative HPLC (0-30% MeCN/water modified with 0.1% formic acid) to afford an off-white solid (10.0 mg, 5%). 1H NMR (DMSO-D6, 400 MHz) 12.39-12.29 (s, 1H), 9.01 (d, J=2.2 Hz, 1H), 8.88 (d, J=2.2 Hz, 31), 8.86 (s, 1H), 8.70 (s, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 3.78 (t, J=6.2 Hz, 2H), 3.57 (t, J=6.2 Hz, 2H), 3.25-3.18 (m, 4H), 2.47 (m, 311), 2.24 (m, 4H), 1.87 (m, 4H). LCMS (Method D): RT=7.36 min, M+H+=441.
Reaction SMILES: O[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1cc(C)c(-c2c3nc(C)nc(O)c3n3ccccc23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(-c2c3nc(C)nc(Cl)c3n3ccccc23)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyrimido-[4,5-b]indolizine (120 mg) in phosphorus oxychloride (2 mL) is heated at 100° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue is partitioned into ice water and dichloromethane. The aqueous phase is separated and extracted twice with dichloromethane. The combined organic extracts are washed with a saturated sodium bicarbonate solution and subsequently dried (Na2SO4), filtered, and concentrated in vacuo. The resulting dark residue is chromatographed on silica gel (10% to 20% ethyl acetate in hexane) to give 54 mg of the title compound as a greenish yellow foam: 1H nmr (400 MHz, CDCl3) d 1.99 (s, 6 H), 2.38 (s, 3 H), 2.79 (s, 3 H), 6.80 (m, 1 H), 7.00 (s, 2 H), 7.19 (m, 2 H), 9.27 (d, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1C)=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1[C:56](C1C=C(C#C)C=CC=1OC)=[O:57].N(CCOC1CCCCO1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[O:57][CH3:56])=[O:18]
Reactant: C#Cc1ccc(OC)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: [N-]=[N+]=NCCOC1CCCCO1
Product: COc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 427 (0.42 mmol) and compound 408 (0.42 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 60:40 as the eluent to afford the title compound as light orange foam.
Reaction SMILES: [CH3:1][CH:2]1[O:10][C:9]2([CH2:15][CH2:14][CH:13]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]4[N:41]=[CH:42][N:43]=[C:17]34)[CH2:12][CH2:11]2)[O:8][CH2:7][C:3]21[CH2:6][CH2:5][CH2:4]2.[B-]C#N.[Na+].S([O-])([O-])(=O)=O.[Mg+2].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:7]([C:3]1([CH:2]([O:10][CH:9]2[CH2:15][CH2:14][CH:13]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:28][CH:29]=4)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]4[N:41]=[CH:42][N:43]=[C:17]34)[CH2:12][CH2:11]2)[CH3:1])[CH2:6][CH2:5][CH2:4]1)=[O:8]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC2(CCC2)C(C)O3)c2ncnn12
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [B-]C#N
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC(C)C3(C=O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4′-{[4-(5-methyl-6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (15.33 g), sodium cyanotrihydroborate (7.01 g), anhydrous magnesium sulfate (12.76 g) and tetrahydrofuran (330 mL) was stirred at room temperature for 10 min. Then, boron trifluoride-diethyl ether complex (13.4 mL) was added dropwise, and the mixture was stirred under an argon atmosphere at 50° C. for 8 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in acetonitrile (300 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.64 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→50/50 (volume ratio)] to give the title compound as a colorless amorphous compound (7.21 g, 47%).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:20]2[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: CC(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCC(C(=O)c2ccc(C(C)(C)C)cc2)CC1

Procedure:
19.1 g of 1-acetylisonipecotoyl chloride, Example 1(b) are added portionwise to a stirring suspension of 13 g of t-butylbenzene and 27 g of aluminum chloride in 175 ml of dichloroethane. The reaction mixture is refluxed for 1 hour, cooled, and poured onto ice. The organic layer is separated and the aqueous layer is extracted with chloroform. The organic layers are combined, dried, and the solvent is removed under reduced pressure leaving the oil 1-acetyl-4-(4-t-butylbenzoyl)piperidine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([N:11]([C:17](=[O:35])[C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:21]=[C:20]([CH3:34])[CH:19]=1)[CH2:12][CH2:13][C:14](O)=[O:15])([CH3:10])[CH3:9].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:69]([NH2:73])([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:69]([NH:73][C:14]([CH2:13][CH2:12][N:11]([CH:8]([CH3:9])[CH3:10])[C:17](=[O:35])[C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[CH:21]=[C:20]([CH3:34])[CH:19]=1)=[O:15])([CH3:72])([CH3:71])[CH3:70]
Reactant: CC(C)(C)N
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC(=O)O)C(C)C)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC(=O)NC(C)(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(isopropyl-{3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-amino)-propionic acid trifluoroacetate (0.018 g) and PyBroP® (0.017 g) in DMF (1 ml) was added DIPEA (0.012 ml) followed by tert-butylamine (0.005 ml), after 1 min. The reaction mixture was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.009 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]([Cl:15])=[CH:4][N:3]=1>C(O)(=O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([Cl:15])[CH:6]=1)[CH3:14]
Reactant: CCOC(=O)COc1cc(Cl)cnc1Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1cncc(Cl)c1

Procedure:
A solution of ethyl (2,5-dichloropyrid-3-yloxy)-acetate (200mg.) in glacial acetic acid (8ml.) was stirred overnight under reflux with acid washed zinc powder (1.0g.). The solution was cooled and filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel to yield ethyl(5-chloropyrid-3-yloxy)acetate, m.p. 38°-40°C. (ether-pentane).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([Cl:23])[C:17]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2].[Cu]Cl.CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH:3]=1
Reactant: OB(O)c1c(Cl)cc(F)cc1Cl
Reactant: NC(=O)c1cc(Br)c2ccccc2n1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2c(Cl)cc(F)cc2Cl)c2ccccc2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
4-Bromoquinoline-2-carboxamide (1-8, 50.0 mg, 0.199 mmol, 1.0 equiv.), (2,6-dichloro-4-fluorophenyl)boronic acid (77.0 mg, 0.398 mmol, 2.0 equiv.), cesium carbonate (130.0 mg, 0.398 mmol, 2.0 equiv), Pd(OAc)2 (2.2 mg, 0.01 mmol, 0.05 equiv.), DPPF (11.0 mg, 0.020 mmol, 0.1 equiv.) and copper(I) chloride (19.7 mg, 0.199 mmol, 1.0 equiv.) were added into DMF (1.0 mL). The mixture was stirred at 100° C. overnight. After cooling, aqueous sodium hydrogen carbonate (saturate, 2.0 mL) was added and the mixture was extracted with dichloromethane (2×5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(2,6-dichloro-4-fluorophenyl)quinoline-2-carboxamide (1-9, 6.20 mg, 9.8%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.281 (s, 1 μl); 8.200-8.226 (m, 1H); 8.175 (br s, 1H); 7.801-7.843 (m, 1H); 7.601-7.637 (m, 2H); 7.137-7.183 (m, 2H); 6.140 (br s, 1H). LRMS m/z (M+H)+ 319.0 found, 319.0 required.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:23][CH3:24])=[CH:8][C:9]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([NH2:22])=[N:19][C:20]=2[NH2:21])=[CH:10][C:11]=1[O:12][CH3:13].C[O:26]C1C=C(C=C(OC)C=1OCCOC)C=O.NC1N=C(N)C=C(O)N=1>>[NH2:22][C:18]1[N:19]=[C:20]([NH2:21])[C:15](=[CH:14][C:9]2[CH:10]=[C:11]([O:12][CH3:13])[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([O:23][CH3:24])[CH:8]=2)[C:16](=[O:26])[N:17]=1
Reactant: COCCOc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reactant: COCCOc1c(OC)cc(C=O)cc1OC
Agent: Nc1cc(O)nc(N)n1
Product: COCCOc1c(OC)cc(C=C2C(=O)N=C(N)N=C2N)cc1OC

Procedure:
A process for preparing Tetroxoprim starting from 3,5-dimethoxy-4-methoxyethoxy-benzaldehyde and 2,4-diamino-6-hydroxy-pyrimidine, by successive hydrogenation, halogenation and hydrogenolysis of the 2,4-diamino-6-oxo-5-(3,5-dimethoxy-4-methoxyethoxy-benzylidene)-pyrimidine obtained in the initial reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7](CC)[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[O:28][CH2:29][C:30]#[N:31])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[O:28][CH2:29][C:30]#[N:31])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)ccc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile to yield a yellow solid. LCMS: m/z=463.13 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.30 (d, 1H, J=7.8 Hz), 8.12 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 7.33 (d, 1H, J=8.6 Hz), 7.13 (m, 6H), 4.90 (s, 2H), 2.43 (m, 2H), 2.11 (m, 2H), 1.41 (s, 6H).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Br)[CH3:18]>C(OCC)C>[Si:5]([O:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH2:17][CH3:18])[CH:12]=[CH:13][CH:14]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC(O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
50 g (0.21 mol) of 3-(tert-butyldimethyl-silanyloxy)benzaldehyde are dissolved in 500 ml of ethyl ether and the mixture is cooled to 0° C. 80 ml (0.24 mol) of a 3.0 M solution of ethylmagnesium bromide are added slowly, and the mixture is stirred for 5 hours. After the usual treatment, the residue obtained is purified by chromatography on a silica column (eluent ethyl acetate 20/hexane 80). A colorless oil is obtained (m=45.8 g; Y=82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:38])([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH2:25][CH3:26])[CH:22]=1)[C:16]([O:18]C)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:38])([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N:23]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:24][CH2:25][CH3:26])[CH:22]=1)[C:16]([OH:18])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)OC)c1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoate (462 mg, 0.842 mmol) in THF (15 mL) was added aq. LiOH (4.21 mL, 4.21 mmol, 1N). After stirring vigorously at rt for 20 h, the reaction mixture was acidified to pH 4 with HCl (4.07 nL, 4.07 mmol, 1N), extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to provide 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid as a white foam. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.96 (s, 1H), 7.61 (s, 1H), 7.30-7.20 (m, 3H), 7.18-7.13 (m, 2H) 4.66-4.57 (m, 3H), 3.68 (t, J=7.2 Hz, 2H), 3.59 (A of AB, br d, J=8.5 Hz, 1H), 3.49 (B of AB, br d, J=8.5 Hz, 1H), 3.15 (A of AB, d, J=13.3 Hz, 1H), 2.93 (B of AB, d, J=13.3 Hz, 1H), 2.91 (s, 3H), 1.57-1.45 (m, 2H), 1.47 (s, 9H), 1.27 (s, 3H), 0.92 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16]C(C)(C)[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:42])[CH:23]2[CH2:26][CH:25]([CH2:27][NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=3)=[O:30])[CH2:24]2)[O:12]1>Cl.CO>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:12][C@H:13]([CH2:21][N:22]([CH3:42])[CH:23]2[CH2:26][CH:25]([CH2:27][NH:28][C:29]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([CH3:41])([CH3:39])[CH3:40])=[CH:36][CH:37]=3)=[O:30])[CH2:24]2)[C@@H:14]([OH:18])[C@H:15]1[OH:16]
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CNC(=O)Nc2ccc(C(C)(C)C)cc2)C1
Agent: Cl
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CNC(=O)Nc2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.5 %

Procedure:
A solution of 1-((3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)methyl)-3-(4-(tert-butyl)phenyl)urea (55 mg) in HCl/MeOH (2.5 mol/L) (2 mL) was stirred at RT for 2 h and then concentrated to dryness. K2CO3 (52 mg) in water (0.5 mL) and MeOH (5 mL) was added. The resulting mixture was stirred for another 10 min at RT, filtered and the filtrate was concentrated. The residue was purified by preparative-HPLC to give Compound 110 (10 mg, yield: 25%) as a white solid. 1HNMR (500 MHz, MeOD): δH 8.26 (s, 1H), 8.18 (s, 1H), 7.26-7.19 (m, 4H), 5.96 (d, J=4.5 Hz, 1H), 4.674-4.655 (m, 1H), 4.24-4.16 (m, 2H), 3.15 (d, J=5.0 Hz, 2H), 2.83-2.73 (m, 3H), 2.20-1.59 (m, 8H), 1.26 (s, 9H) ppm; ESI-MS (m/z): 539.3 [M+1]+.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[F:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[CH:29][C:30]=1[F:31]>>[F:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[F:31])[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: Oc1ccc(F)c(F)c1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)c(F)c2)C1
Yield: 103.6 %

Procedure:
The title compound (D128) (100 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 3,4-Difluorophenol (44.06 mg, 0.338 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])[C:13]([C:29]([O:31][CH3:32])=[O:30])=[C:12]([CH3:33])[N:11]=1.ClC1C(Cl)=CC=CC=1C=O>>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]([CH3:33])=[C:13]([C:29]([O:31][CH3:32])=[O:30])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(CCOCCOCCN)nc(C)c(C(=O)OC)c1-c1cccc(Cl)c1Cl
Agent: O=Cc1cccc(Cl)c1Cl
Product: CCOC(=O)C1=C(CCOCCOCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
The 2-{2-[2-(2-Aminoethoxy)ethoxy]ethyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methylpyridine is obtained starting with the ester described in stage D and 2,3-dichlorobenzaldehyde according to the process described in Example 1, stages B and C. The spectral physical constants of this compound are given in Table I.
Reaction SMILES: [O:1]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:30][C:21]1=[N:22][CH:23]=[C:24]([C:26]([O:28]C)=[O:27])[CH:25]=[C:20]1[CH2:19]2.Cl.[OH-].[Na+]>CO>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:30][C:21]1=[N:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[CH:25]=[C:20]1[CH2:19]2
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 55 °C
Reaction time: 20 h

Procedure:
A solution of methyl (6S)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (238 g, 559 mmol) in methanol (2 L) was saturated with HCl gas, allowing temperature to increase to 55° C. The reaction mixture was cooled to 23° C., stirred for 20 h, then concentrated. Aqueous 10 N sodium hydroxide (400 mL, 4 mol) was added to a solution of the residue in methanol (2 L), and the resulting mixture was heated at reflux for 2 h. The solution was cooled to 23° C. and the pH was adjusted to 3 with concentrated HCl. The resulting solid was filtered, washed with water then heptane, and dried to give the title compound. MS: m/z=282.2 (M+1).
Reaction SMILES: IC.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:16])[CH3:15].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:8]1[C:7]([O:12][CH3:13])=[CH:6][C:5]([C:14](=[O:16])[CH3:15])=[C:4]([NH:3][CH3:17])[CH:9]=1
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1cc(OC)c(OC)cc1C(C)=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Iodomethane (14 ml) was added to a stirred mixture of 2'-amino-4',5'-dimethoxyacetophenone (40 g), potassium carbonate (31.2 g) and dry dimethylformamide (200 ml) and the mixture stirred at ambient temperature for 40 hours. The solvent was evaporated under reduced pressure and the residue triturated with dichloromethane (250 ml). The mixture was filtered and the filter bed washed with dichloromethane (50 ml). The combined filtrate and washing were evaporated and the residue purified by flash chromatography on a silica gel column eluted with dichloromethane:industrial methylated spirit (99:1then 49:1) followed by trituration with diethyl ether (400 ml then 100 ml) to give the novel compound 4',5'-dimethoxy-2'-(methylamino)acetophenone, m.p. 121°-123.5°.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][CH:8]=[CH:9][CH:10]=1)=[N+]=[N-]>[Pd]>[CH2:11]([C:6]1[C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:12]
Reactant: CCc1ncccc1CN=[N+]=[N-]
Agent: [Pd]
Product: CCc1ncccc1CN

Procedure:
The product of Example 124B and Pd/C were processed according to the method of Example 115B to provide the product. MS (ESI+) m/z 137 (M+H)+.