Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:8]=[N:9][CH:10]=2)[C:4](=[S:7])[NH:5][N:6]=1.[Na].[CH2:12](Br)[CH:13]=[CH2:14]>CO>[CH2:14]([S:7][C:4]1[N:3]2[CH:8]=[N:9][CH:10]=[C:2]2[CH:1]=[N:6][N:5]=1)[CH:13]=[CH2:12]
Reactant: S=c1[nH]ncc2cncn12
Reactant: C=CCBr
Agent: [Na]
Solvent: CO
Product: C=CCSc1nncc2cncn12
Reaction time: 0.08 h

Procedure:
A 15.2 gm. portion of imidazo[1,5-d]-as-triazine-4(3H)-thione in 75 ml. of methanol is treated with 2.3 gm. of sodium in 75 ml. of methanol. After 5 minutes, a 12.0 gm. portion of allyl bromide is added and the reaction is continued as described in Example 29 giving the desired product, m.p. 68°-69.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12]([C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[O:16][CH:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:17]([O:16][C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[C:12]2[NH:11][C:10]3[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=3[N:1]=2)[CH2:18]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2nc3c(C(=O)O)cccc3[nH]2)C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
A mixture of 2,3-diaminobenzoic acid (1; 350 mg, 2.3 mmol), tert-butyl 3-(2-formylphenoxy)pyrrolidine-1-carboxylate (30; 670 mg, 2.3 mmol) and Na2S2O5 (568 mg, 1.3 mmol) in DMF (30 mL) was stirred at 90° C. for 18 h. The mixture was cooled to room temperature. The mixture was diluted with water (100 mL), stirred for 1 h, filtered, and washed with water. The filter cake was dried under vacuum to afford 822 mg of the titled compound 31 (84%). MS (ESI) calcd for C23H25N3O5: 423.18; found: 424 [M+H].
Reaction SMILES: C(OC(=O)[N:7]([CH:43]1[CH2:45][CH2:44]1)[CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:42])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[CH:38][CH:39]=[CH:40][C:27]3=4)=[O:25])=[CH:20][C:19]=2[CH3:41])[CH2:11][CH2:10]1)(C)(C)C.Cl>CO.O1CCOCC1>[CH:43]1([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:42])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:35][C:34]5[CH:33]=[N:32][N:31]([CH3:36])[C:30]=5[NH:29][C:28]5[CH:37]=[CH:38][CH:39]=[CH:40][C:27]4=5)=[O:25])=[CH:20][C:19]=3[CH3:41])[CH2:11][CH2:10]2)[CH2:44][CH2:45]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CNC2CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Cyclopropyl-(1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester from Example E86.3 (220 mg, 0.35 mmol) was dissolved in methanol (5 ml) and 4M HCl solution in dioxan (5 ml) was added. The mixture was stirred for 2 h at room temperature then concentrated in vacuo to give an off-white solid identified as the title compound (189 mg, 95%).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:56][CH2:55][C:54]([CH3:58])([CH3:57])[CH3:53])=[O:44])[CH:47]=[CH:48][CH:49]=2)=[N:20][CH:19]=[N:18]1
Reactant: CC(C)(C)CN
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CNC(=O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 60 °C
Reaction time: 67 h
Yield: 134.9 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.431 g, 0.667 mmol) in a tetrahydrofuran/water mixture (2.70 mL/1.62 mL) was added lithium hydroxide monohydrate (0.0840 g, 2.00 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.16 mL), 2,2-dimethylpropyl amine (0.174 g, 2.00 mmol), 1-hydroxybenzotriazole hydrate (0.270 g, 2.00 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.384 g, 2.00 mmol). This reaction mixture was stirred for 67 h at ambient temperature. The mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with an aqueous saturated sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40-60% ethyl acetate/hexanes gave the title compound (0.337 g, 72% yield). ES-MS (m/z) 459 [M+1(−Tr)]+.
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=O.C(I)C>CCOCC>[CH2:13]([O:12][CH:10]=[C:9]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:14]
Reactant: CCOC(=O)CF
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CCOCC
Product: CCOC=C(F)C(=O)OCC
Temperature: 25 °C

Procedure:
NaH (60% suspension in mineral oil, 15.6 g, 0.39 mole) was washed with and suspended in ether (300 mL). To this suspension, ethyl formate (29.1 mL, 0.36 mole, 1.2 eq) was added and the mixture was cooled in an ice bath. Ethyl fluoroacetate (29.0 mL, 0.3 mole) was added slowly over 1 hour. After 2 hours the ice bath was removed and the reaction was stirred for another hour. After evaporation of the solvent, the residue was redissolved in 350 mL of dry DMF and cooled in an ice bath, and ethyl iodide (48 mL, 0.6 mole) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight, then quenched with saturated aqueous solution of NH4Cl (100 mL). The mixture was diluted with ether and extracted with water. The separated ether layer was washed with sodium thiosulfate, brine and dried over MgSO4. After concentration under vacuum, the residue was distilled to give ethyl 3-ethoxy-2-fluoroacrylate (12, R9 =ethyl, 73°-85° C./14 mmHg) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ1.35 (t, 3H), 1.39 (t, 3H), 4.10 (q, 2H), 4.30 (q, 2H), 6.95 (d, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]([F:40])([F:39])[C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(-c2ccc(C(F)(F)F)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 28 using 5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid to afford an off-white solid. UPLC-MS (condition 1) tR=2.77 min, m/z=513.0 [M+H]+, m/z=511.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.15-3.27 (m, 2H) 3.35-3.46 (m, 1H) 4.16-4.26 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.00 (d, J=8.07 Hz, 1H) 8.06-8.14 (m, 2H) 8.80 (d, J=2.20 Hz, 1H) 8.85 (d, J=1.71 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]5[CH2:31][CH2:30]5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[C:32]1(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)[CH:37]=CC=C[CH:33]=1>>[CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]5[CH:31]=[CH:30][CH:37]=[CH:32][CH:33]=5)=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccccc3)cc2)OC1(C)C
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1

Procedure:
A procedure analogous to that used for the preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea was used, using 1-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as the boronic ester component. Yield=0.088 g, 55%. MS; 459.5, M+H.
Reaction SMILES: [OH2:1].O.O.[ClH:4].Cl.Cl.[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1O)[CH:14]([CH2:19][CH2:20][CH:21]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[C:49]3[C:44](=[CH:45][C:46]([OH:51])=[C:47]([OH:50])[CH:48]=3)[CH2:43][CH2:42][NH:41]1)[CH2:22][CH2:23][CH:24]1[C:33]3[C:28](=[CH:29][C:30]([OH:35])=[C:31](O)[CH:32]=3)[CH2:27][CH2:26][NH:25]1)[NH:13][CH2:12][CH2:11]2>C(O)(=O)C>[OH2:7].[OH2:1].[OH2:7].[ClH:4].[ClH:4].[ClH:4].[C:47]([OH:50])(=[O:1])[CH3:48].[C:47]([OH:50])(=[O:1])[CH3:48].[C:47]([OH:50])(=[O:1])[CH3:48].[OH:35][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[CH:24]([CH2:23][CH2:22][CH:21]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[C:49]3[C:44](=[CH:45][C:46]([OH:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]1)[CH2:20][CH2:19][CH:14]1[C:15]3[C:10](=[CH:9][C:8]([OH:7])=[CH:17][CH:16]=3)[CH2:11][CH2:12][NH:13]1)[NH:25][CH2:26][CH2:27]2
Reactant: Oc1cc2c(cc1O)C(CCCCC(CCC1NCCc3cc(O)c(O)cc31)CCC1NCCc3cc(O)c(O)cc31)NCC2
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(c1)CCNC2CCCCC(CCC1NCCc2cc(O)ccc21)CCC1NCCc2cc(O)ccc21

Procedure:
Similarly, when 800 mg. of (10.6) is suspended in 20 ml. glacial acetic acid containing 2 g. of acetyl chloride, and dry hydrogen chloride is bubbled through the mixture, on workup
Reaction SMILES: [O-][CH2:2]CCC.[K+].[CH:7]([CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]4[C:28](=[C:29]([F:31])[CH:30]=3)[O:27][C:26](=[O:32])[CH2:25][CH2:24]4)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:31][C:29]1[CH:30]=[C:21]([CH:18]2[CH2:17][CH2:16][CH:15]([CH:12]3[CH2:11][CH2:10][CH:9]([CH:7]=[CH2:2])[CH2:14][CH2:13]3)[CH2:20][CH2:19]2)[CH:22]=[C:23]2[C:28]=1[O:27][C:26](=[O:32])[CH2:25][CH2:24]2
Reactant: CCCC[O-]
Reactant: O=CC1CCC(C2CCC(c3cc(F)c4c(c3)CCC(=O)O4)CC2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(C2CCC(c3cc(F)c4c(c3)CCC(=O)O4)CC2)CC1
Temperature: -30 °C
Yield: 66 %

Procedure:
Methyltriphenylphosphonium bromide (3.5 g) was suspended in THF (30 ml), to which was then added potassium butoxide (1.2 g) with stirring while cooling at −30° C. After continuing the stirring at the same temperature for 30 minutes, a solution of 6-(4-(4-formylcyclohexyl)cyclohexyl)-8-fluoro-3,4-dihydrocoumarin (3.2 g) in THF (30 ml) was added dropwise to the reaction mixture. After completion of the dropwise addition, the temperature of the reaction mixture was raised to room temperature, and the resulting reaction mixture was added in ice water and extracted with toluene. An organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The resulting oily material was subjected to isolation and purification by silica gel column chromatography and recrystallized, thereby obtaining a titled compound (2.1 g).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=4)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 74.2 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (150 mg, 0.42 mmol), 4-(trifluoromethyl)aniline (191 mg, 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (155 mg, 74%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>ClCCCl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]3[C:6]([N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:23](=[O:24])[NH:22][C:4]=3[C:3]=1[O:2][CH3:1])=[N:7][CH:8]=[N:9]2
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=O)N3c1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (0.2 g, 0.68 mmol) (from Example 1, Step C, supra) in 1,2-dichloroethane (50 mL) was added 1,1′-carbonyldiimidazole (0.55 g, 3.4 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvent was evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.04) as eluent to give the desired 8,9-dimethoxy-3-phenyl-1H,3H-1,3,4,6-tetraaza-phenalen-2-one as a yellow solid. (Yield 0.13 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][CH2:11][CH2:12][CH:13]([OH:27])[CH2:14][CH2:15][NH:16]C(=O)OCC2C=CC=CC=2)=[CH:5][CH:4]=1>CO.[Pd]>[NH2:16][CH2:15][CH2:14][CH:13]([OH:27])[CH2:12][CH2:11][O:10][C:9]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(C(OCCC(O)CCNC(=O)OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(OCCC(O)CCN)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl 5-(bis(4-methoxyphenyl)(phenyl)methoxy)-3-hydroxypentylcarbamate (15.4 g, 27.7 mmoles) is dissolved in methanol (250 mL) and the solution is poured into a hydrogenation flask. 10% Palladium on carbon (1.5 g, 50% water by weight) is added, and the flask is sealed. The atmosphere in the flask is evacuated using a diaphragm pump, and replaced with dry argon to 10 psi. This cycle of evacuation/argon purging is repeated four more times. The flask is then evacuated once more and filled with hydrogen to 30 psi. The suspension is stirred briskly at ambient temperature for 16 hours. Hydrogen is replaced to 30 psi as necessary during the first four hours of reaction. The flask is then evacuated to remove hydrogen, and refilled with argon to atmospheric pressure. The catalyst is removed by filtration using a 0.45 μm nylon membrane, and washed with methanol (100 mL). The combined methanol filtrates are evaporated to dryness to give a white glassy foam, which is further dried in vacuo. The yield is 11.4 g (98%).
Reaction SMILES: [CH3:1][C:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=1[CH3:26]>>[CH3:1][CH:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=3[CH3:26])[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCCC2)O1
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C1(CCCCC1)OC(C)N2

Procedure:
The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclohexane] and 5-bromo-4-methyl-2-thiophenecarbonitrile. A brown solid: 1H-NMR (DMSO-d6) δ 7.78 (s, 1H), 7.17 (d, 1H, J=1.8 Hz), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 6.64 (s, 1H), 6.63 (d, 1H, J=8.2 Hz), 4.74 (m, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 8H), 1.31 (d, 3H, J=5.3 Hz); MS (ESI) m/z 337 [M−H]−.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([OH:9])[C:7]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([NH:1][C@H:2]1[C@H:8]([OH:9])[C:7]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][CH2:4][CH2:3]1)=[O:26]
Reactant: COc1ccc2c(c1)[C@@H](O)[C@H](N)CCO2
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@H](O)[C@H](NC(=O)CCl)CCO2
Reaction time: 24 h
Yield: 81 %

Procedure:
A solution of 17 g of trans-4-amino-7-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-5-ol dissolved in 700 ml of hydrocarbon-stabilized chloroform was treated with 16 ml of triethylamine at room temperature and 10 g of chloroacetyl chloride dissolved in 80 ml of chloroform was slowly added thereto. The reaction mixture was allowed to stand at room temperature for 24 hours and the solid removed by filtration and washed with chloroform. The filtrate was washed twice with dilute hydrochloric acid solution, followed by a wash with water and dried over anhydrous magnesium sulfate. The filtrate was evaporated to dryness and triturated with ether to yield 18.8 g of trans-2-chloro-N-(2,3,4,5-tetrahydro-5-hydroxy-7-methoxy-1-benzoxepin-4-yl)acetamide.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:16]1[CH2:25][C:24]2[C:23](=O)[NH:22][C:21]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:20]=3[C:19]=2[CH2:18][CH2:17]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(O)=O>ClCCl.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].CN(C)C=O>[C:8]([N:16]1[CH2:25][C:24]2[CH:23]=[N:22][C:21]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:20]=3[C:19]=2[CH2:18][CH2:17]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncc3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Temperature: -18 °C
Yield: 45 %

Procedure:
A 2 L, three-necked, round-bottomed flask was equipped with a heating/cooling bath, magnetic stirrer and stir bar, 60 mL addition funnel, thermocouple, thermocouple adapter with a nitrogen inlet. The flask was charged with triethylamine (43 mL, 31.2 g, 308 mmol), 3-benzoyl-8,9-dimethoxy-2,3,4,6-tetrahydrobenzo[c]-2,7-naphthyridin-5(1H)-one (30.2 g, 83 mmol), and dichloromethane (850 mL). The resulting slurry was stirred for 15 minutes at 22° C. and cooled to −18° C. Neat trifluoromethanesulfonic anhydride (34 mL, 202 mmol) was added drop-wise via an addition funnel over 40 minutes, keeping the temperature at −12 to −18° C. Upon completion of the addition, the mixture was warmed to 0° C. over 40 minutes and stirred at 0° C. for 2 hours. Solvents were stripped under reduced pressure. A solution of dichloro[1,1′-bis(diphenylphos-phino)ferrocene]palladium(II) dichloromethane adduct (4.72 g, 5.78 mmol) in a solution of degassed N,N-dimethylformamide (520 mL) and Et3N (120 mL, 87.1 g, 861 mmol) was added to the residue and the batch was degassed by bubbling N2 through it for 10 minutes. Degassed formic acid (15.8 mL, 419 mmol) was added over 1 minute via syringe and the stirred solution was heated to 55° C. Additional dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) dichloromethane adduct (3.20 g, 3.92 mmol) was added after 20 minutes and the batch was heated at 55° C. for another 1 hour. At that time, assay by HPLC showed the reaction to be complete. Concentration in vacuo afforded 149 g of crude dark brown oil, which was dissolved in dichloromethane (180 mL) and loaded into a Biotage® unit (340 g KP-Sil cartridge equilibrated with dichloromethane). The column was eluted isocratically with dichloromethane (8 CV). The product containing fractions were combined and concentrated under reduced pressure; the resulting oil (105 g) was swished with ethyl acetate (520 mL) to give the title compound as a grey solid (13.0 g, 45% yield).
Reaction SMILES: Cl[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[NH3:14]>Cl[Cu]>[NH2:14][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: Cl[Cu]
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: 170 °C
Yield: 85 %

Procedure:
191 parts of 2,3-dichlorobenzoic acid, 80 parts of 50% strength aqueous sodium hydroxide solution, 1004 parts of 25% strength aqueous NH3 solution and 5 parts of CuCl are initially introduced into a 2 l V4A autoclave. 89 parts of liquid NH3 (d20 : 0.61) are also forced in, and the autoclave is heated at 170° C. for 5 hours, during which the pressure drops from initially 25 bar to about 22 bar. When the reaction has ended, the contents of the autoclave are cooled to 25° C. and the autoclave is emptied via the ascending line. The reaction solution is boiled under reflux until a bottom temperature of 100° C. is reached, and the NH3 gas driven off is collected in a waste gas washer. After cooling to 25° C., the reaction solution is brought to pH 3 with 122 parts of 30% hydrochloric acid. The 2-amino-3-chlorobenzoic acid which has precipitated is filtered off with suction, washed with 300 parts of water and dried at 80° C. in vacuo. 145 parts (85% of theory) of 2-amino-3-chlorobenzoic acid of melting point 185° to 187° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[OH:16])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[F:26][C:27]([F:42])([C:38]([F:41])([F:40])[F:39])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[S:30](F)(=[O:32])=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[O:16][S:30]([C:29]([F:34])([F:35])[C:28]([F:36])([F:37])[C:27]([F:26])([F:42])[C:38]([F:41])([F:40])[F:39])(=[O:32])=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2cnccc2n1C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2cnccc2n1C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a stirred solution of 3-hydroxy-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (695 mg, 3.16 mmol) and DMAP (19 mg, 0.16 mmol) in DCM (10 ml) at 0° C. was added DIPEA (1.35 ml, 7.58 mmol) and nonafluorobutylsulfonyl fluoride (0.74 ml, 4.10 mmol). After 10 minutes the reaction was warmed to room temperature and stirred for an additional 4.5 hours. The reaction mixture was diluted with DCM (50 ml) and washed with water (30 ml). The organic phase was isolated, dried over sodium sulphate then filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-PPC, pentane:ethyl acetate, gradient 100:0 to 60:40) to afford the title compound as a colourless oil which crystallised on standing (1.43 g, 90%). LCMS (method B): RT=3.28 min, M+H+=505.