Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][NH:28][C:24]=2[CH:23]=[CH:22][N:21]=1>ClCCl>[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][N:28]([CH:18]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: C1=COCCC1
Reactant: Clc1nccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1nccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
p-Toluenesulfonic acid monohydrate (2.4 g, 13 mmol) and 3,4-dihydro-2H-pyran (99%, 45 mL, 520 mmol) were sequentially added to a suspension of 4-chloro-1H-pyrazolo[4,3-c]pyridine (20.0 g, 130 mmol) in dichloromethane (400 mL). The reaction mixture was allowed to stir at room temperature for 24 hours, at which time it was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluents: 10%, then 30%, then 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 27.51 g, 115.7 mmol, 89%. LCMS m/z 238.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=6.0 Hz, 1H), 8.16 (d, J=0.9 Hz, 1H), 7.47 (dd, J=6.0, 0.9 Hz, 1H), 5.73 (br dd, J=9.0, 2.7 Hz, 1H), 3.97-4.04 (m, 1H), 3.72-3.80 (m, 1H), 2.43-2.53 (m, 1H), 2.07-2.20 (m, 2H), 1.65-1.85 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:10](=[O:27])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:19][C:20]([OH:22])=[O:21])[C:10](=[O:27])[CH2:9]2)=[O:7])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
400 mg (0.97 mmol) of t-butyl [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetate was dissolved in a mixture of 2 ml of dichloromethane and 2 ml of trifluoroacetic acid, and the obtained solution was stirred at room temperature for 1 hour. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>>[C:35]([Si:32]([CH3:34])([CH3:33])[O:31][CH2:30][CH2:29][N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane, to give the desired product as a colorless oil (50%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C(O)(=O)C.C(O)(=O)C.[C:65]1([Bi](C2C=CC=CC=2)C2C=CC=CC=2)[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.C(O)(=O)C.C(=O)(O)O.C1([Bi](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.ClCl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: c1ccc([Bi](c2ccccc2)c2ccccc2)cc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: ClCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 120 h

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1 eq) and Cu(OAc)2 (2.8 mg, 0.014 mmol, 0.11 eq) in CH2Cl2 (1 ml) in a 16 mL screw-cap vial equipped with a magnetic stir-bar was added triphenyl bismuth diacetate [prepared immediately prior to use by addition of acetic acid (0.030 mL, 0.504 mmol, 4 eq) to a suspension of triphenyl bismuth carbonate (127 mg, 0.253 mmol, 2 eq) in CH2 Cl2 (1 ml)]. The reaction vessel was capped and the mixture stirred for five days. The reaction mixture was diluted with several milliliters of saturated aqueous NaHCO3 and extracted 4 times with CH2 Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 3:4 EtOAc/hexanes to afford 46 mg of 17-ethyl-1,14-dihydroxy 12-[2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR, 13C NMR and mass spectral analysis were consistent with the desired structure.)
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.[Br:50][C:51]1[N:56]=[C:55]([C:57](=[O:60])[NH:58][CH3:59])[C:54]([NH:61][C:62]2[C:67]([C:68]([F:71])([F:70])[F:69])=[CH:66][N:65]=[C:64]([NH:72][C:73]3[C:87]([O:88][CH3:89])=[CH:86][C:76]([CH2:77][P:78](=[O:85])([O:82]CC)[O:79][CH2:80][CH3:81])=[C:75]([Cl:90])[CH:74]=3)[N:63]=2)=[CH:53][CH:52]=1>>[Br:50][C:51]1[N:56]=[C:55]([C:57](=[O:60])[NH:58][CH3:59])[C:54]([NH:61][C:62]2[C:67]([C:68]([F:71])([F:70])[F:69])=[CH:66][N:65]=[C:64]([NH:72][C:73]3[C:87]([O:88][CH3:89])=[CH:86][C:76]([CH2:77][P:78](=[O:82])([OH:85])[O:79][CH2:80][CH3:81])=[C:75]([Cl:90])[CH:74]=3)[N:63]=2)=[CH:53][CH:52]=1
Reactant: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(O)Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with diethyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-5-methoxybenzyl)phosphonate (Compound 56D). MS (ESI): m/z 681.02/683.27 [M+H]+. UPLC: tR=1.56 min (analytical—2 min).
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:24]4[CH:25]=[N:26][CH:27]=[N:28][CH:29]=4)=[CH:17][CH:18]=3)[C:13](=[O:30])[C:12]=2[CH:11]=1)[C:5]([CH3:8])([CH3:7])[CH3:6]>C1COCC1>[CH3:1][C:13]1([OH:30])[C:12]2[CH:11]=[C:10]([O:9][CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][C:16]([C:24]1[CH:25]=[N:26][CH:27]=[N:28][CH:29]=1)=[CH:17][CH:18]=2
Reactant: CC(C)(C)COc1ccc2oc3ccc(-c4cncnc4)cc3c(=O)c2c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)COc1ccc2c(c1)C(C)(O)c1cc(-c3cncnc3)ccc1O2
Reaction time: 2 h

Procedure:
Methyl magnesium chloride, 22 wt % in THF (5.0 mL, 14.88 mmol), was added to a solution of 2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-one (2.2 g, 6.10 mmol) in THF (61.0 mL) at 0° C. After 2 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford 9-methyl-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-ol which used directly for the next reaction without further purification. Pyridinium p-toluene-sulfonate (0.140 g, 0.558 mmol) was added to a solution of 9-methyl-2-(neopentyloxy)-7-(pyrimidin-5-yl)-9H-xanthen-9-ol (0.200 g, 0.531 mmol) in DCE (2 mL) at 65° C. The reaction was monitored by and TLC analysis (1:1 Hex/EtOAc) and after 2 hours the solution was allowed to cool and was poured into saturated aqueous sodium bicarbonate (25 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material which was taken up in toluene and concentrated twice to remove residual pyridine. The product was used without further purification. MS m/z=359.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.P(Br)(Br)([Br:14])=O.[OH-].[Na+]>ClC(Cl)C>[Br:14][C:5]1[C:4]2[CH:9]=[CH:10][O:11][C:3]=2[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]cc(Br)c2occc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Brc1ncc(Br)c2occc12
Temperature: 25 °C

Procedure:
Combine 7-bromo-5H-furo[3,2-c]pyridin-4-one (16.16 g, 75.5 mmol), dichloroethane (160 mL), and phosphorus oxybromide (100 g, 348.8 mmol) and heat at reflux for about 2 hours. Cool to room temperature and pour the reaction mixture into ice water (1 L). Adjust the pH to 8 with 5N NaOH, extract into dichloromethane, wash with brine, dry over magnesium sulfate, filter, and concentrate. Purification by flash chromatography, eluting with hexane:ethyl acetate gives the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[C:18]=2S(C)(=O)=O)[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH2:4]1)[CH3:2].CN1CCCC1=[O:32].[OH-].[Na+]>O>[CH2:1]([C:3]1([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[C:18]=2[OH:32])[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH2:4]1)[CH3:2]
Reactant: CCC1=CC(CC)(c2c(S(C)(=O)=O)c(C)nn(C)c2=O)CC(CC)=C1
Reactant: CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1=CC(CC)(c2c(O)c(C)nn(C)c2=O)CC(CC)=C1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a 1 L volume four-necked flask, 4-(1,3,5-triethylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-40) (98.5 g) and N-methyl-2-pyrrolidone (383 ml) were added at room temperature. Sodium hydroxide (43.5 g) dissolved in water (118 ml) and a container washing solution (39 ml of water×2) were added at room temperature. The mixture was heated to 70±2° C., and stirred for 6 hours. To the mixture, toluene (300 ml) and water (500 ml) were added. After the mixture was stirred vigorously, additional toluene (300 ml) was added. The organic layer was removed and ice-water (500 ml) was added to the aqueous layer. pH was adjusted to 1-2 with 20 w/w % of sulfuric acid below 20° C. The precipitated solids were collected by filtration and washed with water. After air-drying, the solids were dissolved in ethyl acetate, and dried over anhydrous sodium sulfate. The insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The resulting crude product was purified by recrystallization (ethyl acetate-hexane) to give 78.0 g of 4-(1,3,5-triethylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-40).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:5]2=[O:23].IC1C(C=O)=C(OC)N=CC=1>CO.CC(O)=O.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:14])[N:6]([CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:5]2=[O:23]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(CCCN1CCCC1)C2=O
Agent: [Pd]
Agent: COc1nccc(I)c1C=O
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc2c(cc1N)C(=O)N(CCCN1CCCC1)C2=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Pd/C (250 mg) was added to a solution of crude 5-amino-6-nitro-2-(3-(pyrrolidin-1-yl)propyl)isoindoline-1,3-dione in MeOH/AcOH (100 mL/5 mL) and hydrogenated for 5 h. The mixture was filtered through Celite and the filtrate was treated with 4-iodo-2-methoxynicotinaldehyde (3.2 g, 12.07 mmol) and stirred at ambient temperature open to air for 12 h and at 80° C. for 5 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to dryness. Purification by flash chromatography gave the title 5,6-diamino-2-(3-(pyrrolidin-1-yl)propyl)isoindoline-1,3-dione as a solid (2.02 g, 32% through 4 steps). 1H NMR (MeOD): δ 8.15 (s, 2H), 8.01-8.08 (t, J=3 Hz 1H), 7.64 (t, J=3 Hz, 1H), 3.89-3.78 (m, 2H), 3.41-3.22 (m, 2H), 2.95-2.81 (m, 6H), 2.15-1.82 (m, 7H). ESMS (m/z) 532 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([NH2:12])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc(Br)c(N)cc1O
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (12 g, 43.8 mmol) in MeOH (90 mL) was added Ni (2.4 g). The reaction mixture was stirred under H2 (1 atm) for 4 h. The mixture was filtered and the filtrate was concentrated. The crude product was recrystallized from ethyl acetate and petroleum ether to give 2-tert-butyl-4-bromo-5-amino-phenol (C-27) (7.2 g, 70%). 1H NMR (DMSO-d6) δ 9.15 (s, 1H), 6.91 (s, 1H), 6.24 (s, 1H), 4.90 (br, s, 2H), 1.22 (s, 9H); ESI-MS 244.0 m/z (MH+).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][F:33])=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:24](=[O:25])[C:23]3[C:18]([Cl:17])=[CH:19][CH:20]=[C:21]([CH2:28][NH:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][F:33])[C:22]=3[F:27])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CF)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)CF)c3F)cccc12
Yield: 25.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 50 mg, 0.23 mmol), 6-chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropanamido)methyl)benzoic acid (Intermediate-67, 84 mg, 0.27 mmol), oxalyl chloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (89 mg, 0.69 mmol) in CH2Cl2 (2 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.41 (s, 1H), 8.69-8.66 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.33 (t, 1H), 8.18-8.15 (d, J=9.3 Hz, 1H), 7.54-7.34 (m, 4H), 4.48-4.33 (m, 4H), 1.55 (s, 9H), 1.16 (s, 6H); MS (m/z): 504.64 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=1)=[O:10].Br>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)c2c(F)cccc2F)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccc(O)c(F)c1)c1c(F)cccc1F
Yield: 97.4 %

Procedure:
A solution of 3.9 g of (2,6-difluoro-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanone (paragraph Hd)) in 30 ml of acetic acid is stirred with 20 ml of aqueous 62% HBr solution at 125° C., then evaporated, re-evaporated with toluene and taken up in ethyl acetate. The organic phase is washed with sat. aqueous NaHCO3 solution and 10% NaCl solution and then dried. 3.6 g of (2,6-difluoro-phenyl)-(3-fluoro-4-hydroxy-phenyl)-methanone MS: m/e 252 (M+), are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:43])([F:42])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([CH2:37]OS(Cl)=O)=[CH:29][N:28]=2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:37][C:30]2[C:31]([C:33]([F:36])([F:34])[F:35])=[N:32][C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][C:19]([F:42])([F:43])[F:18])=[CH:22][CH:23]=3)=[N:28][CH:29]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: O=S(Cl)OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with chlorosulfurous acid 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-ylmethyl ester (example 111F]) to give 2-methyl-2-{2-methyl-4-[2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-ylmethoxy]-phenoxy}-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as a white powder of mp. 153.5–154.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[O:21])[C:19]3[CH:22]=[C:23]([CH2:26][S:27](N(C)C4C=CC=CC=4)(=[O:29])=[O:28])[CH:24]=[CH:25][C:18]=3[CH:17]=[CH:16][C:13]2=[N:14][CH:15]=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[O:21])[C:19]3[CH:22]=[C:23]([CH2:26][S:27]([NH:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)(=[O:29])=[O:28])[CH:24]=[CH:25][C:18]=3[CH:17]=[CH:16][C:13]2=[N:14][CH:15]=1
Reactant: NCc1ccccn1
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=c1c2cc(CS(=O)(=O)NCc3ccccn3)ccc2ccc2ncc(Cl)cc12
Temperature: 132.5 °C

Procedure:
2-Aminomethylpyridine (55.9 ml, 546 mmol) was added to a solution of 1-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-phenylmethanesulfonamide (51.6 g, 121 mmol) in N-methyl-2-pyrrolidinone (1214 ml) at room temperature. The solution was then heated to 130-135° C. for 2 h in a pre-warmed oil bath. The solution was then cooled to room temperature and poured into aqueous sodium hydrogen carbonate (saturated, 3.0 L) and 500 mL ice-water and extracted with ethyl acetate (3×500 mL). The combined organics were dried over anhydrous Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.47 (d, 1H); 8.46 (m, 1H); 8.16 (d, 1H); 7.81 (m, 3H); 7.76 (m, 1H); 7.49 (d, 1H); 7.38 (d, 1H); 7.32 (d, 1H); 7.25 (m, 1H); 4.63 (s, 2H); 4.22 (d, 2H). LRMS (APCI) calculated for C21H17ClN3O3S [M+H]+, 426.1; found 426.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>C(OC(=O)CCCCC)(=O)CCCCC>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:6]([CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ncn2c1COC(=O)c1c(Cl)cccc1-2
Agent: CCCCCC(=O)OC(=O)CCCCC
Product: CCCCCc1nc(-c2ncn3c2COC(=O)c2c(Cl)cccc2-3)no1
Yield: 122.6 %

Procedure:
7-Chloro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][4,1]benzoxazepine-3-amidoxime (2 g, 7 mmole) in caproic anhydride (8 ml) was heated at 150° C. for 30 minutes. The crude product in ethyl acetate:hexane (1:1) was chromatographed on silica to give the product (1.6 g, 63%), m.p. 110°-112° C.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.C([O-])(=O)C.[Cs+].BrC1[CH:40]=[CH:39][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][N:32]=1>[Cu]>[CH3:22][C:14]1([CH3:21])[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([C@H:10]2[CH2:11][C@H:8]([NH:7][C:6]3[CH:40]=[CH:39][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][N:32]=3)[CH2:9]2)[C:13]1=[O:23]
Reactant: CNC(=O)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Product: CNC(=O)c1ccc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Temperature: 100 °C

Procedure:
Intermediate 26 (100 mg, 0.373 mmol), cesium acetate (516 mg, 2.69 mmol), 6-bromo-n-methylnicotinamide (120 mg, 0.560 mmol), and copper (1.899 mg, 0.030 mmol) were weighed into a microwave vial. The vial was evacuated and flushed with nitrogen. DMSO (467 μl) was then added and the mixture was heated at 100° C. for 20 h. The mixture was diluted with ethyl acetate and washed with aqueous ammonium hydroxide. The aqueous layer was back extracted with ethyl acetate and the combined organics dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by silica chromatography, eluting with a gradient of hexane/ethyl acetate (50-100%) to provide 6-((trans-3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)amino)-N-methylnicotinamide (50 mg, 0.137 mmol, 36.6% yield) as off-white solid. M+1: 366. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 6 H) 2.28-2.40 (m, 2 H) 3.00 (d, J=4.82 Hz, 3 H) 3.39-3.54 (m, 2 H) 4.50 (br. s., 1 H) 5.28 (quin, J=8.59 Hz, 1 H) 5.38 (br. d, J=4.80 Hz, 1 H) 5.98 (br. s., 1 H) 6.34 (d, J=8.77 Hz, 1 H) 6.96 (dd, J=7.31, 5.26 Hz, 1 H) 7.43 (dd, J=7.16, 1.61 Hz, 1 H) 7.91 (dd, J=8.70, 2.41 Hz, 1 H) 8.18 (dd, J=5.26, 1.61 Hz, 1 H) 8.51 (d, J=2.05 Hz, 1 H)
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1>>[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for preparation of Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3,5-bis-trifluoromethylphenylboronic acid (202 mg, 1.24 mmol) were coupled to yield 2-(3,5-bis-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 70 mg (16%), as a pale-yellow solid. mp 230° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 3.11 (m, 2H), 3.42 (m, 2H), 7.31 (app t, 1H, J=7.8 Hz), 7.64 (d, 1H, J=8.1 Hz), 7.73 (d, 1H, J=7.5 Hz), 8.13 (br s, 1H), 8.16 (br t, 1H), 8.28 (br s, 2H), 11.95 (br s, 1H); MS (FAB, MH+) 399; Anal. (C19H12F6N2O.0.2 hexanes) C, H, N.