Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:16]([OH:18])=[O:17])[CH2:6][CH:5]([C:7]([OH:9])=O)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][CH:2]1[C:13]([OH:15])=O.C(OC(=O)C)(=O)C>>[CH2:6]1[CH:1]2[C:16]([O:18][C:13](=[O:15])[CH:2]2[CH2:3][CH:4]2[C:10]([O:11][C:7](=[O:9])[CH:5]12)=[O:12])=[O:17]
Reactant: O=C(O)C1CC(C(=O)O)C(C(=O)O)CC1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2CC3C(=O)OC(=O)C3CC12
Yield: 96.7 %

Procedure:
Subsequently, 450 g of the obtained 1,2,4,5-cyclohexanetetracarboxylic acid and 4,000 g of acetic anhydride were charged into a 5-L glass separable flask equipped with a Dimroth condenser. The inner atmosphere of the reactor was replaced with nitrogen gas under stirring. The temperature was raised to the refluxing temperature of the solvent under a nitrogen gas atmosphere to allow the solvent to reflux for 10 min. After that, the temperature was decreased to room temperature under stirring to precipitate crystals. The precipitated crystals were separated by solid-liquid separation and dried to obtain primary crystals. The mother liquor after separation was concentrated under reduced pressure using a rotary evaporator to precipitate crystals. The precipitated crystals were separated by solid-liquid separation and dried to obtain secondary crystals. In total of the primary and secondary crystals, 375 g of 1,2,4,5-cyclohexanetetracarboxylic dianhydride was obtained (yield of the dianhydride: 96.6%).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([O:13]CC1C=CC(OC)=CC=1)=[O:12])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([OH:13])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)OCc1ccccc1C(=O)OCc1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOC(=O)OCc1ccccc1C(=O)O
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
A mixture of 4-methoxybenzyl 2-[(allyloxycarbonyl)oxymethyl]benzoate (6.80 g, 19.1 mmol) obtained from Example 17-(1) and anisole (5 g) was dissolved in trifluoroacetic acid (10 ml) at room temperature. The mixture was stirred for 15 minutes, then diluted with toluene, and the solvent was distilled off under reduced pressure. The residue was washed with hexane to afford the crude title compound (3.87 g, 86%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([S:27][CH3:28])[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:11][CH2:10][C:9]=12)=O.[NH3:29].[K+].[Br-]>CO>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[N:8]3[C:7]([S:27][CH3:28])=[N:6][C:5]([C:3]([NH2:29])=[O:2])=[C:9]3[CH2:10][N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:13]=2[CH:18]=1
Reactant: N
Reactant: COC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CSc1nc(C(N)=O)c2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A mixture of 3 g (0.007 mole) of 8-chloro-6-(2-chlorophenyl) -1-methylthio-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid methyl ester and 60 ml of 25% solution of ammonia in methanol was heated at 130° in a steel bomb for 18 hrs. The contents of the bomb were evaporated at reduced pressure to give light tan crystals, which were recrystallized from methanol/methylene chloride to yield light tan prisms with mp 270°-274° (dec.). Uv λ max 217 mμ (ε=47,200) infl 242 (23,200) sh 270 (11,500), ir (KBr) 3365, 3250, 3215, 3150 cm-1 (NH2) 1675, 1650, 1590 (CON).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.C(O[C:29](=O)[CH:30]=[CH2:31])#N.C([N:35](CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([CH:30]=[CH:31][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1)#[N:35]
Reactant: C=CC(=O)OC#N
Reactant: CCN(CC)CC
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#CC=Cc1ccc2c(c1)-c1c3c(c4c([nH]c5ccccc54)c1C2)C(=O)NC3
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), cyanoacrylate (0.43 ml, 0.51 mmol) and triethylamine (0.5 mL) in DMF (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (20 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 48 h. The mixture was cooled to ambient temperature, filtered through a pad of Celite®, and the solvent was concentrated at reduced pressure. The product was triturated with MeOH to give 90 mg (97%) of a tan solid. Recrystallization from DMF-Et2O gave Compound I-35 as a tan solid, mp>330° C. 1H NMR (DMSO-d6, 300 MHz): d 4.2 (s, 2H), 5.0 (s, 2H), 7.3-7.5 (m, 3H), 7.6-7.95 (m,4H), 8.35 (s, 1H), 8.65 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.25 (s, 1H); IR: 2220 cm-1 ; MS m/e=362 (m+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][NH2:22])[C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH2:16])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18].[Br:23][CH2:24][C:25](Br)=[O:26]>CC(N(C)C)=O>[Br:23][CH2:24][C:25]([NH:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][NH:22][C:25](=[O:26])[CH2:24][Br:23])[C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH:16][C:25](=[O:26])[CH2:24][Br:23])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18])=[O:26]
Reactant: O=C(Br)CBr
Reactant: NCCN(CCN)C(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: O=C(CBr)NCCN(CCNC(=O)CBr)C(=O)c1c(I)c(NC(=O)CBr)c(I)c(C(=O)O)c1I
Temperature: 40 °C
Reaction time: 20 h

Procedure:
50 g (77.8 mmol) of N,N-bis-(2-aminoethyl)-5-amino-2,4,6-triiodoisophthalic acid amide (title compound 6a) is dissolved in 500 ml of dimethylacetamide, and 70.6 g (350 mmol) of bromoacetyl bromide (Aldrich) is added in drops over 15 minutes at 0° C. Then, it is stirred for 20 hours at 40° C. The reaction mixture is poured into 4000 ml of ice water, the accumulating solid is filtered off, dissolved in 800 ml of ethyl acetate and extracted three times with 250 ml each of water. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state. The crude product is recrystallized from methyl-tert-butyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16]>[OH-].[Na+].O>[NH:12]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C@@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
Benzyloxycarbonyl chloride (abbreviated Z-Cl hereafter) (65 ml) and 114 ml of 4 N NaOH were simultaneously added under agitation with ice-cooling to a solution of 50 g of D-Leu in 191 ml of 2 N NaOH and stirred for a further one hour. After the reaction mixture was diluted with one liter of distilled water, it was rinsed three times with 300 ml each of ethyl acetate. The aqueous layer was adjusted to pH 2.0 with 4 N HCl under cooling with ice. The oily material formed was extracted with ethyl acetate. The ethyl acetate extract, after being washed with a saturated solution of sodium chloride, was dehydrated over anhydrous sodium sulfate and then evaporated under reduced pressure to give 44 g of colorless, transparent syrup.
Reaction SMILES: C(O[C:6](=[O:28])[NH:7][CH2:8][CH:9]([C:13]([N:15]1[CH2:19][CH:18]([Cl:20])[CH:17]2[O:21][CH2:22][C:23]([O:26][CH3:27])([O:24][CH3:25])[CH:16]12)=[O:14])[CH:10]([CH3:12])[CH3:11])(C)(C)C.C(Cl)(=O)C.Cl.N1C=CC=C1.Cl.[F:40][C:41]1[S:45][C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)=[N:43][C:42]=1[C:53]1[CH:61]=[CH:60][C:56](C(O)=O)=[CH:55][CH:54]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[Cl:20][CH:18]1[CH2:19][N:15]([C:13]([CH:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][NH:7][C:6](=[O:28])[C:56]2[CH:60]=[CH:61][C:53]([C:42]3[N:43]=[C:44]([N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)[S:45][C:41]=3[F:40])=[CH:54][CH:55]=2)=[O:14])[CH:16]2[C:23]([O:24][CH3:25])([O:26][CH3:27])[CH2:22][O:21][CH:17]12
Reactant: CN1CCN(c2nc(-c3ccc(C(=O)O)cc3)c(F)s2)CC1
Reactant: COC1(OC)COC2C(Cl)CN(C(=O)C(CNC(=O)OC(C)(C)C)C(C)C)C21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CC(=O)Cl
Solvent: c1cc[nH]c1
Product: COC1(OC)COC2C(Cl)CN(C(=O)C(CNC(=O)c3ccc(-c4nc(N5CCN(C)CC5)sc4F)cc3)C(C)C)C21
Yield: 85 %

Procedure:
[2-(6-Chloro-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-methylbutyl]-carbamic acid tertbutyl ester (78 mg, 0.185 mmol) was deprotected under acidic conditions (acetyl chloride in methanol) as described in Example 4, and the crude pyrrole hydrochloride intermediate was then coupled with the HCl salt of 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid using the HATU conditions as described in Example 2, which gave the title compound (98 mg, 85%). MS m/z 624.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: Nc1cccnc1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(Nc4cccnc4)C3=O)N1CC1NC12
Product: NC(=O)O
Reaction time: 44 h
Yield: 104.1 %

Procedure:
To a solution of 60 mg mitomycin A (0.17 mmol) in 5 ml of anhydrous methanol was added 61 mg of 3-aminopyridine (1.2 mmol) with stirring. The progress of the reaction was checked periodically by TLC and the reaction appeared to be complete after 44 hours. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with a mixture of ethyl acetate and acetone (10:1 by volume) was evaporated to dryness. Recrystallization from chloroform gave 38 mg (56% yield) of green solid having a melting point of 78°-80° C. and providing the following analysis:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=O)=[CH:8][CH:7]=1.Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13]/[C:14](=[N:33]\[OH:34])/[C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=[CH:10][CH:11]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1

Procedure:
In analogy to example 151, step 3, N-(2-hydroxy-ethyl)-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=434.4 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)[O:20][C:21]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][CH:9]=1)([CH3:6])[CH3:5].[OH-].[Na+].Cl>C(O)C>[C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][C:26]([C:19]2[O:20][C:21]([C:22]([F:25])([F:24])[F:23])=[C:17]([CH2:16][CH2:15][O:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:38])=[O:2])=[CH:9][CH:10]=3)[N:18]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C(F)(F)F)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A sample of 2-{4-[2-(2-biphenyl-4-yl-5-trifluoromethyloxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid methyl ester (141 mg, 0.21 mmol) was dissolved in ethanol (2 mL) followed by addition of 5.0 N NaOH (0.6 mL). The mixture was warmed with magnetic stirring at 50° C. for one hour. The reaction mixture was then allowed to cool to room temperature then acidified with 1.0 N HCl (3 mL) then extracted with methylene chloride (50 mL). The organic phase was separated, dried over sodium chloride and concentrated under reduced pressure to yield 134 mg (98%, 24% overall) of a glassy solid. HPLC RT1=5.90 min; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.45-7.36 (m, 3H), 6.86 (d, J=9.3 Hz, 2H), 6.78 (d, J=9.3 Hz, 2H), 4.24 (t, J=6.3 Hz, 2H), 3.15 (t, J=6.3 Hz, 2H), 1.48 (s, 6H); MS (EI) 511.95 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:37][CH2:36][C@@H:35]([F:38])[CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][CH:46]1[CH2:49][CH:48]([CH2:50][OH:51])[CH2:47]1>>[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][CH:46]1[CH2:47][CH:48]([CH2:50][O:51][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:37][CH2:36][C@@H:35]([F:38])[CH2:34]5)=[CH:31][CH:32]=4)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:22])[CH2:49]1
Reactant: OCC1CC(OC2CCCCO2)C1
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2
Product: O=C(OCC1CC(OC2CCCCO2)C1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 48b using (R)-1-(4-fluorophenyl)-6-[6-((R)-3-fluoropyrrolidin-1-yl)-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride and [3-(tetrahydro-pyran-2-yloxy)-cyclobutyl]-methanol. LCMS (Method G): 626.6 (M+H)+, Retention time 4.10 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([CH:10]=O)=[C:8]([O:12][Si:13]([CH3:21])([CH3:20])[C:14]([CH3:19])([CH3:18])[CH:15]([CH3:17])[CH3:16])[CH:7]=[C:6]([O:22][CH3:23])[C:5]=1[F:24].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([CH3:10])=[C:8]([O:12][Si:13]([CH3:20])([CH3:21])[C:14]([CH3:19])([CH3:18])[CH:15]([CH3:16])[CH3:17])[CH:7]=[C:6]([O:22][CH3:23])[C:5]=1[F:24]
Reactant: COC(=O)c1c(F)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(C)c(O[Si](C)(C)C(C)(C)C(C)C)cc(OC)c1F
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a solution of 1.3 g of 2-fluoro-6-formyl -3-methoxy-5-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid methyl ester in 4 ml of trifluoroacetic acid, cooled to 0° C., was added over 10 min a solution of 0.6 g of triethylsilane in 4 ml of dichloromethane. The solution was kept at 0° C. for 18 h and then evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was successively washed with water, saturated sodium carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield 1.1 g of 2-fluoro-3-methoxy-6-methyl-5-[dimethyl -(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid methyl ester as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:44]=2)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:40]3[CH:41]=[N:42][N:43]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:44]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n2S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (940 mg, 1.651 mmol) and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate (694 mg, 2.476 mmol) in N,N-dimethylformamide (11.5 mL) was added saturated aqueous bicarbonate solution (3.83 mL) followed by bis(triphenylphosphine)palladium dichloride (81 mg, 0.116 mmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 95% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 596.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.CN1CCN(C(=O)C=CC2C3N(C4C=CC=CC=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)CC1>>[C:15]1([N:13]2[C:14]3[C:6]([CH:5]=[CH:4][C:3]([N:41]4[CH2:42][CH2:37][CH:38]([C:51]([F:54])([F:53])[F:52])[CH2:39][CH2:40]4)=[O:2])=[CH:7][C:8]([C:21]([F:22])([F:24])[F:23])=[CH:9][C:10]=3[N:11]=[CH:12]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: O=C(C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)N1CCC(C(F)(F)F)CC1

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford, after removal of the solvent, the title compound as a white solid (40 mg, 12%), m/z 468.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1N(C2C=CC=CC=2)C2C(C=1)=CC=CC=2)(C)(C)C.[CH3:39][Si:40]([C:43]#[CH:44])([CH3:42])[CH3:41]>[Cu]I.CN(C)CCN(C)C>[CH3:39][Si:40]([C:43]#[C:44][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1)([CH3:42])[CH3:41]
Reactant: COC(=O)C1CC1c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: CC(C)(C)P(c1cc2ccccc2n1-c1ccccc1)C(C)(C)C
Agent: CN(C)CCN(C)C
Product: COC(=O)C1CC1c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared from and according to the general procedure A dry Schlenk flask was charged with methyl 2-(4-iodophenyl)cyclopropanecarboxylate (1.66 g, 5.49 mmol), Na2[PdCl4] (18 mg, 0.06 mmol), 2-(di-tert-butylphosphino)-1-phenylindole (37 mg, 0.11 mmol), CuI (21 mg, 0.11 mmol), and tetramethylethylenediamine (10 mL). The mixture was evacuated and backfilled with Ar (3×), and heated to 70° C. before addition of trimethylsilylacetylene (1.4 mL, 10.8 mmol) through the septum and the temperature was elevated to 80° C. After consumption of the starting material indicated by HPLC, the reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (3×). The combined extracts were washed with brine, dried over MgSO4 and concentrated under vacuum and a fraction of the residue was purified by flash chromatography to give 580 mg (40%) after purification by flash chromatography (SiO2, EtOAc:PE, 1:8): Rt: 14.56 min (HPLC method I).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:30][CH2:29][C@:7]2([O:11][CH2:10][C:9]([C:12]3[CH:17]=[C:16]([N:18]4[CH:22]=[CH:21][N:20]=[C:19]4[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:14][C:13]=3[O:27][CH3:28])=[CH:8]2)[C@@H:6]1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:4].C(O)(=O)C>[OH-].[Pd+2].[OH-].CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:30][CH2:29][C@:7]2([O:11][CH:10]=[C:9]([C:12]3[CH:17]=[C:16]([N:18]4[CH:22]=[CH:21][N:20]=[C:19]4[C:23]([F:24])([F:25])[F:26])[CH:15]=[CH:14][C:13]=3[O:27][CH3:28])[CH2:8]2)[C@@H:6]1[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@@]2(C=C(c3cc(-n4ccnc4C(F)(F)F)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@@]2(CC(c3cc(-n4ccnc4C(F)(F)F)ccc3OC)=CO2)[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 67 mg (0.13 mmol) of (5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]non-3-ene-7-carboxylic acid methyl ester (from Example 69), 20% palladium(II) hydroxide on carbon (32 mg), acetic acid (1.2 mL), and methanol (6.0 mL) was stirred at RT under hydrogen at atmospheric pressure. After 20 min., the catalyst was removed using a 0.45 micron filter and washed with additional methanol. The filtrate was concentrated and the residue was purified by preparative TLC, eluting five times in 3% ethyl ether in dichloromethane. This yielded 15 mg of the title compound and 30 mg of (3S,5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-(trifluoromethyl)imidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane-7-carboxylic acid methyl ester.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C[O-].[Na+].[Cl:12][C:13]1[CH:36]=[CH:35][C:16]2[C:17](=O)[C:18](=[CH:30]N(C)C)[CH2:19][N+:20]([O-:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]=2[CH:14]=1>CO.O>[NH2:7][C:6]1[N:8]=[CH:30][C:18]2[CH2:19][N+:20]([O-:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]3[CH:14]=[C:13]([Cl:12])[CH:36]=[CH:35][C:16]=3[C:17]=2[N:5]=1
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=[N+]([O-])C2

Procedure:
In two equal portions 28 g (150 mmole) of guanidine carbonate and 38 ml (150 mmole) of a 4.09M methanol solution of sodium methoxide was added over a 2 hr period to a solution of 7.0 g (20 mmole) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide in 210 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red solid. Recrystallization from a mixture of methanol and ethyl acetate gave the product as fine yellow needles, m.p. 320°-323° C.