Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C@H:19]([C:20](OCC)=[O:21])[CH2:18][N:17]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:16][C@@H:15]1[C:34](OCC)=[O:35])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH:19]([CH2:20][OH:21])[CH2:18][N:17]([S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:16][CH:15]1[CH2:34][OH:35])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@H]1CN(S(=O)(=O)c2ccccc2)C[C@@H](C(=O)OCC)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CC(CO)N(Cc2ccccc2)C(CO)C1
Yield: 80.1 %

Procedure:
1 M solution of LiAlH4 in THF (70 ml; 70 mmol) was added dropwise under cooling and stirring to 112c (10.7 g; 23.2 mmol) in THF (275 ml). The reaction mixture was refluxed for 20 min, poured on a saturated solution of Na2CO3 and extracted with TBME three times. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield a colorless solid, which was washed with TBME to yield 112d as white crystals (7 g, 80%). MS: [M+H]+: 377
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:13]([O:30][CH3:31])[CH:12]=3)[CH:9]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:3]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50](B2OC(C)(C)C(C)(C)O2)[C:49]([CH3:62])=[N:48]1.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.C1(C)C=CC=CC=1.C(O)C.O>[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[C:13]([O:30][CH3:31])[CH:12]=4)[CH:9]=3)[N:4]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:3]=2)[C:49]([CH3:62])=[N:48]1
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 150.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)piperazine-1-carboxylate (intermediate 58) (200 mg, 0.3 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (130 mg, 0.13 mmol) in sodium carbonate (95 mg, 0.9 mmol), Pd(PPh3)2Cl2 (15 mg, 0.015 mmol), Toluene/ethanol/water (10/2/2.5 ml) to give 150 mg (64.65% yield) of titled compound. MS: m/z=765.3 (M+1).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]([CH2:14][O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26])#[N:13].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:13][CH2:12][CH2:14][O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26]
Reactant: COc1ccc([N+](=O)[O-])cc1OCC#N
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1OCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a suspension of sodium borohydride (0.55 g, 0.015 mole) in dry THF (50 ml) at 0° C., under an argon atmosphere, was added boron trifluoride etherate (2.4 ml, 0.02 mole) dropwise. After addition was completed the mixture was left to stir for 1 hour at room temperature and then a solution of 2-cyanomethoxy-4-nitroanisole (D8 1.0 g, 0,0048 mole) in dry THF (50 ml) was added and the mixture heated under reflux for 1 hour. The mixture was treated with saturated aqueous NaHCO3 solution until effervescence had ceased and then concentrated in vacuo. The residue was treated with water and extracted with dichloromethane. The combined organic extracts were dried and concentrated in vacuo to give the title compound (1.0 g, 100%).
Reaction SMILES: Cl.[CH2:2]([N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:3]([CH3:5])[CH3:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C@H:40]([C:48](O)=[O:49])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:38])=[CH:32][CH:31]=1>>[CH3:4][CH:3]([CH2:2][N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:48]([C@@H:40]([NH:39][C:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)=[O:38])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:49])[CH3:5]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: Cl
Product: COc1ccc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(N)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine hydrochloride (200 mg, 0.45 mmol, example 5, step C) as described in general procedure Bc using Nα-(4-methoxyphenylacetyl)-L-phenylalanine (example 132, step A). The final product, Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-Nε-[N′α-(4-methoxyphenylacetyl)-L-phenylalanyl]-L-lysine was subsequently hydrogenolysed following the indications of general procedure E. Purification by HPLC gave the desired material (7 mg, 4%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)c1ccccc1F
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccccc3F)nc12

Procedure:
From 2-fluorobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4)dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+20.0° (c=1.00, CHCl3), ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=2[S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:10]=1
Reactant: CCS(=O)(=O)c1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 79.5 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.81 g), 1-[5-chloro-2-(ethylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 3 (2.5 g) and potassium carbonate (3.19 g) were stirred in ethanol (30 ml) at 85° C. for 24 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (4 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.3 g).
Reaction SMILES: [N+:1]([CH2:4][C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2)([O-])=O.CO.C(O)C.C(=O)([O-])[O-]>O.C(O)(C)C.C(O)CC>[NH2:1][CH2:4][C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2
Reactant: O=[N+]([O-])CC12CCCN1CCC2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: NCC12CCCN1CCC2
Temperature: 25 °C
Reaction time: 3.25 h

Procedure:
Among two types of said reducing reaction, the former type reaction will be completed within 0.5 to 6 hours, when 1 equivalent amount of 7a-nitromethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine or a salt thereof and 3 to 10 equivalent amount of the acid and 3 to 10 equivalent amount of the metal or the metal salt were dissolved in a suitable solvent to stir the mixture at room temperature. As the solvent, methanol, ethanol, n-propanol, i-propanol or the like alcohol; water; or a mixture of water and an alcohol may be listed. After completion of the reaction, insoluble matters were filtered off, the filtrate was, if necessary, concentrated in vacuo, adding thereto an alkali solution, filtering off, if necessary, insoluble matters, distilling out the solvent, extracting with use of an organic solvent, concentrating the extract, and distilling the residue; or after completion of the reaction, an alkali carbonate or a solution thereof was added to the reaction mixture, filtering off formed insoluble matters, concentrating the filtrate in vacuo, dissolving or suspending the resulting residue in an organic solvent, stirring same for 1 to 12 hours at 20° C., while introducing ammonia gas, filtering-off insoluble matters, concentrating the filtrate in vacuo, and then distilling in vacuo to afford the desired 7a-aminomethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine (Compound III). As the alkali for alkalidizing the reaction mixture, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or the like may be listed. As the extraction solvent, methylene chloride, chloroform, ethyl ether, ethyl acetate or the like may be listed. While, as the basic carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate or the like may be listed. As the organic solvent for dissolving or suspending the residue, benzene, toluene, tetrahydrofuran, dioxane or the like ether solvent; methanol, ethanol, i-propanol, n-propanol, i-butanol, n-butanol or the like alcoholic solvent may be listed.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:14]=3[CH:23]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].C(O)C.Cl.[NH2:28][OH:29].C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1>[OH:29][N:28]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:14]=3[CH:23]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)=O)cc3)ccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)=NO)cc3)ccc2o1

Procedure:
A mixture of 6.2 g of 10A, 100 ml of ethanol and 200 ml of tetrahydrofuran was heated to 60°-70° C. A solution of 1.53 g of hydroxylamine hydrochloride and 1.16 g of sodium carbonate in 20 ml of water was added. The mixture was heated for 3 hours at 60°-70° C. The resulting solid was collected, washed with water, then ethanol, and extracted with methylene chloride. The solvent was evaporated from the extract under reduced pressure to give ethyl 5-(4-(1-(hydroxyimino)ethyl)phenyl)-2-benzofurancarboxylate (12A), mp: 220°-222° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[CH:12]=[C:13](/[C:17](=[N:23]/[OH:24])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:26][C:27]1[CH:46]=[CH:45][C:30]([O:31][CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])=[CH:29][CH:28]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:3]([C:11]1[CH:12]=[C:13](/[C:17](=[N:23]/[O:24][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:45][CH:46]=2)/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C(=N\O)c1cccc(C(=O)c2ccccc2)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Sodium hydride (60% in oil, 399 mg) was added to a solution of ethyl Z-2-(3-benzoylphenyl)-2-hydroxyiminoacetate (2.47 g) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.61 g) in N,N-dimethylformamide (15 ml) at room temperature under nitrogen atmosphere and stirred for 1 hour. 1N hydrochloric acid (15 ml) was added, an aqueous saturated solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl Z-2-(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (1.97 g, yield 41%) as a pale-yellow oil from an ethyl acetate-hexane (1:3, v/v)-eluted fraction.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:23]=[CH:22][N:13]([C@@H:14]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:24])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CO>C(Cl)Cl>[C:31]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[CH:23][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:24])[CH2:15][C@@H:16]1[OH:17])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)n1)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
3.31 g (10 mmol) of N-benzoyl-2'-deoxycytidine were added to 25 ml of pyridine, and then 3.07 g (11 mmol) of trityl chloride were added to the suspension. The resulting suspension was stirred at 100° C. for 1 hour, after which it was allowed to cool to room temperature. The pyridine was then removed by distillation under reduced pressure. The resulting residue was dissolved in a mixture of ethyl acetate and a saturated aqueous solution of sodium chloride. The organic layer was separated and washed twice, each time with a saturated aqueous solution of sodium chloride. The solution was then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel (Lober column Si-60, Size C) using a gradient elution method, with mixtures of methanol and methylene chloride ranging from 2:98 to 5:95 by volume as the eluent, to give 1.47 g (yield 26%) of the title compound.
Reaction SMILES: [CH:1]1([C:6](=[O:11])[CH2:7][CH2:8][C:9]#[CH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N[CH:16]([CH3:18])[CH3:17])(C)C>CN(C=O)C.CCOC(C)=O.[Cu]I.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>[CH:1]1([C:6](=[O:11])[CH2:7][CH2:8][C:9]#[C:10][C:3]2[CH:2]=[C:1]([CH3:5])[C:6]([OH:11])=[CH:18][C:16]=2[CH3:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCCC(=O)C1CCCC1
Reactant: CC(C)NC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C#CCCC(=O)C2CCCC2)c(C)cc1O
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 1-cyclopentyl-pent-4-yn-1-one (0.33 g, 2.2 mmol) from example F(7), Step 2,4-iodo-2,5-dimethyl-phenol (0.54 g, 2.2 mmol), copper (I) iodide (33 mg, 0.18 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol), and diisopropylamine (2.2 mL) in DMF (2.2 mL) was heated to 100° C. for 30 minutes. The reaction was cooled to room temperature and diluted with 10 mL of EtOAc. The resulting slurry was filtered, and the mother liquor was concentrated to a black oil. The oil was then purified by flash chromatography to give the desired product (112 mg, 19% yield). 1H NMR (CDCl3) δ: 1.58-1.84 (m, 8H), 2.15 (s, 3H), 2.29 (s, 3H), 2.68-2.70 (m, 2H), 2.75-2.79 (m, 2H), 2.90 (p, J=8.08 Hz, 1H), 6.57 (s, 1H), 7.10 (s, 1H).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.N1C=CC=CC=1.Cl>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:18]([N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)=[O:25])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2N(C(=O)c2ccncc2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 21.0 g (0.1 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 23.0 g (0.129 mol) of isonicotinic acid chloride hydrochloride, 21 ml (0.26 mol) of pyridine and 300 ml of anhydrous dioxan was refluxed for 3 hours. After cooling, the mixture was poured into 1 liter of ice-cold water, acidified with conc. hydrochloric acid and extracted twice, each time with 200 ml of dichloromethane. The aqueous phase was made alkaline with methylene chloride. The combined methylene chloride extracts were washed with water, dried over sodium sulphate and the solvent was removed in vacuo. The residue was recrystallized from hot methanol. After washing with ether, the beige crystals melted at 277°-279° C. Yield 16.0 g (51% of theory).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1.N1C2C=CC=C(N)C=2C=N1.[F:28]C1C=CC(I)=CC=1>>[F:28][C:6]1[CH:5]=[CH:4][C:3]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[N:9]2)=[CH:2][CH:7]=1
Reactant: Fc1ccc(I)cc1
Reactant: Nc1cccc2c1cnn2-c1ccccc1F
Agent: Nc1cccc2[nH]ncc12
Product: Nc1cccc2c1cnn2-c1ccc(F)cc1

Procedure:
Similarly prepared to Intermediate 1 from 1H-indazol-4-amine and 4-fluoro-1-iodobenzene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:51])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27]=4[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:41][C:42]2[CH:43]=[C:44]3[CH:50]=[CH:49][NH:48][C:45]3=[N:46][CH:47]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:52]([O-:54])=[O:53].[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][NH2:64])=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>CS(C)=O.CO>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:27]2[CH2:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH2:31][C:26]=2[CH2:25][N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:11][S:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:64][CH2:63][C:60]5[CH:61]=[CH:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=5)=[C:3]([N+:52]([O-:54])=[O:53])[CH:4]=4)(=[O:10])=[O:9])=[O:51])=[C:14]([O:41][C:42]4[CH:43]=[C:44]5[CH:50]=[CH:49][NH:48][C:45]5=[N:46][CH:47]=4)[CH:15]=3)[CH2:20][CH2:21]2)=[CH:35][CH:36]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(Cl)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: COc1ccc(CN)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc(CNc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cnc4[nH]ccc4c3)cc2[N+](=O)[O-])cc1

Procedure:
A suspension of EXAMPLE 53A (120 mg), (4-methoxyphenyl)methanamine (31 mg) and Hunig's Base (0.159 mL) in dimethylsulfoxide (2 mL) was heated for 2 hours at 150° C. in a Biotage Initiator microwave reactor. The reaction mixture was diluted with methanol (2 mL) and purified by reverse phase HPLC (C8, 30%-100% CH3CN/water/0.1% trifluoroacetic acid). 1H NMR (500 MHz, pyridine-d5) δ 13.07 (s, 1H), 9.32 (d, 1H), 9.17 (t, 1H), 8.43 (d, 1H), 8.28 (dd, 1H), 8.08 (d, 1H), 7.64-7.68 (m, 2H), 7.44 (d, 2H), 7.38 (d, 2H), 7.07 (d, 2H), 6.97-7.02 (m, 2H), 6.90 (d, 1H), 6.74 (dd, 1H), 6.52 (d, 1H), 6.49 (dd, 1H), 4.55 (d, 2H), 3.68 (s, 3H), 3.03-3.09 (m, 4H), 2.77 (s, 2H), 2.26 (t, 2H), 2.10-2.17 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
Reaction SMILES: C([O-])(=S)C.[K+].[C:6]([S:9][CH:10]1[CH2:15][CH2:14][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12]/[C:11]/1=[CH:35]\[C:36]1[CH:37]=[N:38][N:39]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:40]=1)(=[O:8])[CH3:7].C(SC(C1C=NN(CC(OCC)=O)C=1)C1CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CCC=1)(=O)C.[F:88][C:89]([F:94])([F:93])[C:90]([OH:92])=[O:91]>CS(C)=O.O.ClCCl>[F:88][C:89]([F:94])([F:93])[C:90]([OH:92])=[O:91].[C:6]([S:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12]/[C:11]/1=[CH:35]\[C:36]1[CH:37]=[N:38][N:39]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:40]=1)(=[O:8])[CH3:7]
Reactant: CCOC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)cn1
Agent: CC([O-])=S
Agent: CCOC(=O)Cn1cc(C(SC(C)=O)C2=CCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cn1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cn1cc(/C=C2\CNCCC2SC(C)=O)cn1
Temperature: 80 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
To a solution of the mixture as above in dimethyl sulfoxide (100 ml), was added potassium thioacetate (12.3 g). The resulting mixture was stirred at 80° C. for 15 hours, cooled to room temperature, and diluted with water to stop the reaction. The products were extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous aqueous sodium chloride, and solvents were evaporated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford an approximately 7:6:1 mixture of (E)-4-(acetylsulfanyl)-3-{[1-(ethoxycarbonylmethyl)-1H-pyrazol-4-yl]methylidene}-1-(triphenylmethyl)piperidine, its (Z)-isomer and 5-{(acetylsulfanyl)[1-(ethoxycarbonylmethyl)-1H-pyrazol-4-yl]methyl}-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (5.52 g). To a solution of the above mixture in dichloromethane (300 ml) was added trifluoroacetic acid (1.9 ml). The resulting mixture was stirred at room temperature for 15 minutes. The solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of dichloromethane and methanol (10:1) as the eluent to afford the title compound as a yellow amorphous solid (1.75 g, overall yield: 33%).