Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH3:25])=[CH:11][C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:13]([CH3:14])[C:8]=2[O:7][CH:6]=1.CO.[OH-].[Na+].Cl>C1COCC1>[CH3:24][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:11]=[C:10]([CH3:25])[C:9]3[C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:6][O:7][C:8]=3[C:13]=2[CH3:14])=[CH:22][CH:21]=[C:20]([CH3:23])[N:19]=1
Reactant: COC(=O)Cc1coc2c(C)c(OCc3ccc(C)nc3C)cc(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(COc2cc(C)c3c(CC(=O)O)coc3c2C)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a mixture of methyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-4,7-dimethyl-1-benzofuran-3-yl)acetate (142.0 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (1.21 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl. The precipitate was collected by filtration. The solid was crystallized from IPA-EtOAc to give the title compound (100 mg).
Reaction SMILES: C(NC(C)C)(C)C.CS(O[CH2:13][CH2:14][O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[CH:25][CH:24]=2)=[CH:18][C:17]=1[CH3:39])(=O)=O.[NH2:40][C@@H:41]([CH3:63])[C@@H:42]([C:44]1[CH:45]=[CH:46][C:47]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:48]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:49]=1)[OH:43].O>CN(C)C=O.C(OCC)(=O)C>[CH2:56]([O:55][C:47]1[CH:46]=[CH:45][C:44]([C@@H:42]([OH:43])[C@@H:41]([NH:40][CH2:13][CH2:14][O:15][C:16]2[C:17]([CH3:39])=[CH:18][C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:30])=[CH:25][CH:24]=3)=[CH:20][C:21]=2[CH3:22])[CH3:63])=[CH:49][C:48]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCOS(C)(=O)=O
Reactant: C[C@H](N)[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.102 mL) was added to a mixture of benzyl 4′-(2-hydroxyethoxy)-3′,5′-dimethylbiphenyl-4-carboxylate (0.381 g) and triethylamine (0.213 mL) in methylene chloride (5 mL) at room temperature with stirring. After being stirred at that temperature for 1 hr, water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford benzyl 4′-(2-methanesulfonyloxyethoxy)-3′,5′-dimethylbiphenyl-4-carboxylate as a crude product. Diisopropylamine (0.148 mL) was added to a mixture of the crude benzyl 4′-(2-methanesulfonyloxyethoxy)-3′,5′-dimethylbiphenyl-4-carboxylate and N-{5-[(1R,2S)-2-amino-1-hydoxy-propyl]-2-benzyloxyphenyl}methanesulfonamide (0.154 g) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 80° C. overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=30/1-20/1) to afford the title compound (0.074 g).
Reaction SMILES: CC(N(C)C)=O.Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=2)[N:13]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>O>[F:18][C:17]([F:20])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: Oc1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 40 °C
Yield: 92 %

Procedure:
Dimethylacetamide (250.0 mL) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine [CAS: 40971-95-7] (50.0 g, 225 m mol) at 22-25° C. in a suitable round bottom flask followed by 4-(piperidin-4-yl)phenol [CAS: 62614-84-0] (60.9 g, 236 m mol) at 22-25° C. The reaction mass was stirred to obtain a clear solution. Triethylamine (79.1 mL, 561 m mol) was slowly added to the reaction mass by drop wise addition over a period of 60 min at 25-30° C. Temperature was raised to 40° C. and the reaction mass stirred for 1.0 h. After completion of reaction, water (500.0 mL) was added to the reaction mass by drop wise addition over a period of 30 min at 40-43° C. The slurry mass was stirred for 30 min at 40° C. and then filtered under reduced pressure. The wet material was slurry washed using water (500.0 mL) for 30 min at 40° C. The solid was collected by filtration and the material washed with water (125.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (75.1 g, 89.9%) as a free flowing solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:13](=O)[CH3:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])([CH3:3])[CH3:2].Cl.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][O:25][NH2:26])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25]/[N:26]=[C:13](/[C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)\[CH3:14])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: COc1ccc(C(C)=O)cc1OC(C)C
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1OC(C)C
Yield: 88.7 %

Procedure:
3′-Isopropoxy-4′-methoxyacetophenone (8) (150 mg, 0.720 mmol) was condensed with compound 19 (162 mg, 0.792 mmol) according to the general procedure II-A defined above. After being heated for 3 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing yellow oil was dissolved in CH2Cl2 (20 mL) and the resulting solution washed with H2O (2×15 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (15:85 v/v ethyl acetate/hexane elution) to afford the title compound CP30254 (229 mg, 89%) as a pale-yellow oil, which solidified upon extensive standing, m.p. 44.5-46.1° C., Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[N:8]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)CBr
Reactant: C1CNCCNCCCNCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1CCCNCCNCCCNCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a first phase, ethyl (1,4,8,11-tetraazacyclotetradec-1-yl)ethanoate is obtained by slowly adding 6.68 g (40.0 mmol) of ethyl bromoacetate onto a solution of 40 g (200.0 mmol) of cyclam and 16 g (116 mmol) of potassium carbonate in 1 L of chloroform. The reaction mixture is maintained under stirring at room temperature for 48 h. After filtration on celite and evaporation of the solvent, the residue is taken up in petroleum ether. The excess cyclam is filtered off, the filtrate is concentrated and ethyl (1,4,8,11-tetraazacyclotetradec-1-yl)ethanoate (so-called compound 5.0) is thereby obtained, as 11.21 g of a slightly yellow oil (yield=98%) which is used without any purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:10]=[N:11][C:6]=2[CH:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[CH:31]=2)[CH:3]=1>[Pd]>[NH2:36][C:32]1[CH:31]=[C:30]([C:4]2[CH:3]=[C:2]([CH3:1])[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([S:19]([NH:22][CH2:23][CH2:24][N:25]5[CH2:26][CH2:27][CH2:28][CH2:29]5)(=[O:20])=[O:21])=[CH:17][CH:18]=4)[N:10]=[N:11][C:6]=3[CH:5]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Agent: [Pd]
Product: Cc1cc(-c2cccc(N)c2)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Reaction time: 3 h
Yield: 99.3 %

Procedure:
4-[5-methyl-7-(3-nitro-phenyl)-benzo[1,2,4]triazin-3-yl amino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.16 g, 0.3 mmol, 1 equiv) was combined with 10% palladium on carbon (0.135 g) and flushed with argon. The reactants were then diluted with methanol (15 mL), and rthe eaction atmosphere was evacuated and replaced with hydrogen. A hydrogen balloon was affixed and the reaction was allowed to stir for 3 hours. Argon was then bubbled through the reaction mixture and the contents were filtered though a pad of Celite. The solvents were evaporated to provide the product as an orange solid (0.15 g, 98% yield). MS (ESI+): m/z=504.6, LC retention time: 1.84 min. 1H NMR (DMSO-d6): δ 1.64 (bs, 4H), 2.72 (s, 3H), 2.87 (bs, 2H), 5.26 (s, 2H), 6.65 (d, J=7.8 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 7.05 (m, 1H), 7.18 (t, J=7.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 8.12 (s, 1H), 8.21 (d, J=8.8 Hz, 2H), 8.27 (d, J=1.7 Hz, 1H), 11.44 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12]O)=[CH:2]1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:15][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: OCCCc1c[nH]c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
To a suspension of litium aluminum hydride (8.0 g) in tetrahydrofuran (500 mL) was a solution of 3-indolepropionic acid (20 g) in tetrahydrofuran (100 mL) added dropwise. The reaction mixture was stirred for 1 h at room temperature and subsequently cooled to 5° C. After sequential addition of water (16 mL), 15% aqueous sodium hydroxide (8.0 mL) and water (40 mL), the reaction mixture was stirred at room temperature over night and filtered. Evaporation of the volatile solvents gave pure 3-(1H-indol-3-yl)propanol (19.1 g) as an oil. 3-(1H-Indol-3-yl)propanol (18.6 g) and carbon tetrabromide (42.1 g) was dissolved in acetonitrile (1 L) and cooled to 0° C. and triphenylphosphine (30.7 g) was added in small portions. The reaction was stirred for further 3 h at room temperature, the volatile solvents evaporated in vacuo and the remaining oil purified by silicagel chromatography (heptane:ethyl acetate/2:1) to give 3-(3-bromopropyl)-1H-indole (25.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[N:6]=1.[CH2:20](Cl)[C:21]#[CH:22]>>[Br:1][C:2]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:3]=1[N:4]([CH2:22][C:21]#[CH:20])[C:5]1[N:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: C#CCCl
Reactant: Cc1cc(C)nc(Nc2ccc(C(C)C)cc2Br)n1
Product: C#CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1Br

Procedure:
By using 2-(2-bromo-4-(1-methylethyl)anilino)-4,6-dimethylpyrimidine and substituting propargyl chloride in Example 9, the title compound was isolated as the free-base, Mass spec. (NH3 --CI/DDIP): 358 (m+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[N:26]=[N:27][CH:28]=[CH:29][CH:30]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:31])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.[C:32]([CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)#[CH:33].C(NC(C)C)(C)C.CN(C=O)C>O.C(OCC)(=O)C.[Cu]I.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.CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[N:26]=[N:27][CH:28]=[CH:29][CH:30]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:31])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[C:33]#[C:32][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C#CC1CCCC1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3cccnn3)ccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COc1nc(C#CC2CCCC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3cccnn3)ccc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
A RBF was charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (0.075 g, 0.157 mmol), ethynylcyclopentane (0.074 ml, 0.784 mmol), diisopropylamine (0.134 ml, 0.941 mmol), copper(i) iodide (2.66 μl, 0.078 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.016 mmol), and DMF (0.784 ml). The reaction was stirred at 100° C. for 18 hrs. The mixture was diluted with water and Ethyl Acetate. The organic portion was collected, dried with sodium sulfate, filtered, and concentrated. The crude material was purified via column chromatography (RediSep Gold 40 g, gradient elution 10-75% [3:1 EtOAc/EtOH]:Heptane to give 1-(5-chloro-6-(cyclopentylethynyl)-2-methoxy-3-pyridinyl)-2-oxo-N-3-pyridazinyl-1,2-dihydro-6-quinolinesulfonamide (55 mg, 0.103 mmol, 65.4% yield) as an off-white solid. m/z (ESI) 536.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1

Procedure:
{5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine prepared in Example 160 and ethyl sulfonylchloride were reacted according to the same procedure as Step B of Preparation 29 to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Ic1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: c1ccc(COc2ccc(-c3cccnc3)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 4-benzyloxyphenylboronic acid (1.48 g, 6.5 mmol) in DME (10 mL) was added 3-iodo pyridine (1.03 g, 5.0 mmol) in DME (8 mL), potassium carbonate (2.0 g, 15 mmol) in 1:1 mixture of EtOH:water (3 mL), palladium(II) acetate (56 mg, 0.25 mmol), and triphenyl phosphine (202 mg, 1.0 mmol) in DME (2 mL). The resulting mixture was warmed up to 90° C. and stirred for 16 h at that temperature. After cooling to rt, reaction mixture was poured into ice-water (200 mL) and product was extracted with EtOAc, washed with brine, filtered through pad of Celite and concentrated to a yellow solid. The crude mixture was purified by silica gel flash chromatography (20% EtOAc/Hexane) to obtain the title product as yellow solid (1.2 g, 92%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:36])=[CH:17]/[CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([O:33][CH2:34][CH3:35])[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13](/[C:16](/[CH3:36])=[CH:17]/[CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C@H:27]([O:33][CH2:34][CH3:35])[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(C(C)=O)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(C(C)=O)c3)cc2)cc1)C(=O)O
Yield: 25 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′-acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (Example 105) (140 mg, 0.288 mmol) and sodium hydroxide (1M, 0.58 ml, 0.58 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′-acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (33 mg, 25%) as a yellow coloured solid.
Reaction SMILES: [OH:1][C:2]1[C:12]2[N:11]=[CH:10][CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17].[OH2:18]>C(#N)C>[OH:1][C:2]1[C:12]2[NH:11][CH:10]([OH:18])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1ccc2c(c1O)N=CC1CCCN1C2=O
Reactant: O
Solvent: CC#N
Product: Cc1ccc2c(c1O)NC(O)C1CCCN1C2=O
Reaction time: 2 h

Procedure:
64.4 mg of 2,3,5,11 a-tetrahydro-9-hydroxy-8-methyl-1H-pyrrolo[2,1-C] [1,4]benzodiazepin-5-one was dissolved in 2.5 ml of hot acetonitrile, 0.5 ml of water was added thereto, and the mixture was allowed to stand first at room temperature for 2 hours and then at -20° C. for 1 day. Thus, 51.1 mg of 2,3,5,10,11,11 a-hexahydro-9,11-dihydroxy-8-methyl-1H-pyrrolo[2,1-C] [1,4]benzodiazepin-5-one was obtained as a yellow-colored crystal. Recrystallization of the resulting product from aqueous acetonitrile gave a yellow-colored prismatic crystal having a melting point of 154° to 156° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([CH2:10][CH2:11][CH:12]=[O:13])=[C:6]([CH:9]=1)[C:7]#[N:8].C1COCC1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][OH:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)c(Cl)cc1CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(N)c(Cl)cc1CCCO
Temperature: 0 °C
Reaction time: 6 h
Yield: 61.9 %

Procedure:
5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (200 mg, 0.959 mmol) was taken up in MeOH (2 mL) and THF (2 mL) and cooled to 0° C. NaBH4 (54.4 mg, 1.438 mmol) was added, and the reaction was stirred at 0° C. for 6 h (reaction followed by TLC). The reaction was quenched with water and extracted 2× with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-50% EtOAc/DCM; 40 g column). 5-amino-4-chloro-2-(3-hydroxypropyl)benzonitrile (125 mg) was obtained as a yellow glass.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(N(CC)CC)C.[C:18](=[O:26])([O:23][CH2:24][CH3:25])[O:19][CH:20](Cl)[CH3:21].CCOCC>C1(C)C=CC=CC=1.O>[C:1]([O:10][CH:20]([O:19][C:18]([O:23][CH2:24][CH3:25])=[O:26])[CH3:21])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: CCOC(=O)OC(C)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)OC(C)OC(=O)c1ccccc1O

Procedure:
A mixture of 2.76 g salicylic acid, 2.02 g triethylamine and 3.5 gm 1-chloroethyl ethyl carbonate in 25 ml of toluene is refluxed for three hours. The reaction mixture is cooled and 25 ml of ether and 25 ml of water added. The organic layer is separated, washed 2× with 25 ml water, dried through sodium sulfate and concentrated in vacuo. The residue (3.88 g) is chromatographed on 200 g silica gel. Elution with 25% methylene chloride in hexane gives 1-(ethoxycarbonyloxy)ethyl salicylate which is directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[C:30]([CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)#[N:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][C:30]#[N:31])[CH2:35][CH2:36]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: N#CCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCC#N)CC3)ccc21
Yield: 99.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (40.8 mg, 0.0993 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 1-(2-cyanoethyl)piperazine (59.8 mg, 0.430 mmol), acetic acid (0.115 mL, 2.01 mmol) and sodium triacetoxyborohydride (74.3 mg, 0.351 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-cyanoethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone (53.0 mg, yield 100%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1.C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36]>>[CH:35]([NH:38][C:39]([N:11]1[CH2:12][CH2:13][C:14]2[N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:3]=3[F:2])[N:7]=[C:8]([C:15]3[CH:22]=[CH:21][CH:20]=[C:17]([C:18]#[N:19])[CH:16]=3)[C:9]=2[CH2:10]1)=[O:40])([CH3:37])[CH3:36]
Reactant: CC(C)N=C=O
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
To a mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.060 g, 0.171 mmol) and triethylamine (138 mg, 1.37 mmol) at 0° C. was added isopropylisocyanate (17.5 mg, 0.21 mmol) and the mixture was stirred at room temperature for 16 h. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic) to give 19 mg of 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide (11a).