Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][O:23][CH2:24][C:25]3([C:28]#[N:29])[CH2:27][CH2:26]3)[C:11](=[O:32])[C@@H:10]([CH2:33][C:34]([OH:36])=[O:35])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:42]>CC(O)(C)C>[C:28]([C:25]1([CH2:24][O:23][CH2:22][C@@H:21]([N:12]2[C@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][C@H:10]([CH2:33][C:34]([OH:36])=[O:35])[C:11]2=[O:32])[CH2:30][CH3:31])[CH2:27][CH2:26]1)(=[O:42])[NH2:29]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC[C@@H](COCC1(C#N)CC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC[C@@H](COCC1(C(N)=O)CC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of 10 mg (0.02 mmol) 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyclopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 11) and potassium hydroxide (3.2 mg, 0.06 mmol) in t-BuOH (189 μL) was stirred at 85° C. for 24 h. The reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 35 to 75% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:26](Cl)(Cl)=[S:27]>C(Cl)(Cl)Cl.CCCCCC>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:26]=[S:27])[C:14]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1nc2cc(N3CCOCC3)c(N)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)c1nc2cc(N3CCOCC3)c(N=C=S)cc2s1
Reaction time: 10 h

Procedure:
To a cooled mixture of 143 g of 6-amino-2-tert-butyl-5-morpholinobenzothiazole and 168 g of sodium bicarbonate in 200 ml of CHCl3 is added 75 g of thiophosgene under stirring. The stirring is continued at ambient temperature for 10 hours. The solide are filtered off and the filtrate is evaporated. The solid thus obtained is dissolved in hexane and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-6-isothiocyanato-5-[morpholin-4-yl]benzothiazole melting at 141°-143°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(Nc3nc(C)cs3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(OC)c2c(CN)ncc(Nc3nc(C)cs3)c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
To a solution of [6,8-dimethoxy-4-(4-methyl-thiazol-2-ylamino)-isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester (20 mg, 0.045 mmol) in 1 mL CH2Cl2 was added a 4.0 M HCl solution in dioxane (0.70 mL). After the reaction mixture was stirred at room temperature for 20 h, the resulting yellow solid was collected by suction filtration, and dried in vacuo to give (1-aminomethyl-6,8-dimethoxy-isoquinolin-4-yl)-(4-methyl-thiazol-2-yl)amine hydrochloride salt (9.0 mg, 53%). 1H-NMR (D2O): δ, 8.35 (s, 1H), 6.75 (s, 2H), 6.35 (s, 1H), 4.78 (s, 2H), 3.89 (s, 3H), 3.77 (s, 3H), 2.06 (s, 3H); MS: calculated for C16H19N4O2S (M−Cl) 331.0; found: 331.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C=O)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C=CC=C([CH:28]=[O:29])C=2C=C1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH:28]=[O:29])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C=O)cc21
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)n1ccc2c(C=O)cccc21

Procedure:
4-Formyl-indole-1-carboxylic acid tert-butyl ester was synthesized by a procedure similar to 6-Formyl-indole-1-carboxylic acid tert-butyl ester from starting materials 1H-Indole-4-carbaldehyde and di-tert-butyl-dicarbonate to yield the product as a clear yellow oil (2 g, 80%). LC-MS (ES) calculated for C14H15NO3, 245.1; found m/z 244 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[C:8]1([C:14]2[C:18]([C:19](Cl)=[O:20])=[C:17]([CH3:22])[O:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>ClCCl>[CH3:22][C:17]1[O:16][N:15]=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]=1[C:19]([C:2]1[CH2:14][C:8]2[C:13]([C:1]=1[N:3]1[CH2:6][CH2:7][CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:20]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1onc(-c2ccccc2)c1C(=O)C1=C(N2CCCC2)c2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The solid obtained from step a) was dissolved in dichloromethane (20 ml) and cooled to 0° C. Triethylamine (1 ml, 7.5 mmol) was added followed by 3-phenyl-5-methyl-4-isoxazolecarbonyl chloride (0.9 ml (1.8 mmol) of a 1.96M solution in dichloromethane. The reaction was warmed to 25° C. and stirred for 2 h. Water (10 ml) was added and the reaction mixture extracted into dichloromethane. The organic layer was dried (MgSO4) and evaporated to obtain the title compound as a brown oil m/z (ES+) 371(M+H)+.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:18])([CH3:17])[CH2:9]/[C:10]/2=[CH:13]\[C:14](Cl)=[O:15])=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:18])([CH3:17])[CH2:9]/[C:10]/2=[CH:13]\[C:14]([NH2:2])=[O:15])=[CH:6][CH:5]=1
Reactant: CC1(C)C/C(=C\C(=O)Cl)c2cc(F)ccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)C/C(=C\C(N)=O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 95.4 %

Procedure:
A solution of 30% aqueous ammonium hydroxide (10 ml, 76 mmol, Mallinckrodt) was added to the solution of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetyl chloride (0.01363 mol) obtained from Example 41h diluted with dichloromethane (200 ml) and cooled to 0° C. The biphasic solution was stirred rapidly and allowed to warm to room temperature over 18 h. The reaction solution was concentrated by spin evaporation in vacuo, diluted with dichloromethane (200 ml), and washed with IN aqueous hydrochloric acid (McIntosh), a solution of 5% aqueous sodium bicarbonate (Mallinckrodt), dried with magnesium sulfate (Mallinckrodt), and concentrated by spin evaporation in vacuo. The residue was chromatographed on Silica Gel 60 using ethyl acetate-hexanes (1:1), and then ethyl acetate. Fractions containing (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene) acetamide were combined and concentrated by spin evaporation in vacuo. Recrystallization from dichloromethane-hexanes gave 2.85 g (95%) of (E)-2-(6fluoro-3,3-dimethyl-1-indanylidene)acetamide as a white crystalline solid, m.p., 167°-168° C.;
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].O>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:17]2[N:16]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:20][C:19](=[O:21])[C:18]=2[CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reaction time: 16 h
Yield: 92.7 %

Procedure:
Benzoyl chloride (5.3 mL, 45 mmol) was added dropwise to a suspension of Na2CO3 (3.8 g, 36 mmol) and 2-amino-5-chloro-benzoic acid (3.1 g, 18 mmol) in THF (60 mL). The mixture was allowed to stir for 16 h and then H2O (200 mL) was added. The resulting precipitate was collected by filtration, washed with MeOH/H2O (1/1, 100 mL) and then dried in vacuo to provide 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (4.3 g, 92%). To a suspension of the benzoxazinone (5.0 g, 19 mmol) in CH2Cl2 (100 mL) at −78° C. was added o-tolylmagnesium chloride (2 M in THF, 48 mmol) dropwise. The mixture was allowed to warm to −30° C. and stir for 1 h. 1N HCl (100 mL) was then added. The organic phase was collected and the aqueous phase was washed with CH2Cl2 (2×50 mL). The combined organic portions were washed with 0.1N NaOH (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo to provide N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (6.3 g, 93%). The acylated amino-benzophenone (3.5 g, 10 mmol) was dissolved in MeOH (50 mL) containing KOH (3 M, 30 mmol) and was refluxed for 16 h. The solution was then cooled to room temperature and diluted with H2O (50 mL) and EtOAc (100 mL). The organic phase was collected, washed with 120 (3×50 mL), dried over MgSO4, filtered and evaporated to dryness in vacuo to provide 1m (2.4 g, 98%) MS m/z=246 (M+H).
Reaction SMILES: [NH:1]=[C:2]([C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12)[S:3][CH2:4][C:5](=O)[C:6]([OH:8])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>C1COCC1>[CH:36]1([NH:39][C:6]([C:5]2[N:1]=[C:2]([C:10]3[N:11]=[CH:12][N:13]4[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=34)[S:3][CH:4]=2)=[O:8])[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nnc2c(-c3nc(C(=O)NC4CC4)cs3)ncn2c1=O
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 3-(imino(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-yl)methylthio)-2-oxopropanoic acid (0.500 g; 1.8 mmol) in dry THF (30 mL) under nitrogen was added isobutyl chloroformate (0.47 mL; 3.6 mmol), followed by triethylamine (0.51 mL; 3.6 mmol). The mixture was stirred for 1 hours, and then cyclopropylamine (0.206 g; 3.6 mmol) was added, and stirring continued for a further 3 hours. The precipitate was filtered, washed with water (5×20 mL) and diethyl ether (2×15 mL) to yield the title compound as a pale yellow solid (0.278 g; 49%). δH (DMSO-d6) 8.94 (1H, s), 8.41 (1H, s), 8.22 (1H, d, J=4.3), 3.89 (3H, s), 2.88 (1H, m), 0.66-0.76 (4H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[N:3]1.[NH2:15][C:16]1[N:21]=[C:20]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:24])[CH:19]=[CH:18][C:17]=1Br.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.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>[NH2:15][C:16]1[N:21]=[C:20]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:24])[CH:19]=[CH:18][C:17]=1[C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=1
Reactant: Nc1nc(NC(=O)c2ccccc2F)ccc1Br
Reactant: Cn1nc(-c2ccco2)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cn1nc(-c2ccco2)cc1-c1ccc(NC(=O)c2ccccc2F)nc1N
Temperature: 110 °C
Yield: 28.6 %

Procedure:
The boronic acid 91 (19.2 mg, 0.1 mmol) and 61 (31 mg, 0.1 mmol) was dissolved in 1 mL dimethoxyethane and 1 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-pallacium(0) (Pd(Ph3P)4, 11 mg, 0.01 mmol). The reaction was heated at 110° C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 100 (10.8 mg, 29%) as white solid. LC-MS: calcd. for C20H16FN5O2: 378 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[NH:10][C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3[C:11](=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]=3[F:20])[N:10]([S:33]([CH:30]3[CH2:32][CH2:31]3)(=[O:35])=[O:34])[C:9]2=[O:21])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccc(Br)cc2Cl)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.26 mmol) in CH2Cl2 (10 mL) was added triethylamine (80 mg, 0.78 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (55 mg, 0.39 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (15 mL×2). The combined organic phase was washed with water (15 mL) and brine (20 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (110 mg, 86.5% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.71-7.69 (m, 2H), 7.32 (m, 1H), 3.35 (m, 1H), 1.69 (m, 2H), 0.88 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]([OH:10])=O.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:19]2)=[CH:26][CH:27]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)C(c1ccccn1)c1ccccn1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C(c1ccccn1)c1ccccn1

Procedure:
Bis(2-pyridyl)acetic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)bis(2-pyridyl)acetamide.
Reaction SMILES: [CH2:1]([CH:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([O:23]C)=[O:22])=[CH:18][CH:19]=2)[NH:14][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[K+].C>C(O)C.O>[CH2:1]([CH:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[NH:14][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC1CNc2cc(C(=O)OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCC1CNc2cc(C(=O)O)ccc21
Yield: 100.2 %

Procedure:
(RS)-Methyl 3-(n-undecyl)indoline-6-carboxylate (12.4 g) in ethanol (350 ml), containing potassium hydroxide (3.33 g) and water (45 ml), was stirred and refluxed for 24 hours. The solvent was removed in vacuo to give an off-white solid. The solid was dissolved in water, and the solution was treated with charcoal and filtered through diatomaceous earth. Glacial acetic acid (50 ml) was slowly added to the stirred solution and an off-white solid was collected and recrystallised from ethyl acetate to give (RS)-3-(n-undecyl)indoline-6-carboxylic acid (11.9 g), in the form of a white solid, m.p. 107°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][NH:31][C:30]1=[O:39]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:36]3[CH2:35][CH2:34][C:33]4([O:29][C:30](=[O:39])[NH:31][CH2:32]4)[CH2:38][CH2:37]3)[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Reactant: O=C1NCC2(CCNCC2)O1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCC5(CC4)CNC(=O)O5)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to Example 106 Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (19.5 mg, 0.05 mmol) and 1-oxa-3,8-diaza-spiro[4.5]decan-2-one (7.6 mg, 0.05 mmol) as the starting materials.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].CN(C)C=O.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>[Cu]I.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:34]=[N:35][NH:36][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1cccc(C)n1)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2cccc(C)n2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 2.94 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-(6-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 112) (90 mg, 0.282 mmol) and copper(I) iodide (5.37 mg, 0.028 mmol) then filled with N,N-dimethylformamide (DMF) (0.9 mL) and methanol (0.100 mL) and the resulting mixture was treated with trimethylsilyl azide (0.150 mL, 1.127 mmol). The flask was flushed with nitrogen then the mixture was stirred at 100° C. for 1 hr under microwave irradiation then cooled to room temperature. Most of the methanol was removed in vacuo and the remaining organic phase was purified by MDAP (modifier: ammonium bicarbonate) to give (2S,4R)-1-acetyl-2-methyl-N-(6-methyl-2-pyridinyl)-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinamine (3 mg, 8.28 μmol, 2.94% yield) as a colourless glass.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:4][CH:3]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])=[CH:3][N:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 120 °C
Yield: 80.4 %

Procedure:
To a solution of 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (500 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (530 mg) and tripotassium phosphate (651 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (177 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazole (D77) (500 mg) as a brown oil. MS (ES): C23H24ClNO2S requires 413. found 414.2 (M+H+).
Reaction SMILES: [C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1Br.[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].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.C1(C)C=CC=CC=1>[C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1[C:20]1[CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1Br
Reactant: OB(O)C1=CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1C1=CCCC1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A microwave tube was charged with 2-bromo-4-tert-butyl-5-nitrophenyl methyl carbonate (200 mg, 0.60 mmol), 1-cyclopentenylboronic acid (91 mg, 0.81 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol), 2 M Na2CO3 (1.5 mL), ethanol (1.5 mL) and toluene (3 mL) under inert atmosphere and was heated under microwave irradiation at 80° C. for 4 h. The reaction was extracted with ethyl acetate then washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate/hexanes) provided 4-tert-butyl-2-cyclopentenyl-5-nitrophenyl methyl carbonate (76 mg, 40% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.57 (s, 1H), 6.28 (t, J=1.9 Hz, 1H), 3.86 (d, J=12.5 Hz, 3H), 2.69 (td, J=7.5, 3.2 Hz, 2H), 1.93 (dd, J=7.6, 15.0 Hz, 2H), 1.36-1.33 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[S:23]1[CH:27]=[C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=2)[N:25]=[N:24]1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]([C:5]1[N:33]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:26]3[N:25]=[N:24][S:23][CH:27]=3)=[CH:35][CH:34]=2)[C:7](=[O:6])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: NCc1ccc(-c2csnn2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(-c2csnn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid methyl ester (359 mg) in methanol (20 ml) were added 4-[1,2,3]thiadiazol-4-ylbenzylamine (956 mg) and triethylamine (1.4 ml) and the mixture was stirred at room temperature for 72 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1→1/1) to give the title compound (80 mg, 15%).