Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)C2C(=CC=C(C)C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.[C:36]([O:44][CH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([Cl:54])[CH:52]=2)[N:47]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:46]1=[O:59])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:44][C:45]1([CH2:23][C:24]2[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([Cl:54])[CH:52]=2)[N:47]([CH2:55][CH:56]([CH3:57])[CH3:58])[C:46]1=[O:59])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: CC(C)CN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Product: COc1cc(CC2(OC(=O)c3ccccc3)C(=O)N(CC(C)C)c3ccc(Cl)cc32)cc(OC)c1OC

Procedure:
This compound was prepared in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 5-chloro-1-isobutyl-2-oxoindolin-3-yl benzoate.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>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.[Cu]I>[OH:17][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)c1ccc(C#CCCCO)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
Methyl 4-iodobenzoate (13.1 g, 60 mmol), PdCl2(PPh3)2 (2.0 g, 3 mmol), and CuI (855 mg, 4.5 mmol) were added to TEA (60 mL). The mixture is degassed while stirring by bubbling N2 vigorously into the solution. Pent-4-yn-1-ol (5.5 g, 66 mmol) was added by syringe. The mixture was heated at 90° C. overnight. After cooling, the crude mixture was concentrated by rotary evaporation and pumped on the high vacuum for 1 h. The oil was dissolved in DCM and adsorbed onto Celite followed by purification by chromatography (gradient 10-100% EtOAc/Hexanes) to give the title compound as a light yellow powder (9 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, 2H, J=9.0, 1.5 Hz), 7.44 (dd, 2H, J=9.0, 1.5 Hz), 3.90 (s, 3H), 3.85 (m, 2H), 2.57 (t, 2H, J=5.5 Hz), 1.87 (m, 2H), 1.42 (t, 1H, J=5.5 Hz); ES/MS calcd. for C13H15O3+ 219.1. found m/z=219 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH2:29][OH:30])=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH2:29][O:30][C:38](=[O:40])[CH3:39])=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2CO)n2c1COCC2)c1ccccc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2COC(C)=O)n2c1COCC2)c1ccccc1
Yield: 55 %

Procedure:
A mixture of 6-((R)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16ei) (0.213 mmol), triethylamine (31 mg, 0.31 mmol), acetyl chloride (24 mg, 0.31 mmol) and 4-dimethylamino-pyridine (ca. 1 mg) in dry dichloromethane was stirred overnight. After addition of aqueous sodium hydrogencarbonate, extraction (3 times with dichloromethane), and drying of the combined organic layers over sodium sulfate, the solvents were evaporated and the residue was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give acetic acid (R)-1-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidin-2-ylmethyl ester (54 mg, 55%). LC/MS (method 4): Rt=1.23 min; m/z=454.31 (M+H+).
Reaction SMILES: O.[F:2][C:3]([F:9])([F:8])[S:4]([OH:7])(=[O:6])=[O:5].[OH-].[Ca+2:11].[OH-]>C1CCCCC1>[F:2][C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5].[Ca+2:11].[F:2][C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
The trace amount of trifluoromethane sulfonic acid monohydrate in the non-aqueous, cyclohexane-rich phase is neutralized with calcium hydroxide to produce calcium trifluoromethane sulfonate, which is filtered from the finished product. The calcium trifluoromethane sulfonate can be converted to trifluoromethane sulfonic acid monohydrate and the recovered trifluoromethane sulfonic acid monohydrate reused.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:28]
Reactant: COc1ccccc1/C=C/C(=O)O
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: COc1ccccc1/C=C/C(=O)Nc1cnn(CCCCC(C)=O)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-methoxy-phenyl)-acrylic acid.
Reaction SMILES: C([O:3][C:4]([NH:6][C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[O:18][CH3:19])=O)C.[Na]>C(O)C>[Cl:17][C:12]1[C:11]([O:18][CH3:19])=[C:10]([N:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[NH:6][C:4]2=[O:3])[CH:15]=[C:14]([Cl:16])[CH:13]=1
Reactant: CCOC(=O)Nc1ccccc1Nc1cc(Cl)cc(Cl)c1OC
Agent: [Na]
Solvent: CCO
Product: COc1c(Cl)cc(Cl)cc1-n1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-ethoxycarbonylamino-N-(3,5-dichloro-2-methoxyphenyl)-aniline (1.94 g, 5 4 mmol) in absolute ethanol (20 ml) was at room temperature added small pieces of sodium (0.25 g, 10.8 mmol) The mixture was heated at reflux for 11/2 hours after all the sodium has reacted The mixture was after cooling to room temperature poured into ice water (50 ml) and after stirring for 15 minutes the crystalline product was collected by filtration yielding the title compound as slightly pink crystals, M.p. 202°-203° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.CN(C=O)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=3)[N:28]=2)[CH:25]=1.C(Cl)Cl.CO>S(Cl)(Cl)=O.N1C=CC=CC=1>[F:13][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([F:1])[C:10]=1[O:11][CH3:12])[C:5]([NH:33][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:28]=[C:23]3[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]3[CH:26]=2)=[CH:35][CH:34]=1)=[O:7]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Reactant: COc1c(F)cc(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: CO
Solvent: c1ccncc1
Product: COc1c(F)cc(C(=O)Nc2ccc(-c3cn4cc(C)ccc4n3)cc2)cc1F
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a stirred solution of 3,5-difluoro-4-methoxybenzoic acid (0.25 g, 1.34 mmol) in thionyl chloride (4 ml) was added a drop of DMF and the reaction mixture was then heated under reflux for 5 h. On cooling to room temperature the excess reagent was removed under reduced pressure to give a crude residue. The amide was prepared as described in the Amide Coupling section using the crude residue and 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.30 g, 1.34 mmol) in dry pyridine (14 ml) to give the title compound (0.33 g, 62%) as a pale yellow solid after work-up and flash chromatography (DCM/MeOH 20:1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:34][CH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([CH2:35][Cl:34])=[CH:37][CH:38]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccc(S(=O)(=O)CCN2CCC(Cc3ccccc3)C(O)C2)cc1)c1ccc(CCl)cc1
Yield: 39.8 %

Procedure:
To a solution of 500 mg (1.33 mmol) (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol in 10 ml CH2Cl2 were added 20 mg (0.16 mmol) DMAP and 162 mg (1.60 mmol) Et3N and 302 mg (1.60 mmol) 4-chlormethylbenzoylchloride. After 1 hour water was added and the aequous phase was extracted with methylenechloride (3×20 ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by chromatography over silica gel to give 280 mg (0.53 mmol, 40%) 4-chloromethyl-benzoic acid 4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as colorless foam.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].S(O)(O)(=O)=O.[CH:16]1([C:19]2[CH:23]=[C:22]([CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:29](=[NH:31])[NH2:30])[O:21][N:20]=2)[CH2:18][CH2:17]1.C[O:33][CH2:34][C:35](=O)[CH2:36][C:37]([O:39][CH3:40])=O>C1COCC1.CO>[CH:16]1([C:19]2[CH:23]=[C:22]([CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[C:29]3[N:30]=[C:34]([OH:33])[CH:35]=[C:36]([CH2:37][O:39][CH3:40])[N:31]=3)[O:21][N:20]=2)[CH2:17][CH2:18]1
Reactant: COCC(=O)CC(=O)OC
Reactant: N=C(N)N1CCCC1c1cc(C2CC2)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(O)nc(N2CCCC2c2cc(C3CC3)no2)n1
Yield: 29.3 %

Procedure:
Sodium bis-(trimethylsilyl)amide (3.65 ml of a 2M solution in THF, 7.3 mmol) was added to a solution of 2-(3-cyclopropylisoxazol-5-yl)pyrrolidine-1-carboximidamide mono sulphate (Method 17) (1.83 g, 6.09 mmol) and methyl 4-methoxyacetoacetate (0.867 ml, 6.7 mmol) in methanol (30 ml) and the mixture heated at reflux for 4 hours. The solvent was removed by evaporation and the residue purified by chromatography on silica gel eluting with DCM/Methanol (100:0 increasing in polarity to 95:5). The purified product was triturated with ether and the solid then recrystallised from methanol to give the title compound (565 mg, 29%) as white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].C(O[CH:16](OC(C)(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>CN(C=O)C>[CH3:16][N:17]([CH:19]=[C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][C:2]1=[O:10])[CH3:18]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1Cc2cccnc2N1
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2ncccc21

Procedure:
This compound was prepared in situ (during library synthesis) from 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and dimethylformamide di-t-butylacetal in DMF.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH3:17])[C:9]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:18][OH:19].[Mn]([O-])(=O)(=O)=[O:21].[K+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH3:17])[C:9]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][C:5]=2[N:4]=[C:3]1[C:18]([OH:21])=[O:19]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCC(=O)c1cc2nc(CO)n(C)c2cc1C
Agent: [K+]
Product: CCCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1C

Procedure:
In a manner analogous to that described in Example 12, 4.7 g of 1,6-dimethyl-5-valeryl-benzimidazole-2-methanol are oxidised with 4.5 g of potassium permanganate to give 1,6-dimethyl-5-valeryl-benzimidazole-2-carboxylic acid with a melting point >88° (decomposition).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[C:4]=1[C:12]([O:14]CC)=[O:13].[OH-].[K+]>C(O)C>[CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([C:8]([F:11])([F:9])[F:10])[C:4]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1c(C(F)(F)F)nsc1SC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1snc(C(F)(F)F)c1C(=O)O

Procedure:
A 5.2 g (19.2 mmol) sample of ethyl 5-methylthio-3-(trifluoromethyl)isothiazole-4-carboxylate was combined with 1.39 g (21 mmol) of 85 percent potassium hydroxide and 25 mL of 95 percent ethanol and the mixture was heated on a steam bath for 45 min and then concentrated under reduced pressure to remove the volatiles. The residue was dissolved in water and acidified with concentrated hydrochloric acid. The white precipitate that formed was collected by filtration and dissolved in a mixture of acetone and ether. The resulting solution was dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 3.75 g (80 percent of theory) of the title compound as a white solid melting at 260°-262° C.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]>C(O)(=O)C>[CH3:14][O:13][C:10]([C@@H:6]1[C@@H:5]([CH2:4][CH:3]=[O:2])[NH:8][C:7]1=[O:9])([CH3:12])[CH3:11]
Reactant: COC(C[C@H]1NC(=O)[C@@H]1C(C)(C)OC)OC
Solvent: CC(=O)O
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC=O
Yield: 92.1 %

Procedure:
A solution of (3S, 4R)-4-(2,2-dimethoxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (1.03 g) in 80% aqueous acetic acid (50 ml) was stirred at 50° C. for 4 hours, and the solution was evaporated in vacuo. The residue was dissolved in toluene (8 ml) and evaporated in vacuo to give (3S, 4R)-3-(1-methoxy-1-methylethyl)-4-(2-oxoethyl)azetidin-2-one (760 mg) as an oil.
Reaction SMILES: [Li+].[CH3:2]CC[CH2-].C(NC(C)C)(C)C.CN1C(=O)N(C)CCC1.[CH3:22][C:23]1[CH2:24][C:25]2([CH2:31][CH:32]([CH3:34])[CH:33]=1)[C:29](=[O:30])[CH2:28][CH2:27][CH2:26]2.CI.C(O)(=O)C>C1COCC1>[CH3:2][CH:28]1[CH2:27][CH2:26][C:25]2([CH2:31][CH:32]([CH3:34])[CH:33]=[C:23]([CH3:22])[CH2:24]2)[C:29]1=[O:30]
Reactant: [CH2-]CCC
Reactant: CC1=CC(C)CC2(CCCC2=O)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CC1=CC(C)CC2(CCC(C)C2=O)C1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
N-Butyllithium (1.6 M in hexanes, 172 ml, 0.275 mol) was added to a solution of diisopropylamine (30.4 g, 0.3 mol) in THF (300 ml), while maintaining the internal temperature around −40° C. Then DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone) (38.4 g, 0.3 mol) was added, followed, after 15 minutes, by a mixture of 6,8 and 7,9-dimethylspiro[4,5]dec-7-en-1-one (44.74 g, 0.25 mol) in THF (50 ml) in 30 minutes. After stirring for 30 more minutes, methyl iodide (106 g, 0.75 mol) was added rapidly. After 15 minutes, the reaction was quickly warmed up to 0° C. Acetic acid (18.6 g, 0.31 mol) was added and the reaction warmed up to room temperature. The reaction was quenched with water (500 ml) and extracted twice with pentane. Each organic fraction was treated successively with water, aqueous NaHSO3, aqueous saturated NaHCO3, and brine. Combined organic fractions were dried over Na2SO4. The liquid obtained after filtration and evaporation of solvents was purified by bulb to bulb distillation (B.p.=105° C./0.47 mbar). The title product was obtained as a colorless liquid (42.85 g, yield=89%), as a mixture of isomers.
Reaction SMILES: [NH3:1].Cl[CH2:3][C:4]([N:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11](/[CH:15]=[CH:16]/[S:17]([N:20]2[CH2:41][CH2:40][C:23]3([N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=4)[NH:25][C:24]3=[O:39])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[C:10]([CH3:42])[CH:9]=1)[CH3:7])=[O:5]>C(O)C>[NH2:1][CH2:3][C:4]([N:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11](/[CH:15]=[CH:16]/[S:17]([N:20]2[CH2:41][CH2:40][C:23]3([N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=4)[NH:25][C:24]3=[O:39])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[C:10]([CH3:42])[CH:9]=1)[CH3:7])=[O:5]
Reactant: Cc1cc(N(C)C(=O)CCl)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Reactant: N
Solvent: CCO
Product: Cc1cc(N(C)C(=O)CN)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Temperature: 55 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
Ammonia (6 N solution in ethanol, 0.3 ml) was added to a solution of 2-chloro-N-(3,5-dimethyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-N-methyl-acetamide (38 mg, 0.06 mmol) in anhydrous ethanol (0.5 ml), and the mixture was stirred at 50 to 60° C. for five hours. The mixed solution was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (dichloromethane) to give 2-amino-N-(3,5-dimethyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-N-methyl-acetamide (11 mg, 31%).
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=O)[CH:7]([Cl:11])[C:8]([CH3:10])=[O:9])C.C([Li])CCC.[CH:18]1([C:23](=[O:28])[CH2:24][CH2:25][C:26]#[CH:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[CH2:24]([C:23]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[O:28][C:6](=[O:5])[CH:7]([Cl:11])[C:8](=[O:9])[CH2:10]1)[CH2:25][C:26]#[CH:27]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: C#CCCC(=O)C1CCCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Temperature: -40 °C
Yield: 76.3 %

Procedure:
To a slurry of sodium hydride (480 mg, 60% suspension in mineral oil, 12 mmol) in THF (30 mL) cooled to −10° C. was added ethyl-2-chloroacetoacetate (1.66 mL, 12 mmol). The reaction was stirred until all gas evolution ceased. The reaction was then cooled to −40 ° C. and a solution of butyl lithium (4.8 mL, 2.5 M in ether, 12 mmol) was added. The reaction was stirred for 10 minutes, and then 1-cyclopentyl-pent-4-yn-1-one (0.60 g, 4 mmol) was added as a solution in THF (10 mL). The reaction was stirred for 1 hour, and then quenched with 40 mL saturated ammonium chloride. The solution was acidified further with 5 mL of 6 N HCl. The layers were separated, and the aqueous was extracted with ethyl acetate. The organics were combined and washed with water and then saturated sodium chloride. The organic phase was dried over sodium sulfate, filtered, and then concentrated. The crude product was then dissolved in toluene (13 mL) and bis(dibutylchlorotin) (1.027 g) was added. The solution was heated to reflux for one hour. The reaction was then concentrated and chromatographed (40 g silica gel, 2% MeOH in CH2Cl2) to yield the title compound (0.820 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][O:14][C:13]4[CH:16]=[C:17]5[C:21](=[CH:22][C:12]3=4)[CH2:20][CH2:19][O:18]5)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CC1C2C=[C:30]3[C:35]4(C5C(=CC=CC=5)NC4=O)[CH2:34][O:33][C:31]3=[CH:32]C=2ON=1.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][O:14][C:13]4[CH:16]=[C:17]5[C:21](=[CH:22][C:12]3=4)[CH2:20][CH2:19][O:18]5)[C:7](=[O:11])[N:8]2[CH2:32][C@H:31]2[CH2:30][CH2:35][CH2:34][O:33]2)=[CH:4][CH:3]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2cc(F)ccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(C[C@H]2CCCO2)c2cc(F)ccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one was obtained (47%) as a colorless solid: mp 137-139° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.08-7.03 (m, 1H), 6.88-6.83 (m, 1H), 6.73-6.66 (m, 1H), 6.46 (s, 1H), 6.38 (s, 1H), 4.74 (ABq, 2H), 4.52 (t, J=9.0 Hz, 2H), 4.25-4.20 (m, 1H), 3.96-3.60 (m, 4H), 2.98 (t, J=9.0 Hz, 2H), 2.08-1.86 (m, 3H), 1.73-1.64 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.0, 161.9, 161.2, 128.1, 124.7, 120.0, 118.8, 109.5, 109.2, 98.8, 98.4, 93.2, 80.6, 72.4, 68.3, 57.3, 44.8, 29.2, 28.9, 25.7; MS (ES+) m/z 382.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=2)=[CH:5][CH:4]=[N:3]1>CO.[Pd]>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C1=CN(C(=O)OC(C)(C)C)CCC1
Agent: [Pd]
Solvent: CO
Product: Cn1nccc1C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a solution of tert-butyl 5-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate (800 mg, 3.00 mmol) in MeOH (20 mL) was added 10% Pd/C (80 mg). The reaction mixture was stirred under H2 (1 atm) for 16 h. After concentration, the residue was purified by silica gel chromatography eluting with a 0-30% gradient of EtOAc in petroleum ether to give tert-butyl 3-(1-methyl-1H-pyrazol-5-yl)piperidine-1-carboxylate (0.68 g, 86% yield) as pale yellow oil. LCMS (ESI) m/z: 265.2 [M+H+]
Reaction SMILES: C([CH:3]([C:35]([OH:37])=[O:36])[N:4]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:23]([C:33]#[N:34])[CH:22]=1)[C:5]([C:7]1[C:8]([CH3:20])=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6])C.[OH-].[Na+]>C(O)C>[C:33]([C:23]1[CH:22]=[C:21]([N:4]([C:5]([C:7]2[C:8]([CH3:20])=[N:9][N:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH:11]=2)=[O:6])[CH2:3][C:35]([OH:37])=[O:36])[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])#[N:34]
Reactant: CCC(C(=O)O)N(C(=O)c1cn(-c2ccc(OC)cc2)nc1C)c1ccc(OCC(C)(C)C)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2cc(C(=O)N(CC(=O)O)c3ccc(OCC(C)(C)C)c(C#N)c3)c(C)n2)cc1
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
Ethyl N-(3-cyano-4-neopentyloxyphenyl)-N-[1-(4-methoxyphenyl)-3-methylpyrazol-4-ylcarbonyl]glycine (1.8 g) was added to ethanol (20 ml). 10% aqueous sodium hydroxide solution (20 ml) was added and the mixture was stirred at a refluxing temperature for 30 min. The solvent was evaporated under reduced pressure. Dilute hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of chloroform-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous acetic acid to give the title compound (1.6 g), melting point: 98–101° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7](F)[CH:8]=[C:9]([Br:11])[CH:10]=1>CO.CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([Br:11])[CH:10]=1
Reactant: C[O-]
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (8.80 ml of a 4.5M solution in methanol, 41.0 mmol) was added dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol) in N,N-dimethylformamide (95 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature, stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ether and the resulting solution was washed with water (3×300 ml) and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (5.13 g) as a white solid.