Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(=O)(=O)(O)O.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[OH:25][C:19]1[CH:24]=[CH:23][C:22]([C:7]([C:22]2[CH:23]=[CH:24][C:19]([OH:25])=[CH:20][CH:21]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)c1ccccn1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccccn1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
50 g. Ethyl 2-pyridine-glyoxylate were cautiously added dropwise to a pre-cooled mixture of 100 ml. 85% sulphuric acid and 100 g. phenol, while stirring. The reaction mixture was externally cooled with water and ice to keep it at ambient temperature and to control the exothermic reaction. After stirring for 60 hours, the reaction mixture was poured into ice-water and washed with chloroform. The gum-like precipitate which separated and the aqueous phase were rendered alkaline with ammonium hydroxide and the resulting solution was treated with activated charcoal. After filtration, the solution obtained was adjusted to about pH 7 with diluted sulphuric acid to give a high yield of a crystalline precipitate of ethyl α, α-di(4-hydroxyphenyl)-2-pyridine-acetate. After crystallisation from isopropanol or ethyl acetate, the product was obtained in the form of a colourless, crystalline solid which melted, with decomposition, at 252° - 254°C.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][CH:4]([O:6][Si:7]([O:16][CH:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])([O:9][CH:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:11])[OH:8])[CH3:5].C(N(CC)CC)C.[CH3:31][C:32]1C=C(O)C=C[C:33]=1[OH:34].C(Cl)(=O)C=C>C1(C)C=CC=CC=1>[C:33]([O:8][Si:7]([O:6][CH:4]([CH2:3][CH:2]([CH3:23])[CH3:1])[CH3:5])([O:16][CH:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])[O:9][CH:10]([CH2:12][CH:13]([CH3:14])[CH3:15])[CH3:11])(=[O:34])[CH:32]=[CH2:31]
Reactant: Cc1cc(O)ccc1O
Reactant: CC(C)CC(C)O[Si](O)(OC(C)CC(C)C)OC(C)CC(C)C
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)O[Si](OC(C)CC(C)C)(OC(C)CC(C)C)OC(C)CC(C)C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
0.23 moles of tris(4-methyl-2-pentoxy)silanol, 0.23 moles of triethylamine, 0.02 gms. of methyl hydroquinone as polymerization inhibitor and 82 cc of toluene were placed in a three necked flask equipped with a stirrer, addition funnel, a thermometer and a condenser. A solution of 0.23 moles of acryloyl chloride in 23 cc of toluene was added slowly to the reaction mixture at 3°-5° C. At the end of the addition, the mass is allowed to stir for 1/2 hour at 5° C. The solid triethylamine hydrochloride was filtered and the solvent was distilled under vacuum. The residual crude product was distilled (bp 148°-162° C./3 mm/Hg) to give 41 gms. of product (G.C. purity 80%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])=[CH:11][CH:10]=1.C(N(CC)CC)C.[O:39]1[CH2:43][CH2:42][CH2:41]C1.O.[C:45](Cl)(=[O:48])[CH:46]=[CH2:47]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH2:28][O:29][C:43](=[O:39])[CH:42]=[CH2:41])[CH2:30][O:31][C:45](=[O:48])[CH:46]=[CH2:47])=[CH:11][CH:10]=1
Reactant: OCC(CO)CCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: C1CCOC1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCC(CCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)COC(=O)C=C
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
First, 2.4 g of 2,3-difluoro-4'-[12,12-bis(hydroxymethyl)dodecyl]oxybiphenyl, 1.3 g of triethylamine, and 100 ml of tetrahydrofuran were placed in a 200 ml flask. Then, 15 ml of tetrahydrofuran solution in which 1.1 g of acryloyl chloride was dissolved was added dropwise to the reaction mixture under ice water cooling, and the resultant reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with diluted hydrochloric acid and water in this order, and then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=20/1) and recrystallized from hexane to obtain 1.7 g of 2,3-difluoro-4'-[12,12-bis(acryloyloxymethyl)dodecyl]oxybiphenyl (Y: 57%). The compound thus obtained had a purity of 99.6% by GC, 100% by HPLC, and 1 spot by TLC. The compound thus obtained had an m.p. of 33.4° C. to 34.4° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](Cl)(=[O:22])C([Cl:21])=O.C(N(CC)CC)C.[CH2:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32]>ClC(Cl)C(Cl)Cl>[ClH:21].[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[C:10]([C:18]([N:36]3[CH2:37][CH2:38][N:33]([CH2:31][CH3:32])[CH2:34][CH2:35]3)=[O:22])=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN1CCNCC1
Reactant: Fc1ccc2c(ccn2CC2CCCCC2)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)C(Cl)Cl
Product: CCN1CCN(C(=O)c2cn(CC3CCCCC3)c3ccc(F)cc23)CC1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 1-(cyclohexylmethyl)-5-fluoroindole (208 mg, 0.9 mmol) in 1,1,2,2-tetrachloroethane (15 ml) at 0° C., was added oxalyl chloride (0.122 ml, 0.945 mmol) with stirring under a stream of nitrogen. The mixture was allowed to warm to room temperature over 1 hour, then heated to 120° C. for a further 1.5 hours. The mixture was cooled to room temperature and triethylamine (0.138 ml, 0.99 mmol) was added. Stirring was continued for a further 10 minutes before the addition of N-ethylpiperazine (0.125 ml, 0.99 mmol). The mixture was stirred at room temperature for 15 hours and then partitioned between 0.4 M sodium hydroxide solution (10 ml) and dichloromethane (10 ml). The organic layer was washed with water (10 ml), dried over Na2SO4 and concentrated. The resulting brown oil was purified by flash chromatography using 95% dichloromethane, 5% methanol as eluent to yield the title compound as the free base.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].O[CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>>[N:16]1([CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: OCCn1ccnc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: O=c1oc(=O)n(CCn2ccnc2)c2ccccc12

Procedure:
Prepared by a similar procedure as described for preparation 7B, starting from isatoic anhydride and 1-(2-hydroxyethyl)-imidazole (Fluorochem). 13C-NMR (DMSO-d6) δ 158.7, 147.5, 141.3, 137.6, 136.9, 129.4, 128.5, 123.6, 119.7, 114.0, 111.3, 45.1, 43.3.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].C(N(CC)CC)C.[CH2:21]([NH2:24])[CH2:22][CH3:23]>C(O)C>[CH2:21]([NH:24][CH2:2][CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])[CH2:22][CH3:23]
Reactant: CCCN
Reactant: Clc1cc(Cl)c(OCCBr)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCNCCOc1c(Cl)cc(Cl)cc1Cl
Yield: 67.6 %

Procedure:
A solution of sodium hydroxide (7.8 g, 0.195 mol) in water (20 ml) was added to a solution of 2,4,6-trichlorophenol (38.0 g, 0.192 mol) in ethanol (200 ml). 1,2-dibromoethane (47 g, 0.25 mol) was then added and the resultant mixture was refluxed overnight. On cooling, the solid was filtered off and the filtrate concentrated under reduced pressure. Ether was added to the residue and the solution was then washed with dilute sodium hydroxide solution and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation, the residue was recrystallised from ethanol to give 1-bromo-2-(2,4,6-trichlorophenoxy)ethane as a white solid (39.4 g). A mixture of the 1-bromo-2-(2,4,6-trichlorophenoxy) ethane (20.0 g, 0.066 mol), triethylamine (6.7 g, 0.066 mol) and propylamine (3.9 g, 0.066 mol) in ethanol (500 ml) was then refluxed overnight. After removal of the solvent by evaporation, the residue was dissolved in ether, washed with water and dried (MgSO4). Evaporation of the solvent left an oil which, after flash chromatography on silica gel using chloroform as the eluant, yielded N-propyl-N-2-(2,4,6-trichlorophenoxy)ethylamine as an oil (12.6 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]1([N+:13]#[C-:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:15][C:16]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:17]=1[CH:18]=O>Cl(O)(=O)(=O)=O>[CH:7]1([NH:13][C:14]2[N:6]3[C:2]([S:3][CH:4]=[CH:5]3)=[N:1][C:18]=2[C:17]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:16]=2[CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: Nc1nccs1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccc(-c2nc3sccn3c2NC2CCCCC2)c(C)c1

Procedure:
Compound 50 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-amino thiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) cyclohexylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,4-dimethylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:8])[CH:7]=1.C[O:11][C:12]1[CH2:17][CH2:16]C=[CH:14][CH:13]=1.Cl.[CH:19]1C=CC=CC=1>CO>[OH:8][C:6]1[C:5]([CH3:19])=[CH:4][C:3]2[O:9][C@H:14]3[CH2:13][C:12](=[O:11])[CH2:17][CH2:16][C@H:1]3[C:2]=2[CH:7]=1
Reactant: COC1=CC=CCC1
Reactant: c1ccccc1
Reactant: CC1=CC(=O)C=CC1=O
Agent: Cl
Solvent: CO
Product: Cc1cc2c(cc1O)[C@@H]1CCC(=O)C[C@@H]1O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 0.57 g (5.0 mmol) of 2-methyl-1,4-benzoquinone and 1.10 g (10.0 mmol) of 1-methoxy-1,3-cylcohexadiene in 10 mL of benzene was heated at reflux for 2 h. The solution was concentrated in vacuo and the residue dried under high vacuum to afford a pale yellow oil. This material was dissolved in 15 mL of methanol and to that solution was added 1 mL of 2.0M HCl. The solution was stirred at room temperature for 6 hours, then was concentrated to about 5 mL volume. This was partitioned between ethyl acetate and water and the aqueous layer was washed with two portions of ethyl acetate. The organic extracts were sequentially washed with water and NaCl solution, combined, dried over magnesium sulfate, and concentrated. The residue was crystallized from ether-hexane to afford 0.452 g white crystals, 41%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]=[CH2:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH:16]=[CH2:17])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: C=Cc1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=Cc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Temperature: 55 °C
Yield: 101.3 %

Procedure:
4-Benzyloxy-2-vinylphenol (0.40 g, 1.77 mmol) was dissolved in anhydrous DMF (4 mL), followed by the addition of ethyl bromoacetate (0.29 mL, 2.65 mmol), and cesium carbonate (0.75 g, 2.30 mmol). The mixture was then heated for 18 h (55° C.). The reaction mixture was then cooled and concentrated in vacuo. The crude residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was washed with brine, dried (Na2SO4), and removed in vacuo to give 0.56 g (100%) of a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 4H), 7.13 (d, J=2.9 Hz, 1H), 7.10-7.06 (m, 1H), 6.82 (dd, J=8.8, 2.9 Hz, 1H), 6.73 (d, J=9.3 Hz, 1H), 5.76 (dd, J=17.1 Hz, 1.5 Hz, 1H), 5.30 (dd, J=11.2, 1.5 Hz, 1H), 5.03 (s, 2H), 4.58 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H); MS (FIA) m/e 313 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].[CH2:35]([N:37](CC)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.CN>C(Cl)Cl.O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:37][CH3:35])=[O:29])=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:32])[F:33])#[N:2]
Reactant: CCN(CC)CC
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Agent: CN
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)CCCc1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoic acid (Compound 227, 85 mg, 0.17 mmol) in DCM (2 mL) were added triethylamine (0.013 mL, 0.09 mmol) and 4-nitrophenyl chloroformate (15 mg, 0.07 mmol). The mixture was stirred at room temperature for 1 h and methylamine (0.3 mL, 2M in THF) was added. After 30 min, the mixture was diluted with water and extracted with EtOAc (2×). The organic layers were dried over magnesium sulfate and concentrated. Column chromatography on silica gel (Hexane:EtOAc=1:1) afforded 35 mg (40%) of 4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)-N-methylbutanamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.11 (d, 1H), 8.38 (d, 1H), 7.42 (d, 2H), 7.22 (d, 2H), 2.86-2.81 (m, 3H), 2.81-2.73 (t, 2H), 2.73-2.64 (m, 2H), 2.64-2.53 (m, 2H), 2.26 (t, 2H), 2.24-2.17 (m, 1H), 2.11-2.01 (m, 2H), 1.69 (m, 1H). LCMS [M+1]+ 502.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][NH:12][CH2:13][C:14](OCC)=[O:15])=[CH:9][CH:8]=1.[CH3:24][NH:25][CH3:26]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][NH:12][CH2:13][C:14]([N:25]([CH3:26])[CH3:24])=[O:15])=[CH:9][CH:8]=1
Reactant: CCOC(=O)CNCc1ccc(OCc2cccc(Cl)c2)cc1
Reactant: CNC
Product: CN(C)C(=O)CNCc1ccc(OCc2cccc(Cl)c2)cc1
Product: Cl
Reaction time: 8 h
Yield: 23 %

Procedure:
7.07 g (0.066 mol) of glycine ethyl ester, hydrochloride are diluted in 200 ml of dry methanol and 3.32 g (0.053 mol) of sodium cyanoborohydride are added, while stirring under nitrogen. To this solution, 15 g (0.0608 mol) of 3-chlorobenzyloxybenzaldehyde are added in a single portion. Stirring is continued for 18 hours at room temperature, the mixture is evaporated to dryness and the crude residue chromatographed on silica gel (eluant: cyclohexane/ethyl acetate; 60/40). 6.8 g (34%) of [4-(3-chlorobenzyloxy)benzyl]amino acetic acid, ethyl ester are obtained (m.p. 114°-115° C. as hydrochloride). 3 g (0.0090 mol) of the above ester (free base) are heated in 70 ml of dimethylamine at 60° C. for 7 hours. The solution is allowed to stand overnight at room temperature, then evaporated and the residue is purified on silica gel (eluant: chloroform/methanol/30% NH4OH; 95/5/0.5) to afford 0.7 g (23%) of [4-(3-chlorobenzyloxy)benzyl]amino-N,N-dimethylacetamide, hydrochloride (m.p. 120°-125° C.). Analogously the following compounds can be obtained, starting from the corresponding ethyl esters:
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)C1C=CC=CC=1.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1
Reactant: [H][H]
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CC(N)CC1CC
Yield: 98.9 %

Procedure:
To a vessel containing a slurry of 20 wt % Pd(OH)2 on C (12.9 g, 18.4 mmol) in EtOH (1.0 L) was added ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol, Preparation #X.1). The reaction was shaken for about 90 min at about 50° C. under about 30 psi of hydrogen. After removal of the hydrogen source and introduction of a nitrogen atmosphere, the resulting mixture was filtered through a pad of Celite® and the filtrate was concd under reduced pressure to give ethyl 4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup: 1H NMR (CDCl3) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H), 2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H), 1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2cnn(CCN3CCCC3)c2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-nitroindazole (2.00 g, 12.3 mmol) and potassium carbonate (5.10 g 37.0 mmol) in DMF (40 mL) was stirred for 30 minutes, after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (3.20 g 18.9 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 4H), 2.47 (m, 4H), 2.90 (t, 2H, J=6.45), 4.68 (t, 2H, J=6.44), 7.94 (m, 1H), 8.00 (m, 1H), 8.31 (s, 1H), 8.77 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][O:2][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCC3CC3)(CC1)CC2
Yield: 58.7 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and cyclopropylmethyl bromide (12.8 mg) were used to obtain (2S,4S)-1-[[N-(4-cyclopropylmethyloxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (13.7 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[C:4]([F:27])[CH:3]=1.O1CCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C([Sn](CCCC)(CCCC)[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1)CCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:4]1[CH:3]=[C:2]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([C:11]([N:13]2[CH2:17][CH2:16][C@@:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19](=[O:26])[O:18]3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4F)CC3)C2)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccncc5)cc4F)CC3)C2)c2ccccc21
Temperature: 120 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromo-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (30 mg, 0.00007 mol, this compound was prepared by using a method that was analogous to that used for the synthesis of 238) in tetrahydrofuran (0.2 mL, 0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.000003 mol), tri-tert-butylphosphine (1.7 mg, 0.0000083 mol), 4-(tributylstannyl)pyridine (30.7 mg, 0.0000835 mol), and the mixture was heated to 120° C. under microwave for 30 minutes. The reaction mixture was then filtered and the filtrate was diluted with methanol, and the product was isolated and purified by prep-HPLC. LC/MS (M+H+) 429.2.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[CH2:15]([O:17][P:18](Cl)([O:20][CH2:21][CH3:22])=[O:19])[CH3:16]>ClCCl.CCOCC>[CH2:15]([O:17][P:18]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])([O:20][CH2:21][CH3:22])=[O:19])[CH3:16]
Reactant: OCCNCCO
Reactant: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOP(=O)(OCC)N(CCO)CCO
Yield: 53.5 %

Procedure:
To a solution of diethanolamine (5.0 g, 48 mmol) and triethylamine (8.0 ml) in dichloromethane (75 ml) was added dropwise with stirring under Argon, a solution of diethylchlorophosphate (8.2 g, 48 mmol) in dichloromethane (25 ml) over approximately 15 minutes and then allowed to stir at room temperature overnight. The mixture was washed with brine (50 ml) then dried (Na2SO4) and evaporated in vacuo to give the crude product as a viscous oil. The oil was dissolved in ether (100 ml) and the white solid which precipitated was filtered off (triethylamine hydrochloride). The ether solution was evaporated in vacuo giving N-diethoxyphosphoryldiethanolamine (6.2 g, 54%) as a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[C:13](=[O:16])([O-])[O-].[K+].[K+].OO.[OH2:21]>CS(C)=O>[OH:16][CH2:13][CH:3]1[CH2:4][CH2:5][N:1]2[C:9]3[C:4]([C:3]([CH2:10][C:11]([NH2:12])=[O:21])=[C:2]2[CH2:2]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: O=C([O-])[O-]
Reactant: O
Reactant: N#CCc1c[nH]c2ccccc12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)Cc1c2n(c3ccccc13)CCC(CO)C2
Temperature: 25 °C

Procedure:
Dissolve (1H-indol-3-yl)acetonitrile (3.40 mmol) in dry dimethyl sulfoxide (3.0 mL), cool in an ice bath, combine with anhydrous potassium carbonate (0.200 g) and 30% hydrogen peroxide (0.6 mL), keeping the reaction temperature below 20° C. Warm to room temperature, add water (10 mL) and filter the resulting solid, dry under vacuum.