Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3].[CH3:22][NH2:23]>C(Cl)Cl.CCO>[CH3:22][NH:23][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3]
Reactant: CC(I)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Product: CNC(C)c1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
A solution of 4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indole (50 mg, 122 μmol; Intermediate 99) in CH2Cl2 (1.5 mL) was treated with MeNH2 (153 μL of a 8 M solution in EtOH, 1.22 mmol) at rt for 2 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH/THF and purified by prep. HPLC (System B, 22-52% MeCN, 50 mM NH4HCO3) to yield the title compound as a white, waxy solid (13.2 mg, 12% over two steps). MS (ESI+) for C17H18N2O2S m/z 284 (M-NHMe)+, 315 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14](O)=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([Cl:20])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)nc21
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCn1cc(C(=O)Cl)c(=O)c2ccc(Cl)nc21

Procedure:
7-Chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (29.5 g) and thionyl chloride (18 ml) in dry toluene (900 ml) were stirred and heated under reflux for 1 hour. The solution was cooled and the solid that separated was collected. It had m.p. 186.5°-188.5° (98%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15][C:10]21OCC[O:11]2>Cl>[O:21]=[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:19]=[CH:18][CH:17]1[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)c1ccccc1
Agent: Cl
Product: O=C(C=CC1CCC(=O)C1CCCCCCCO)c1ccccc1
Reaction time: 1 h
Yield: 18.1 %

Procedure:
A suspension of 6-(7-hydroxyheptyl)-7-(3-phenyl-3-oxoprop-1-enyl)-1,4-dioxaspiro[4,4]nonane [1.0 g; prepared as hereinafter described in Example 9(ii)] in dilute hydrochloric acid (2 N; 30 ml.) was stirred at 60°-65° C. for 1 hour. The mixture was extracted with diethyl ether and then the combined ethereal extracts were washed with aqueous sodium bicarbonate solution (10% w/v) and then with water, and then dried over anhydrous magnesium sulphate. The solution was evaporated and the residue was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, n-hexane and ethyl acetate (2:1:1 by volume) as eluant, to give 7-[5-(3-oxo-3-phenylprop-1-enyl)-2-oxocyclopentyl]heptanol (0.16 g.), in the form of a yellow oil. [Elemental analysis: Found: C, 76.9; H, 8.9%, C21H28O5 requires C, 76.8; H, 8.6%, νmax 990 cm-1, 1620 cm-1, 1665 cm-1, 3400 cm-1. N.M.R. (approximately 10% w/v solution in deuterochloroform): triplet at 3.6δ (J=6 cycles/second), multiplets at 7.85-8.05δ, 7.4-7.65δ, 6.85-7.15δ, 2-2.9δ and 1.1-2.0δ].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[OH:14].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[O:14][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1
Reactant: COc1c(C)c(C)c(OC)c(O)c1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)c(C)c(OC)c(Oc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
5.8 g of 2,5-dimethoxy-3,4,6-trimethylphenol [prepared as described in step (a) above] in 10 ml of dimethylformamide were added to a suspension of 1.4 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 50 ml of dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours. At the end of this time, a solution of 4.6 g of p-fluoronitrobenzene in 10 ml of dimethylformamide was added to the mixture, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour, and then at 80° C. for 7 hours. At the end of this time, the mixture was poured into water, and the resulting crude oil was extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting oil was purified by column chromatography through silica gel, using a 4:1 by volume mixture of benzene and hexane, followed by benzene alone, as the eluent, to give 3.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:38][C:39]#[N:40])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Mg]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[CH2:16][NH:15][C:14]3=[N:38][C:39]#[N:40])=[CH:11][CH:12]=2)=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](c3cccc(C(F)(F)F)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=NC#N)cc1
Agent: [Mg]
Solvent: CO
Product: N#CN=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of (S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-tosyl-4-(3-(trifluoromethyl)-phenyl)imidazolidin-2-ylidene)cyanamide (1.06 g, 1.73 mmol) in MeOH (17 mL) is added magnesium powder (0.42 g, 17.3 mmol). The reaction mixture is heated to reflux for 45 min. After cooling down to room temperature, the mixture is quenched with saturated NH4Cl aqueous solution (150 mL) and extracted with EtOAc (3×75 mL). The combined organic layer is washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography (20˜70% EtOAc/Hexanes) to provide the title compound (0.62 g, 78% yield) as a white solid product; 1H NMR (CDCl3, 400 MHz) δ 7.60 (m, 1H), 7.51 (m, 3H), 7.27 (d, 2H), 7.15 (d, 2H), 6.88 (m, 4H), 6.65 (br, 1H), 5.40 (dd, 1H), 4.21 (t, 1H), 3.63 (dd, 1H); HPLC-MS calculated for C23H16ClF3N4O (M+H+) 457.1, found 457.1.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>O1CCOCC1.O>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccco1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3ccco3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 74 mg, 0.2 mmol) in dioxane/water (10:1, 4.4 mL) was degassed for 20 min and then added to a reaction vial containing potassium carbonate (82 mg, 0.6 mmol) and furan-2-boronic acid (0.6 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was degassed for a further 2 min and then bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 14 mg, 0.02 mmol) was added. The mixture was degassed for 30 seconds and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), dimethylacetamide (1 mL), and 20% methanol in dichloromethane (1 mL). The filtrate was placed in a vial and 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl was added until a solid formed (approxiamtely 2 mL). The vial was centrifuged and the solvent was removed. The product was dried overnight in the oven. Mass spectrum MH+=295.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]2=[O:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C:8]2=[O:13]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N)c2C1=O
Reaction time: 3 h
Yield: 54.9 %

Procedure:
A mixture of tert-butyl 2-(4-nitro-1,3-dioxoisoindolin-2-yl)acetate (1.44 g, 4.70 mmol) and 10% w/w Pd/C (a catalytic amount) in MeOH (150 ml) was hydrogenated in a Parr apparatus at 25 psi for 3 hours. The catalyst was filtered off and the filtrate was evaporated; the residue was purified by a quick flash chromatography on silica gel (Hexane/EtOAc 1/1) to obtain tert-butyl 2-(4-amino-1,3-dioxoisoindolin-2-yl)acetate (712 mg, 2.58 mmol, 54.8% yield, MS/ESI+ 299.0 [MNa]+).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([NH:12][CH:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)(=O)C>>[NH2:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 8 h

Procedure:
A reaction solution (100 ml) containing 100 mM potassium phosphate buffer (pH 6.5), 1 U of N-acylamino acid racemase, 1 U of L-aminoacylase (Sigma Co.), and 15% N-acetyl-DL-tryptophan was incubated at 30° C. overnight. As the reaction progressed, L-tryptophan produced was saturated in the aqueous phase and precipitated upon oversaturation in the aqueous phase, during which process the reaction was continued. The L-tryptophan precipitated in the aqueous phase was separated by filtration, washed with water, and dried (70% recovery). The optical purity of L-tryptophan thus produced was determined as follows. CHIRALPAK WH (DAICEL CHEMICAL INDUSTRIES, LTD.) was used to measure the purity at room temperature using 0.25 mM cupric sulfate as eluent (flow rate, 1 ml/min; detection wavelength, 254 nm). As a result, L-tryptophan with the optical purity of nearly 100% ee was obtained by the method of the present invention.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([NH:48][C:29]([C:26]1[CH:27]=[CH:28][C:23]([C:15]2[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH:9]2[CH:8]3[CH2:34][C:35]4[C:40]([CH:7]3[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=3)[NH:10]2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:24]([O:32][CH3:33])[CH:25]=1)=[O:30])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCc3ccccc3)cc2OC)cc1O

Procedure:
Example 236 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and benzylamine. Mass Spectrum: 625 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCCCCCCC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1)CCCC(F)(F)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CCCCCCCC[C@H]1c2ccc(O)cc2SC[C@@]1(C)c1ccc(O)cc1)CCCC(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A solution of ethyl 10-[(3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate (3.23 g, 4.902 mmol) in dichloromethane (60 ml) was cooled to −78° C. To this solution, a solution of boron tribromide in dichloromethane (1M, 39.22 ml, 39.22 mmol) was slowly added dropwise, and the resulting mixture was stirred for 1 hour. The reaction vessel was then transferred to an ice-bath and the reaction mixture was further stirred for 3 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20) to give ethyl 10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate (2.08 g, Yield 67%) as a foam.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1([C:18]([O:20]CC)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:4]>C1COCC1.C(OCC)C>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([C:3]#[N:4])([C:18]([OH:20])=[O:19])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C#N)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
An aqueous solution of lithium hydroxide (2M, 39.0 mL, 77.92 mmol) was added to a stirred solution of 1-tert-butyl 4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (Intermediate 7) (5.5 g, 19.48 mmol), in THF (78 mL) at 25° C. The resulting mixture was stirred at 25° C. for 3 hours and monitored by TLC. The reaction mixture was diluted with diethyl ether (150 mL), and washed with water (100 mL). The aqueous layers were combined and then acidified with citric acid (1N, 200 mL). The product was extracted into DCM. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford 1-(tert-butoxycarbonyl)-4-cyanopiperidine-4-carboxylic acid (4.50 g, 91%). This material was used in the next steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][CH2:8][C@@H:9]2[O:14][C@@H:13]([O:15][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:17]Br)[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][CH2:8][C@@H:9]2[O:14][C@@H:13]([O:15][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:17][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(CSC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CSC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
130 mg of the isomer of lesser polarity of trans-6-(4-chlorobenzylthiomethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran, 67.5 mg of imidazole and 74 mg of sodium iodide were reacted in dimethylformamide at 130° C. for 9 hours and then treated and the product purified essentially as described in Example 34(b)(i), to give 60 mg of the title compound in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=O)=[CH:6][CH:5]=1)[CH3:2].[O-]CC.[Na+].[C:19](#[N:21])[CH3:20]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH2:20][C:19]#[N:21])=[O:10])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(OCC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)CC#N)cc1
Reaction time: 26 h
Yield: 45 %

Procedure:
Ethyl 4-ethoxybenzoate (45.3 mL, 250 mmole) was added to a suspension of sodium ethoxide (17.0 g, 250 mmole) and acetonitrile (16 mL, 300 mmole) in dry toluene (100 mL) and the mixture was mechanically stirred at 106°-110° for 26 hours. The reaction was then cooled and diluted with water (400 mL). After most of the solid had dissolved, the solution was washed with ethyl ether (2×200 mL) and then acidified with concentrated HCl (approximately 20 mL) to pH of about 5. The copious off-white precipitate was collected by suction filtration and air dried. Crystallization from 95% ethanol (350 mL) provided 21.3 g. of the subtitled compound as white needles, sufficiently pure for further transformation (yield: 45%). 1H NMR (CDCl3, δ) 7.85 (d, 2H, J=8 Hz, o-phenyl), 6.95 (d, 2H, J=8 Hz, m-phenyl), 4.1 (q, 2H, J= 7 Hz, OCH2), 4.0 (s, 2H, CH2CN), 1.45 (t, 3H, CH3).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:53])([CH3:52])[CH2:9]/[CH:10]=[CH:11]/[C:12](=[O:51])[N:13]([CH3:50])[C@@H:14]([C:26](=[O:49])[N:27]([CH3:48])[C@@H:28]([C:36](=[O:47])[N:37]([CH3:46])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:50][N:13]([C@@H:14]([C:26](=[O:49])[N:27]([CH3:48])[C@@H:28]([C:36](=[O:47])[N:37]([CH3:46])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[C:12](=[O:51])/[CH:11]=[CH:10]/[CH2:9][C:8]([NH2:7])([CH3:52])[CH3:53]
Reactant: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 70.1 %

Procedure:
((3E)-1,1-Dimethyl-4-{N-methyl-N-[(1R)1-(N-methyl-N-{(1R)-1-[N-methyl-N-(2-(pyridin-2-yl)ethyl)carbamoyl]-2-phenylethyl}carbamoyl)-2-(2-naphthyl)ethyl]carbamoyl}but-3-enyl)carbamic acid tert-butyl ester (5.28 g, 7.2 mmol) was dissolved in dichloromethane (50 mL). The solution was cooled to −10° C. Trifluoroacetic acid (50 mL) was added to the stirred solution. The reaction mixture was stirred for 45 min at −10° C. The reaction mixture was added to a solution of ice, sodium hydrogen carbonate and water. The reaction mixture was neutralised with sodium hydrogen carbonate. Dichloromethane (400 mL) was added. The aqueous phase was extracted with dichloromethane (300 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using 15% of a solution, 7% ammonium in ethanole, in dichloromethane as eluent, to give 3.2 g of the title compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([CH3:40])([CH3:39])[C:9]([O:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([OH:38])=[CH:19][C:20]=2[O:24][CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:15]=[CH:14]1)=[O:10].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:7][C:8]([CH3:40])([CH3:39])[C:9]([O:11][CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([O:38][CH3:1])=[CH:19][C:20]=2[O:24][CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:15]=[CH:14]1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(O)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.9 %

Procedure:
Potassium carbonate (1.60 g, 12.6 mmol) was added to a solution of tert-butyl (2R)-2-{[(3-{[(2,2-dimethylpropanoyl)oxy]methyl}-7-hydroxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (1.50 g, 3.2 mmol) in dimethylformamide (10 ml) and the mixture stirred at 0° C. for 5 minutes. Dimethyl sulphate (0.6 ml, 6.3 mmol) was added and the reaction stirred at 0° C. for a further 5 minutes and then warmed to room temperature and stirred for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue dissolved in dichloromethane (20 ml) and washed with water (2×20 ml). The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give tert-butyl (2R)-2-{[(3-{[(2,2-dimethylpropanoyl)oxy]methyl}-7-methoxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (0.750 g, 48% yield) which was used in the next stage without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:19]([OH:20])[C:18]3[CH:17]=[CH:16][N:15]=[C:14](F)[C:13]=3[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>CCN(C(C)C)C(C)C.C(O)CCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:19]([OH:20])[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:13]=3[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3F)C2O)cc1
Reactant: NCc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3NCc3ccncc3)C2O)cc1
Temperature: 170 °C

Procedure:
A mixture of 2-(4-tert-butyl-phenyl)-4-fluoro-1-hydroxy-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one (0.11 g, 0.38 mmol, Step B) and 4-(aminomethyl)pyridine (0.070 mL, 0.68 mmol) in 0.70 mL of DIEA and 1.0 ml of BuOH was subjected to microwave heating at 170° C. for 17 min. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (0 to 5% of MeOH in CH2Cl2) to provide the titled compound as an off-white solid. MS (ES+): 389.1 (M+H)+. Calc'd for C23H24N4O2-388.46.
Reaction SMILES: [CH2:1]([C:4]1([CH2:19][CH:20]=O)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].Cl.[NH2:23][OH:24].N1C=CC=CC=1>ClCCl>[CH2:1]([C:4]1([CH2:19][CH:20]=[N:23][OH:24])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(CC=O)c2ccccc2CCc2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCC1(CC=NO)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Dissolved 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-ethanal (1.00 g, 3.62 mmol) in 10 mL of dry dichloromethane under a nitrogen atmosphere. Added 3A sieves, hydroxylamine hydrochloride (0.38 g, 5.43 mmol), and pyridine (0.58 mL, 0.57 g, 7.24 mmol). Stirred at room temperature for 16 hours. Filtered to remove sieve dust, and washed solid with water and dichloromethane. Separated layers of filtrate. Dried organic solution with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 20% EtOAc-CH2Cl2. Combined appropriate fractions and evaporated to give 0.65 g (62% yield) of 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-ethanone oxime as a colorless oil.