Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:20][CH2:19][C:18]([F:22])([F:21])[F:17])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)(O)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 31.5 g (15.5 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 400 ml of tetrahydrofuran 16.9 g (17.1 mmol) of 2,2,2-trifluoroethylamine, 32.7 g (17.1 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 23.1 g (17.1 mmol) of 1-hydroxybenzotrizole hydrate and 58.1 ml (34.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The solvent was removed by distillation and the residue was extracted with water/ethylacetate. Chromatography on silicagel with heptane/ethylacetate 1:1 yielded 25.4 g (67%) 2-hydroxy-2-methyl-N-(2,2,2-trifluoroethyl)-malonamic acid ethyl ester, MS m/e (%): 242.1 (M−H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@@H:12]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:29][C:28]4=[CH:30][N:31]=[C:32]([CH3:33])[N:27]4[C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:14][S:15][CH3:16])=[O:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C@@H:12]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:29][C:28]4=[CH:30][N:31]=[C:32]([CH3:33])[N:27]4[C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:14][S:15]([CH3:16])=[O:43])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Solvent: ClCCl
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)[C@@H](CCS(C)=O)NC(=O)Nc3ccc(Cl)cc3)CC1)C2
Yield: 55.4 %

Procedure:
To a solution of N—(4-chlorophenyl)—N′—((1R)-1-((4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)carbonyl)-3-(methylthio)propyl)urea (0.21 g) obtained in Example 65 in dichloromethane (15 ml) was added 3-chloroperbenzoic acid (0.10 g), and mixed at 0° C. for 20 minutes. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=10/1). The product was recrystallized from ethanol-diethyl ether to obtain the title compound as colorless powder (0.12 g, 54%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:35]=[C:36]([F:38])[CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:43][CH2:44][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:46][CH2:47]2)[CH:35]=[C:36]([F:38])[CH:37]=1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Reactant: Fc1cc(F)cc(CCCC2CCNCC2)c1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cc(F)cc(F)c3)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-(3-(3,5-difluorophenyl)propyl)piperidine.HCl (from EXAMPLE 95, Step E) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: 1H NMR (500 MHz, CD3OD) δ 1.14-1.47 (1OH). 1.58-1.68 (6H). 1.77-1.84 (6H). 2.06 (t, J=11.0, 1H), 2.36 (d, J=12.3, 1H), 2.53-2.59 (3H). 2.75-2.81 (2H). 2.96 (d, J=10.5, 1H), 3.11 (q, J=10.5, 1H), 3.30-3.42 (3H). 3.57-3.60 (2H). 6.67-6.72 (m, 1H). 6.74-6.76 (2H). 7.25-7.28 (m, 1H). 7.34-7.89 (4H); ESI-MS 539 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])=[CH:16][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:42])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>C(OCC)(=O)C.O1CCCC1>[O:13]=[C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:42])[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:7][CH:6]=2)[N:9]=[CH:10][N:11]1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])=[CH:18][CH:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
2-(4-Aminophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy) phenyl]-3(2H,4H)-1,2,4-triazolone (4.6 g) and pyridine (1.43 g) were dissolved in ethyl acetate (200 ml). To the resultant was added dropwise at room temperature a solution of phenyl chlorocarbonate (2.83 g) in ethyl acetate (20 ml). After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. Water (200 ml), ethyl acetate (600 ml) and tetrahydrofuran (300 ml) were added thereto. The separated organic layer was washed with 5% phosphoric acid (200 ml×2) and water (200 ml) successively, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated to about 50 ml and the precipitated crystals were collected by filtration. The crystals thus obtained were washed with diethyl ether and dried to give phenyl 4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H,4H-1,2,4-triazol-1-yl]phenylcarbamate (5.6 g, 93%) as colorless scaly crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[N:27]1([CH2:26][CH2:25][CH2:24][N:18]2[CH2:19][CH2:20][N:21]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:22][CH2:23]2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: C(CN1CCNCC1)CN1CCOCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1cc(N2CCN(CCCN3CCOCC3)CC2)ncn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.368 g, 2.84 mmol) and diisopropylethylamine (0.367 g, 2.84 mmol) were suspended in n-butanol. 4-(3-piperazin-1-ylpropyl)morpholine 10-1 (0.61 g, 2.84 mmol) was then added. The reaction was stirred at 125° C. for 18 hours. Upon cooling the resulting solid was filtered off, washed with ethyl ether and dried to afford 10-2. 1NMR (DMSO): 7.94 ppm (s, 1H); 6.18 ppm (s, 2H); 5.58 ppm (s, 1H); 3.56 ppm (t, 4H); 3.39 ppm (t, 4H); 2.38 ppm (t, 4H); 2.31 ppm (m, 8H); 1.60 ppm (p, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:25]=[C:24]([NH2:26])[C:23]3[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=3)[N:17]=2)[CH2:12][CH2:11]1.[CH3:31]I>CS(C)=O>[CH3:28][O:27][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:29][CH3:30])[N:17]=[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:2]3[N:3]([CH3:31])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH2:11][CH2:12]1)[N:25]=[C:24]2[NH2:26]
Reactant: CI
Reactant: COc1cc2nc(N3CCN(c4nc5ccccc5[nH]4)CC3)nc(N)c2cc1OC
Solvent: CS(C)=O
Product: COc1cc2nc(N3CCN(c4nc5ccccc5n4C)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-[4-(1H-2-benzimidazolyl)-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine (0.75 g, described in Example 10) and methyl iodide (1.0 ml) in dimethyl sulfoxide (10 ml) was stirred at room temperature for 4 hr and poured into ice. The resulting mixture was extracted with chloroform. The organic extract was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed through silica gel using 4% methanol in chloroform. The appropriate fractions were combined and evaporated to give a residue (0.42 g) of the title compound. The latter residue was crystallized from hexane-chloroform: mp 249°-251° C.; ir (CHCl3) 3400 and 3300 cm-1 ; uv max (MeOH) 213 (ε=49,870), 250 (ε=64,830); 284 (ε=26,545) and 341 nm (ε=6,565); and Anal. Calcd. for C22H25N7O2 : C, 62.99% H, 6.01% N, 23.37% and Found: C, 62,81% H, 6.18% N, 23.71%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=2[O:22][CH2:23]C(O)=O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CO.[C].[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]2[C:15]3[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=3[O:22][CH:23]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=CC(=O)c2c(O)cccc2OCC(=O)O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
To a mixture of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (2.24 g) and 4-acetylaminobenzaldehyde (2.45 g) in ethanol (30 mL) were added water (10 mL) and potassium hydroxide (6.73 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (70 mL), and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-acetylamino-2′-(carboxymethoxy)-6′-hydroxychalcone (3.35 g). A mixture of the obtained 4-acetylamino-2′-(carboxymethoxy)-6′-hydroxychalcone (3.3 g) and 10% palladium-carbon powder (1 g) in methanol (50 mL) was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was dissolved in acetic acid (13.2 mL). To the solution were added sodium acetate (4.77 g) and acetic anhydride (4.8 mL), and the mixture was stirred at 115° C. for 20 hours. The reaction mixture was poured in to water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL). To the solution was added sodium methoxide (28% methanol solution, 5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue were added 1 mol/L hydrochloric acid (30 mL) and ethyl acetate, and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with dichloromethane-methanol. The precipitated crystals were collected by filtration. The crystals were washed with dichloromethane and dried under reduced pressure to give the title compound (0.86 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:40])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[CH2:23][CH2:22]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>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:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:40])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=2)[CH2:23][CH2:22]3)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: N#Cc1c(Cl)cncc1-c1ccc2c(c1)CCN2C(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 54.8 %

Procedure:
To 3,5-dichloro-4-pyridinecarbonitrile (300 mg, 1.74 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (823 mg, 1.908 mmol) in a 5 mL sealable vial was added 1,4-Dioxane (5 mL) and saturated NaHCO3 (2.5 mL). The mixture was then bubbled with N2 gas for 5 minutes then Pd(Ph3P)4 (200 mg, 0.173 mmol) was added. The vial was then capped and heated at 100° C. overnight. The reaction was then diluted with water (10 ml) and extracted with EtOAc (3×20 ml). The organic was combined then washed brine, dried over MgSO4, filtered and concentrated. The crude solid was then dissolved in 3 mL of DMF and loaded on to a 50 g Biotage SNAP column conditioned with hexane and purified by silica gel chromatography with 0 to 60% EtOAc in Hexane over a 30 minute gradient. The fractions with the desired product were pool and concentrated. The semi-solid oil was then treated with 20 ml of 5% DCM/Hexane to induce precipitation. The solid was isolated by filtration to give 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (421 mg, 54.9% yield) as a off yellow solid. LC/MS (ES) m/z=442.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.83 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 7.69 (s, 1H), 7.56-7.67 (m, 3H), 7.51 (d, J=8.08 Hz, 1H), 4.31 (t, J=8.59 Hz, 2H), 4.06 (s, 2H), 3.29 (t, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S@:5](=[O:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:6][C:7](=[O:32])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=3)=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[CH3:40][NH:41][CH3:42]>>[CH3:40][N:41]([CH3:42])[CH2:2][CH2:3][CH2:4][S@:5](=[O:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:6][C:7](=[O:32])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=3)=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CCCBr)c4ccccc4)c3)c2)n(C)n1
Reactant: CNC
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CCCN(C)C)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described for example 508, (S)-N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide and dimethylamine were converted to the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)COCCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:16])=[C:6]([CH:15]=1)[C:7](=[N:18][NH2:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(F)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1ccccc1)c1cc(F)ccc1N

Procedure:
In the manner given in Preparation 1, 5-fluoro-2-aminobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 5-fluoro-2-aminobenzophenone hydrazone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].Br[C:14]1[CH:15]=[C:16]([O:20][CH3:21])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([OH:12])=[O:11])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(C(=O)O)cc3ccccc32)c1
Temperature: 170 °C
Yield: 45.7 %

Procedure:
The starting ester is prepared in the following manner: A mixture of indole-2-carboxylic acid (8.06 g), m-bromoanisole (9.35 g), anhydrous potassium carbonate (7 g) and cupric oxide (0.25 g) in dimethylformamide (10 ml) is heated at 170° C. under nitrogen for 18 hrs., diluted with a further 20 ml of solvent and heated 6 hours longer. It is cooled, diluted with water (500 ml) and extracted with methylene chloride (3×100 ml). The filtered aqueous layer is acidified with cold concentrated hydrochloric acid, refrigerated overnight and the precipitated product recrystallized from methanol to afford pure 1-(3-methoxypheny)indole-2-carboxylic acid (6.1 g), mp. 194°-196°. This acid (3.3 g) absolute ethanol (100 ml) and concentrated sulphuric acid (1.1 ml) are refluxed overnight, cooled, treated with water (50 ml) and the ethyl ester crystallizes. The crude ester (34 g) in trifluoroacetic acid (280 ml) is reduced with sodium borohydride (17.3 g) as described in Example 5 to afford ethyl 2,3-dihydro-1-(3-methoxyphenyl)indole-2-carboxylate as an oil.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([CH2:18][NH2:19])([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:29][C:30]1[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].O>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([CH2:18][NH:19][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:40])[F:41])=[N:38][C:30]=3[CH3:29])([CH2:14][CH:15]3[CH2:16][CH2:17]3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
To a stirred solution of C-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethyl-cyclohexyl)-methylamine (200 mg; 0.701 mmol) and N-ethyldiisopropylamine (0.15 ml; 0.841 mmol) in DCM (5 ml) was added 2-methyl-6-(trifluoromethyl)nicotinoyl chloride (172 mg; 0.771 mmol). The mixture was stirred for 90 minutes. Water (4 ml) and DCM (4 ml) were added and the mixture was stirred vigorously for 5 minutes then passed through a PTFE separation frit. The organic phase was collected and evaporated in vacuo to give an oil. The crude product was chromatographed on silica eluted with 15% EtOAc in DCM to give a yellow oil, which still contained impurities. The oil was rechromatographed on silica eluted with 20% EtOAc in DCM to give a yellow oil. The oil was crystallised from EtOAC using hexane to give a white solid (170 mg). 1H NMR (500 MHz, CDCl3): δ 7.82 (1H, d, J 7.8), 7.55 (1H, d, J 7.9), 5.90 (1H, t, J 6.0), 3.61 (2H, d, J 6.4), 2.98-2.88 (3H, m), 2.72 (3H, s), 2.07-1.85 (6H, m), 1.43-1.37 (2H, m), 1.24 (2H, d, J 6.6), 1.20-1.12 (1H, m), 0.77-0.69 (3H, m), 0.54-0.50 (2H, m), 0.42-0.40 (2H, m), 0.06-0.04 (2H, m). MS (m/e)=473. MPt=148-151° C.
Reaction SMILES: [SH:1][CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])=[O:4].[OH-:18].[Na+].II>O.C(O)C>[O:18]=[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])[CH2:2][S:1][S:1][CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])=[O:4]
Reactant: [OH-]
Reactant: O=C(O)C1CCc2ccccc2N1C(=O)CS
Agent: II
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCc2ccccc2N1C(=O)CSSCC(=O)N1c2ccccc2CCC1C(=O)O

Procedure:
(±)-1,2,3,4-Tetrahydro-1-(2-mercapto-1-oxoethyl)-2-quinolinecarboxylic acid (3 g) was suspended in water (40 ml) and the pH was adjusted to 6.5 with 2 N sodium hydroxide. A saturated solution of iodine in ethanol was then added dropwise while maintaining the pH at 6.5 by the slow addition of 2 N sodium hydroxide. When a yellow color remained for at least five minutes, addition of the iodine solution was terminated and the yellow color was discharged with saturated aqueous sodium thiosulfate. The mixture was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with 10% hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The (±) 1,1'-[dithiobis(1-oxo-2,1-ethanediyl)]-bis-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid was recrystallized from ethyl acetate; yield 0.7 g, m.p. 172°-174°.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].C([O-])(O)=O.[Na+].[CH3:27][C:28](OC(C)=O)=[O:29]>C1(C)C=CC=CC=1.CC#N>[C:28]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)C1(O)CC=C2C[C@@H]3[C@@H]4C=C[C@H](O)[C@@H]5OC1=C2[C@]45CCN3C
Yield: 98.8 %

Procedure:
A mixture of morphine (23.63 g, 83 mmol), NaHCO3 (28.2 g, 336 mmol), Ac2O (8.69 g, 85 mmol) in toluene (500 ml) and CH3CN (900 ml) was heated at reflux for 21 hrs. The reaction mixture was evaporated to dryness in vacuo. To the residue was added water (80 ml) and extracted with chloroform (500 ml). The extracts were dried, combined and evaporated to dryness in vacuo to obtain a residue, which was chromatographed on silica gel (column: d=6 cm, l=8 cm, packed with 141 g of silica gel; solvent system: 5-10% MeOH in CH2Cl2) to yield 3-acetylmorphine (27 g, 100% yield). IR (KBr)(ν, cm-1): 3500 (m, sharp, --OH), 1750 (s, sharp, AcO); NMR (δH)(CDCl3): 6.73 (1, d, J, 8.1, 2-H), 6.57 (1, d, J, 8.1, 1-H), 5.74 (1, dm, J, 10.1, 7-H), 5.25 (1, dm, J, 9.9, 8-H), 4.91 (1, d, J, 6.9, 5-H), 4.25-4.10 (1, m, 6-H), 3.50-3.35 (1, m, 9-H), 3.05(1, d, J, 19.1, 10-Hβ), 2.8-2.7 (1, m, 14-H), 2.85-2.60 (1, m, 16-He), 2.50-2.25 (1, m, 16-Ha), 2.45 (3, s, NCH3), 2.5-2.2 (1, m, 10-Hα), 2.28 (3, s, AcO), 2.06 (1, td, J, 12.1 & 5.0, 15-Ha), 2.0-1.85 (1, m, 15-He).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][PH:12](=[O:14])[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:11][P:12](=[O:14])([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[PH](C)=O
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CP(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 36.3 %

Procedure:
A degassed suspension of 1-iodo-4-nitrobenzene (90 mg, 0.36 mmol), dimethylphosphane oxide (29.2 mg, 0.38 mmol), bis(dibenzylideneacetone)palladium (3.31 mg, 0.0036 mmol), XantPhos (6.27 mg, 0.0108 mmol), and Cs2CO3 (165 mg, 0.506 mmol) in dry dioxane (0.4 mL) was heated in a sealed tube at 90° C. for 4 h. The cooled mixture was filtered, the filtrate concentrated in vacuo, and the residue chromatographed over silica gel eluting with 5% MeOH in dichloromethane to afford 26 mg of dimethyl(4-nitrophenyl)phosphane oxide (yield: 36%).