Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:31][N:32]2[CH2:52][CH2:51][C:35]3([O:40][CH2:39][CH2:38][N:37]([C:41]([C:43]4[N:44]=[C:45]([CH:48]([CH3:50])[CH3:49])[S:46][CH:47]=4)=[O:42])[CH2:36]3)[CH2:34][CH2:33]2)[S:29][CH:30]=1.FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:48]([C:45]1[S:46][CH:47]=[C:43]([C:41]([N:37]2[CH2:36][C:35]3([CH2:34][CH2:33][N:32]([CH2:31][C:28]4[S:29][CH:30]=[C:26]([CH2:25][CH:24]=[O:23])[CH:27]=4)[CH2:52][CH2:51]3)[O:40][CH2:39][CH2:38]2)=[O:42])[N:44]=1)([CH3:50])[CH3:49]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)cs4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CC=O)cs4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (0.25 g) was added to a stirred solution of (9-((4-(2-hydroxyethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 36, step b) (0.17 g) and trifluoroacetic acid (0.07 mL) in DCM (5 mL). After 1 h, ethyl acetate (30 mL) was added followed by a mixture of saturated sodium thiosulphate solution (5 mL) and saturated sodium bicarbonate solution (5 mL). The reaction mixture was shaken well and separated. The ethyl acetate solution was washed with saturated sodium bicarbonate solution, water and brine. Acetic acid (0.07 mL) was added, the solution dried over sodium sulphate, filtered and evaporated in vacuo (bath temperature ˜30° C.) to give the subtitled compound as a gum. Yield 0.19 g. Used directly
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[S:13][C:14]=2[N+:15]([O-])=O)=O)[CH:5]=[CH:6][CH:7]=1.CCO>[Fe].C(O)(=O)C>[NH2:15][C:14]1[S:13][C:12]([C:18]#[N:19])=[CH:11][C:10]=1[S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cc(S(=O)c2cccc(Br)c2)c([N+](=O)[O-])s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1cc(Sc2cccc(Br)c2)c(N)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
4-(3-Bromo-benzenesulfinyl)-5-nitro-thiophene-2-carbonitrile (Example 25: step e; 5.20 g, 15.33 mmol) was dissolved into EtOH (45 mL) and acetic acid (5 mL). The reaction was heated to 50° C. and then iron (4.28 g, 76.69 mmol) was added and the reaction was allowed to heat with stirring overnight. The reaction mixture was filtered through celite which was washed with MeOH and EtOAc to ensure that the product does not remain on the celite. The filtrate was concentrated and then dissolved into EtOAC and washed with brine. The organic layer was dried (MgSO4) and concentrated. The crude reaction mixture was purified by flash column (20% EtOAc in Hexanes) resulting in the desired product as a brown oil (1.5 g, 32%). 1H-NMR (CDCl3): δ 7.38 (1H, s), 7.31-7.29 (1H, m), 7.18 (1H, t, J=1.8, Hz), 7.14 (1H, t, J=7.9 Hz), 6.99-6.96 (1H, m), 5.06 (2H, br s).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27](Cl)=[N:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1C(=O)CCC1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([O:13][CH:10]2[CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH2:9]2)=[N:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: Clc1ccc(OCc2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: c1ccc(COc2ccc(OC3COC(c4ccccc4)OC3)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Phenyl-[1,3]dioxan-5-ol (164 mg. 910 μmol) was dissolved in 5 ml of NMP. Addition of sodium hydride (60% in oil, 72.8 mg, 1.8 mmol) was followed by stirring at RT for 30 min and, after addition of 5-benzyloxy-2-chloropyridine (200 mg, 910 μmol), stirring in a microwave reactor at 200° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and water, and the organic phase was concentrated. The resulting crude product (386 mg) was directly reacted further.
Reaction SMILES: [Br:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29](C([O-])=O)[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)[O-])CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.3 %

Procedure:
A 20 mL vial was charged with tert-butyl. 4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (100 mg, 0.145 mmol) and CH2Cl2 (2 mL). TFA (2 mL) was added and stirred at ambient temperature for 5 minutes. The reaction was poured into water and diluted with CH2Cl2. Solid Na2CO3 added slowly to neutralize the TFA. The reaction was extracted and dried to afford 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine (88 mg, 103% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[O:4].[H-].[Na+].I[CH3:18]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH3:18])[CH:11]=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2ccn(C)c12
Yield: 91.7 %

Procedure:
A solution of the 5-bromo-indole-7-carboxylic acid methyl ester (300 mg, 1.18 mmol) in DMF (15 mL) was cooled to 0° C. under nitrogen and treated with sodium hydride (60% in mineral oil) (56.6 gm, 1.4 mmol). After stirring for 15 minutes the iodomethane (0.08 mL, 1.3 mmol) was introduced and the cooling bath was removed (reaction became light purple). After 30 minutes the reaction was quenched with water (5 ml) and then concentrated to reduce the volume of DMF. The reaction was poured into water (1.6 L) and EtOAc (200 ml). The layers were separated and the aqueous phase was extracted with EtOAc (3×200 ml). The combined organics were washed with water (3×) and then dried (MgSO4). The solution was filtered and the filterate was concentrated. The residue was purfied by CombiFlash with 10% EtOAc in Hexane as the eluent to afford the desirable product 5-Bromo-1-methyl-1H-indole-7-carboxylic acid methyl ester (290 mg, 92%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH2:15])[CH:12]([OH:14])[CH3:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[CH2:15])[C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(c1ccc(CCCC)cc1)C(C)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=C(C(C)=O)c1ccc(CCCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.07 g of alcohol 51 is dissolved in 100 ml of methylene chloride, and 9.1 g of manganese dioxide is added under nitrogen. It is stirred overnight at room temperature, filtered on Celite and the residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 301 mg of title compound 52 in addition to 395 mg of the starting material are obtained as colorless oils.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:27])=[N:24][O:25][N:26]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:23]1[C:22]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[N:26][O:25][N:24]=1)=[O:6]
Reactant: Nc1nonc1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2nonc2-c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
200 mg (0.85 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid and 167 mg (0.85 mmol) of 4-(4-chlorophenyl)-1,2,5-oxadiazol-3-ylamine are dissolved in 24 ml of CH2Cl2 at RT and treated with 0.12 ml (0.85 mmol) of triethylamine, 21 mg (0.17 mmol) of DMAP and 1814 mg (1.28 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 30 h at RT and subsequently washed twice with in each case 5 ml of water. The organic phase is dried over Na2SO4 and evaporated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield 140 mg (36%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:31])[C@H:13]([CH3:30])[NH:14][C@H:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:31])[C@H:13]([CH3:30])[NH:14][C@H:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][C@H:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](CC(=O)c1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](C[C@@H](O)c1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
13.4 g (30 mmoles) of N-[1-(S)-ethoxycarbonyl-3-phenyl-3-oxo-propyl]-(S)-alanyl-(S)-proline-t - butylester are dissolved in 120 ml of ethanol and hydrogenated in the presence of 1.5 g of 10% palladium-on-charcoal catalyst at room temperature. After the uptake of the theoretically needed hydrogen (720 ml), the catalyst is filtered off. A mixture of N-[1-(S)-ethoxycarbonyl-3-phenyl-3(S)-hydroxypropyl]-(S)-alanyl-(S)-proline-t-butylester and N-[1-(S)-ethoxycarbonyl-3-phenyl-3(R)-hydroxypropyl]-(S)-alanyl-(S)-proline-t-butylester is obtained.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].Br[C:29]1[N:34]=[C:33]([CH2:35][OH:36])[CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:27][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:29]3[N:34]=[C:33]([CH2:35][OH:36])[CH:32]=[CH:31][CH:30]=3)=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:25])=[O:26]
Reactant: CN1c2cc(B3OC(C)(C)C(C)(C)O3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: OCc1cccc(Br)n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1c2cc(-c3cccc(CO)n3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 120 °C

Procedure:
1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (12-1) (131 mg, 0.33 mmol, 1.0 eq), (6-bromopyridin-2-yl)methanol (61 mg, 0.33 mmol, 1.0 eq), cesium carbonate (317 mg, 0.97 mmol, 3.0 eq) and bis(tri-t-butylphosphine) palladium(0) (16.6 mg, 0.03 mmol, 0.1 eq) were combined in dioxane (1.0 mL) and water (0.2 mL). The resulting mixture was heated in the microwave at 120° C. for 20 minutes. The reaction mixture was diluted with EtOAc (10 mL), washed with water (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (12 g SiO2, 0-80% EtOAc in hexanes) to afford (6-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}pyridin-2-yl)methanol (25-1). LRMS m/z (M+H) 382.2 found, 382.1 required.
Reaction SMILES: C(O[C:9]1[C:14]([F:15])=[C:13]([O:16]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[NH:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)=[C:28]([F:37])[CH:27]=1)C1C=CC=CC=1>[C].[Pd].C1COCC1>[CH:34]1([CH2:33][O:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]3[O:38][C:9]4[C:14]([F:15])=[C:13]([OH:16])[CH:12]=[CH:11][C:10]=4[N:24]=3)=[CH:27][C:28]=2[F:37])[CH2:36][CH2:35]1
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(F)c1OCc1ccccc1)c1ccc(OCC2CC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
A mixture of N-(2,4-bis(benzyloxy)-3-fluorophenyl)-4-(cyclopropylmethoxy)-3-fluorobenzamide (12.3 g), 10% palladium-carbon (containing water (50%), 12.0 g) and THF (80 mL) was stirred at room temperature for 20 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure, and the solid was washed with diethyl ether. To a solution of the obtained solid, hexachloroethane (14.6 g) and triphenylphosphine (16.2 g) in acetonitrile (50 mL) was added triethylamine (10.3 mL) at 0° C., and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 2 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.96 g).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[CH2:11]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:24])=[CH:26][CH:27]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(CCc2ccccc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.552 g (3.458 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.78 g (3.46 mmol) of 4-phenethylbenzoic acid and 1.93 ml (13.8 mmol) of triethylamine in 15 ml of N,N-dimethylformamide, 0.63 ml (4.15 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield 6-(4-phenethylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][C:21]#[N:22])[CH:16]=3)[C:11]2=[O:23])=[CH:7][CH:6]=1.Br[CH2:27][CH2:28]Br>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4([C:21]#[N:22])[CH2:28][CH2:27]4)[CH:16]=3)[C:11]2=[O:23])=[CH:7][CH:6]=1
Reactant: COc1ccc(CN2CCc3cc(CC#N)ccc3C2=O)cc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCc3cc(C4(C#N)CC4)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a suspension of 228 mg of 60% sodium hydride in 15 ml DMF was added 1.2 g of [2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-acetonitrile and after stirring for 15 minutes at room temperature 1.1 g of 1,2-dibromo-ethane in 1.5 ml DMF was added. The resulting mixture was stirred 0.5 hour at room temperature and then more sodium hydride (0.114 g, 2.86 mmole) was added and the reaction mixture was heated for about 10 minutes at 30-35° C. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic layer was dried over sodium acetate and concentrated in vacuo. Purification by silica gel column chromatography with 30%-50% ethylacetate in hexane afforded 1 g of 1-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-cyclopropanecarbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:45])[C@H:19]([NH:30][C:31](=[O:44])[C:32]([N:35](C)[C:36](=O)OC(C)(C)C)([CH3:34])[CH3:33])[CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH2:13]3)[C:11](=[O:46])[N:10]([CH3:47])[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:45])[C@H:19]([NH:30][C:31](=[O:44])[C:32]([CH3:33])([NH:35][CH3:36])[CH3:34])[CH2:20][O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[CH2:13]3)[C:11](=[O:46])[N:10]([CH3:47])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(COC[C@@H](NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)C(=O)N2CCCC3(C2)C(=O)N(C)CC3c2ccc(F)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)(C)C(=O)N[C@H](COCc1ccc(C)cc1)C(=O)N1CCCC2(C1)C(=O)N(C)CC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 1-((2R)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-3-(4-methylbenzyloxy)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-yl(methyl)carbamate (128 mg, 0.196 mmol) in DCM (2 ml) was added TFA (0.6 ml, 7.79 mmol). The mixture was stirred at RT for 30 mins then concentrated in vacuo. The residue was suspended in sat. sodium bicarbonate soln. (10 ml) and extracted with EtOAc (2×50 ml). The extracts were dried and concentrated. The residue was applied to a 20 g silica cartridge in DCM and this was eluted with 5% MeOH/DCM [diluted from 10% MeOH/DCM containing 1% aqueous 880 ammonia]. The relevant fractions were combined and concentrated to give a foam. This was dried at 40° C. overnight under vacuum to give the title compound as a glass.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21].C([O-])(=O)C.[Na+]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[C:4]([CH3:15])[N:3]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1nc(Cl)c2cc([N+](=O)[O-])ccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(Nc2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1OC

Procedure:
The title compound was prepared from 4-chloro-2-methyl-6-nitro-quinazoline (80 mg, 0.36 mmol), 3,4-dimethoxy-aniline (54.8 mg, 0.36 mmol) and sodium acetate (35.2 mg, 0.43 mmol) similar to example 20 to give 109 mg (89.5%) of yellow solids. 1H NMR (CDCl3): 8.87 (d, J=2.7 Hz, 1H), 8.56 (dd, J=2.4 Hz, J=9.0 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.63-7.61 (m, 2H), 7.28-7.24 (m, 1H), 6.94 (d, J=8.7 Hz, 1H), 3.96 (s, 3H)), 3.93 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [S:1]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:13][CH2:14][C:15]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:4]=1)=[O:16]
Reactant: COC(=O)CSc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CSc1ccc(C(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl thiophenoxyacetate (60g.) in methylene chloride (100ml.) was added over 20 minutes to a stirred suspension of chloroacetyl chloride (45.2g.) and aluminium chloride (134g.) in methylene chloride (400ml.) at room temperature. The resulting solution was stirred at room temperature overnight and poured onto a mixture of ice (2kg.) and concentrated hydrochloric acid (50ml.). This mixture was then stirred at room temperature for 1 hour. The methylene chloride phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was recrystallised from methanol to give methyl 4-(chloroacetyl)-thiophenoxyacetate (60.1g.), m.p. 61°-63° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:19]=[CH:18][C:14]3[CH2:15][O:16][CH2:17][C:13]=3[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Pd]>[CH2:15]1[C:14]2[CH:18]=[CH:19][C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[CH:12][C:13]=2[CH2:17][O:16]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)COC3)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc3c(c2)COC3)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A solution of 5-[(4-nitrophenyl)oxy]-1,3-dihydro-2-benzofuran (Intermediate 74, 190 mg, 0.739 mmol), hydrazine hydrate (0.046 ml, 1.477 mmol) and Pd/C (157 mg, 0.148 mmol) in ethanol (6 ml) was stirred under argon at 90° C. After 4.5 hours 0.2 equivalents of Pd/C and 2 equivalents of hydrazine hydrate were added. After 1 more hour, the reaction mixture was cooled to room temperature and then filtered over celite and washed with methanol. The organic phase was concentrated and the residue was purified by SCX to afford the title compound (152 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([O:26]C)=[O:25])[CH:5]=[C:6]([Br:22])[C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)(=[O:10])=[O:9].[OH-].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([OH:26])=[O:25])[CH:5]=[C:6]([Br:22])[C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)(=[O:9])=[O:10]
Reactant: COC(=O)Cc1cc(Br)c(S(=O)(=O)c2ccc(OC)c(C(C)C)c2)c(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)c2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C

Procedure:
Methyl 3,5-dibromo-4-(3-isopropyl-4-methoxyphenylsulfonyl)phenylacetate (0.6 g), prepared by the method of Example 1, was treated with KOH in 10% aqueous MeOH for 0.5 hour, acidified and the product collected by filtration, washed with water, and dried in a vacuum oven to yield 3,5-dibromo-4-(3-isopropyl-4-methoxyphenylsulfonyl)phenylacetic acid. MP 170°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:27])[NH:22]2>>[CH3:1][O:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([CH:7]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[CH:26][C:18]=3[CH3:17])[NH:22][C:21]2=[O:27])=[CH:9][CH:10]=1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Reactant: Cc1cccc2c1CC(=O)N2
Product: COc1ccc(C=C2C(=O)Nc3cccc(C)c32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 4-methyl-2-oxindole to give 0.3 g of 3-(6-methoxybiphenyl-3-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.CC(C1C=CC(Br)=CC=1)=O.BrC1C=CC([C@@H](O)C)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Agent: CC(=O)c1ccc(Br)cc1
Agent: C[C@H](O)c1ccc(Br)cc1
Product: C[C@@H](O)c1ccc(Br)cc1
Reaction time: 264 h
Yield: 57 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized buckwheat protein for the substrate (±)-1-(4-bromophenyl)ethanol (200 mg) requires 11 days by going through bioconversion to 4-bromoacetophenone accompanying sterically selective oxidation of (S)-1-(4-bromophenyl)ethanol to obtain 114 mg of (R)-1-(4-bromophenyl)ethanol at a yield of 57%. Optical purity was obtained at 88% e.e.