Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:22])[N:8]2[C@H:11]2[C:20]3[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=3)[O:14][CH2:13][CH2:12]2)=[C:4]([Cl:23])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:77]1[CH:82]=[C:81]([F:83])[CH:80]=[CH:79][C:78]=1[N+:84]([O-:86])=[O:85]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:23][C:4]1[N:3]=[C:2]([NH:1][C:77]2[CH:82]=[C:81]([F:83])[CH:80]=[CH:79][C:78]=2[N+:84]([O-:86])=[O:85])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:22])[N:8]2[C@H:11]1[C:20]2[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=2)[O:14][CH2:13][CH2:12]1
Reactant: Nc1nc(Cl)c2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(Cl)nc(Nc3cc(F)ccc3[N+](=O)[O-])nc2n1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.6 %

Procedure:
To an oven-dried vial was added (R)-2-amino-6-chloro-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one (152 mg, 0.45 mmol, 1 equiv.) in anhydrous toluene (2.5 mL), followed by freshly grounded cesium carbonate (207 mg, 0.64 mmol, 1.4 equiv.) with stirring at room temperature under Ar. After 10 min, Pd(OAc)2 (30.3 mg, 0.045 mmol, 0.1 equiv.), racemic BINAP (42 mg, 0.067 mmol, 0.15 equiv.) and 1-bromo-5-fluoro-2-nitrobenzene (130 mg, 0.59 mmol, 1.3 equiv.) were added as solids. The vial was purged with Ar for 3 min, then closed and heated at 80° C. for three days. The reaction mixture was cooled to room temperature, then poured into saturated aqueous NH4Cl (10 mL). To this mixture, saturated aqueous Na2EDTA (10 mL) was added and the mixture was stirred for 10 min. Then the reaction mixture was extracted with ethyl acetate (4×20 mL), the collected organic layers were washed with brine, dried (anhydrous Na2SO4) and the solvent evaporated in vacuo. Column chromatography of the residue on silica gel (gradual elution with 1% methanol in 4/2/1 hexane/methylene chloride/ethyl acetate to 2% methanol in 4/2/1 hexane/methylene chloride/ethyl acetate) afforded, after evaporation and drying, the desired product as an orange solid (76 mg, 46% yield based on 78% conversion), along with 33 mg of recovered starting material. 1H NMR (300 MHz, CDCl3) δ, ppm: 10.64 (s, 1H), 8.58 (s, 1H), 8.29-8.16 (m, 2H), 7.02-6.95 (m, 1H), 6.74-6.60 (m, 2H), 5.88-5.82 (m, 1H), 4.66-4.62 (m, 1H), 4.38 (app t, J=11.0 Hz, 1H), 4.38-4.28 (br m, 1H, overlapping with 4.38 ppm), 2.96-2.92 (m, 1H), 2.26-2.23 (m, 1H); MS (EI) m/z 475.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O:25][CH3:26])=[O:24]>>[CH3:26][O:25][C:23](=[O:24])[C:27]1[CH:32]=[CH:31][C:30]([O:22][CH2:21][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Product: COC(=O)c1ccc(OCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1

Procedure:
Prepared from {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (INTERMEDIATE B1.1) and 4-carbomethoxyphenol using a similar procedure as described in the preparation of example B2.1. MS: M+H=471.
Reaction SMILES: [C:1]12[C:12](O)=[CH:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.P(Cl)(Cl)([Cl:16])=O>O1CCOCC1>[Cl:16][C:12]1[C:1]2[C:2]3[CH2:3][CH2:4][CH2:5][C:6]=3[S:7][C:8]=2[N:9]=[CH:10][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2sc3c(c12)CCC3
Solvent: C1COCCO1
Product: Clc1ccnc2sc3c(c12)CCC3
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of 7-thia-9-azatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-ol (280 mg, 1.46 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added phosphoroyl trichloride (1.12 g, 7.30 mmol, 5.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 2 h at 90° C. in an oil bath and concentrated under reduced pressure. The pH value of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate and extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to afford 12-chloro-7-thia-9-azatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraene (0.25 g, 81%) as a white solid. MS (ES): m/z 210 and 212 (M+H)+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[NH2:19][C:20]1[CH:31]=[CH:30][C:23]2[N:24]([CH3:29])[C:25](=[O:28])[CH2:26][O:27][C:22]=2[CH:21]=1>>[CH3:29][N:24]1[C:23]2[CH:30]=[CH:31][C:20]([NH:19][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:21][C:22]=2[O:27][CH2:26][C:25]1=[O:28]
Reactant: CN1C(=O)COc2cc(N)ccc21
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Product: CN1C(=O)COc2cc(Nc3ncc4ccc(-c5cccnc5)n4n3)ccc21

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using 2-methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine and 7-amino-4-methyl-4H-benzo[1,4]oxazin-3-one to give 4-methyl-7-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-4H-benzo[1,4]oxazin-3-one as a yellow lyophilate (29.4, 13.3% yield). LCMS (E/I+) 373 (M+H). 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.70 (s, 1H), 8.60 (d, 1H, J=3.8 Hz), 8.37 (d, 1H, J=7.7 Hz), 7.52 (s, 1H), 7.39 (dd, 1H, J=4.6, 7.5 Hz), 7.01 (m, 2H), 6.96 (d, 1H, J=8.4 Hz), 6.79 (s, 1H), 4.5 (s, 2H), 3.2 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8](=[O:21])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=O)[CH:7]=1.S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:22][C:10]([C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)=[CH:9][C:8]2=[O:21]
Reactant: O=C(CC(=O)c1cc(Br)ccc1O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc([N+](=O)[O-])cc2)oc2ccc(Br)cc12

Procedure:
A mixed solution consisting of compound 3 (2.00 g, 5.49 mmol), concentrated sulfuric acid (0.5 ml), and acetic acid (40 ml) was heated to reflux for 1 hour. The temperature of the resultant was returned to room temperature, and ice pieces were then added to the reaction solution. The precipitated crystal was collected by filtration, so as to obtain a product of interest, 6-bromo-4′-nitroflavone (compound 4). Yield: 1.79 g (yield constant: 94.2%) MS m/z 347 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:15])=[CH:10][C:11]=3[C:12](=[S:14])[NH:13][C:4]=2[CH:3]=1.[CH3:18]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>CC(OC)(C)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:15])=[CH:10][C:11]=3[C:12]([S:14][CH3:18])=[N:13][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc2c(s1)Nc1ccc(Cl)cc1NC2=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: COC(C)(C)C
Product: CSC1=Nc2cc(Cl)ccc2Nc2sc(C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
Stir 7-chloro-2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (59.1 g, 0.210 mol) and DMF (236.4 mL) under nitrogen for 15 minutes at ambient temperature. Add powdered potassium carbonate (61.1 g, 0.442 mol); stir 15 minutes at ambient temperature. Add iodomethane (26.2 mL, 0.421 mol) and stir 2.5 hours at ambient temperature. Add MTBE (591 mL) and stir 15 minutes at ambient temperature. Filter and rinse solids with MTBE (59.1 mL). Wash the organic filtrate with water (3×591 mL), then dry over sodium sulfate, filter and concentrate under reduced pressure to give 60.0 g (96.7%) of crude product. 1H NMR (500 MHz, DMSO-d6) δ 2.22 (s, 3H), 2.39 (s, 3H), 6.47 (d, 1H), 6.57 (d, 1H), 6.86 (d, 1H), 6.97(dd, 1H), 8.09 (bs, 1H). 13C NMR (100 MHz, DMSO-d6) δ 13.24, 14.70, 120.58, 120.62, 121.67, 125.64, 127.51, 127.52, 127.77, 141.65, 142.16, 153.99, 165.48.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([OH:30])([CH2:23][CH2:24][CH2:25][C:26]([CH:28]=[CH2:29])=[CH2:27])[CH3:22].C/C(/C=C)=C/CCC(O)(C)C.CC(C)=CC(O)/C=C(/C=C)\C>>[CH3:27][C:26]1([CH:28]=[CH2:29])[CH2:25][CH2:24][CH2:23][C:21]([CH3:20])([CH3:22])[O:30]1
Reactant: C=CC(=C)CCCC(C)(C)O
Agent: C=C/C(C)=C/C(O)C=C(C)C
Agent: C=C/C(C)=C\CCC(C)(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC1(C)CCCC(C)(C)O1
Yield: 13.1 %

Procedure:
Example 13 was repeated except that 0.210 g triphenylphosphine was used and 22.6 g N,N-diethyl-7-hydroxynerylamine. After 171/2 hours at 120° C. there was obtained a yield of 13.1% 2,6,6-trimethyl-2-vinyltetrahydropyran, 28.6% myrcenol, 16.1% cis-ocimenol, 21.9% trans-ocimenol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12]([C:18]([OH:20])=O)=[CH:11]2.[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].O.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.C1COCC1.CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12]([C:18]([NH:21][C:22]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:11]2
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: Cn1c(C(=O)O)cc2cc(Br)ccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cc2cc(Br)ccc2n1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.8 %

Procedure:
A catalytic amount of DMF and 560 mg (4.41 mmol) of oxalyl chloride were added to a THF (8 mL) solution comprising 800 mg (3.15 mmol) of 5-bromo-1-methyl-1H-indole-2-carboxylic acid at 0° C., and the mixture was stirred at room temperature for 40 minutes. After the solvent was distilled off under reduced pressure, 8 mL of DMAc and 585 mg (3.15 mmol) of methyl 2-amino-5-chlorobenzoate were added to the residue in this order at 0° C., and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, saturated sodium bicarbonate water was added under ice-cooling, and the mixture was stirred. The resulting solids were collected by filtration, washed with water, and dried under reduced pressure at 50° C. for 3 hours, thereby giving 1.22 g of methyl 2-{[(5-bromo-1-methyl-1H-indol-2-yl)carbonyl]amino}-5-chlorobenzoate (yield: 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6](=[O:28])[C@@H:7]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][CH2:9][C:10]([O:12]CC1C=CC=CC=1)=[O:11]>[C].[Pd].C(O)C>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:28])[C@@H:7]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CN(C)CCOC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCOC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.6 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-(2-dimethylamino-ethyl)ester (370 mg, 0.70 mmol; 77% purity) described in Manufacturing Example 3-1 and ethanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred overnight at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-(2-dimethylamino-ethyl)ester (300 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 0.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-(2-dimethylamino-ethyl)ester (crude, 190 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (160 mg, 0.42 mmol) in this order at 0° C., which was stirred overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=30:1), so as to obtain the titled compound (56 mg, purity of 75%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:15]2[C:11](=[CH:12][O:13][N:14]=2)[CH:10]=[CH:9][CH:8]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:14]1[O:13][CH:12]=[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:6])[C:15]=12
Reactant: COc1cccc2conc12
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cccc2conc12
Temperature: -78 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
18.5 ml of a 1M solution of boron tribromide in dichloromethane are added to a solution of 1.38 g (9.25 mM) of 7-methoxy-2,1-benzisoxazole in 50 ml of dichloromethane cooled to −78° C., and the mixture is then stirred at ambient temperature overnight. The reaction medium is poured into water and the mixture is brought to pH=7-8 by adding a solution of sodium carbonate, and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The crude product obtained is purified by silica gel chromatography, elution being carried out with a methylcyclohexane/ethyl acetate mixture (gradient of 100/0 to 50/50; v/v). The expected product is obtained in the form of a yellow solid with a yield of 10%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2.CO.[ClH:18]>O1CCOCC1.O=[Pt]=O.O>[ClH:18].[F:15][C:2]([F:1])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
2-(trifluoromethyl)-1H-indole-5-carbonitrile (Intermediate 3A, 25 g), PtO2.H2O (3%, 750 mg) and MeOH (175 mL) were added to a hydrogenation flask. 4M HCl in dioxane (89 mL) was added and the reaction vessel is purged with N2 and then H2. The mixture was hydrogenated at 60 psi of H2 and 17-23° C. for 24 hrs. The mixture was filtered through celite and then through a 0.2 μm PTFE filter. MP-TMT resin (15 wt %) was then added and the slurry was stirred for 3 hrs at 40° C., cooled to 17-23° C., and then filtered through a pad of celite. The celite pad and resin were washed with MeOH (100 mL). The solution was concentrated to a minimum by vacuum distillation and n-propanol (200 mL) was added and concentrated to a minimum. Toluene (200 mL) was added and then cyclohexane (75 mL) and the slurry was allowed to stir for 2 hrs at 17-23° C. The mixture was then cooled to 0-5° C. and allowed to stir for 2 hrs. The solid was filtered and washed with toluene to give the title compound (25.3 g);
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]=1.[Cl:7][C:8]([Cl:13])([Cl:12])[C:9](Cl)=[O:10].C([O-])([O-])=O.[K+].[K+]>C(OCC)C>[Cl:7][C:8]([Cl:13])([Cl:12])[C:9]([C:4]1[NH:3][C:2]([CH3:1])=[CH:6][CH:5]=1)=[O:10]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1ccc(C(=O)C(Cl)(Cl)Cl)[nH]1
Reaction time: 1 h

Procedure:
2-Methyl-1H-pyrrole (Intermediate 31, 10 g, 0.123 mmol) in anhydrous diethyl ether (30 ml) was added dropwise over 1 h to a stirred solution of trichloroacetyl chloride (29 g, 0.16 mmol) in anhydrous Et2O (100 ml). The mixture was stirred for a further 1 h then K2CO3 (10 g/30 ml) was added slowly through a dropping funnel. The organic phase was dried over Na2SO4 and treated with decolorizing charcoal (3 g) for 30 min at room temperature. The resulting purple solution was concentrated and triturated with n-hexanes to give the title compound as a purple solid. (16.72 g). NMR (CDCl3): 2.36 (s, 3H), 6.04 (dd, 1H), 7.45 (dd, 1H), 10.344 (s, 1H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[O:29][CH3:30].[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](O)(=[O:40])=[O:39]>>[CH3:30][O:29][C:23]1[CH:24]=[C:25]([CH3:28])[C:26]([S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH3:31])(=[O:40])=[O:39])=[CH:27][C:22]=1[O:21][CH3:20]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: COc1ccc(C)cc1OC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cc(C)c(S(=O)(=O)c2ccccc2C)cc1OC
Temperature: 0 °C

Procedure:
50 g of phosphorus pentoxide are covered, by pouring, with 400 ml of methanesulphonic acid and the whole is stirred at 60° until a clear solution has formed. 30.4 g (0.2 mol) of 1,2-dimethoxy-4-methylbenzene and 43 g (0.2 mol) of 2-methylbenzenesulphonic acid (80% strength) are then added, and the internal temperature is increased to 80° for 30 minutes. The mixture is poured onto 4 liters of ice-water and extracted with ethyl acetate. The extract solution is washed twice with water, dried over sodium sulphate, filtered and concentrated by evaporation in a rotary evaporator. The oil remaining crystallises immediately. It is triturated with diethyl ether and filtered off. In this manner colourless crystals of 1,2-dimethoxy-4-(2-methylphenylsulphonyl)-5-methylbenzene having a melting point of 126°-128° are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:37]([O:39][C:40](=[O:44])[CH2:41][CH2:42][Zn+])[CH3:38]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[C:31]([CH2:42][CH2:41][C:40]([O:39][CH2:37][CH3:38])=[O:44])[CH:32]=[CH:33][CH:34]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC[Zn+]
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(Br)c2)cc1
Agent: [Br-]
Product: CCOC(=O)CCc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1

Procedure:
The product from Example 65D and 3-ethoxy-3-oxopropylzinc bromide (purchased from Aldrich) were processed as described in Example 49 to provide the title compound. MS (ESI+) m/z 573 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])[CH3:2].C[O:11][C:12](=O)[CH2:13][C:14]1([NH2:17])[CH2:16][CH2:15]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([NH:17][C:14]1([CH2:13][CH:12]=[O:11])[CH2:16][CH2:15]1)=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)CC1(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NC1(CC=O)CC1
Yield: 40.3 %

Procedure:
Chlorocarbonyl-acetic acid ethyl ester (2.75 ml; 22.1 mmol) is added dropwise under stirring and cooling to a solution of (1-amino-cyclopropyl)-acetic acid methyl ester (Chemstep Product List, 13926) (3.00 g; 23.2 mmol) in triethylamine (6.4 ml; 46.2 mmol) and CH2Cl2 (150 ml). After stirring at room temperature for 30 minutes, the reaction mixture is poured on a saturated solution of NaHCO3 and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness. Purification via chromatography (SiO2; hexane/acetone 6:4) yield the title compound as crystalline light-yellow solid (1.9 g; 34%) 1H-NMR (400 MHz; DMSO-d6): 8.40 (s, 1H); 4.07 (q, 2H); 3.60 (s, 3H); 3.12 (s, 2H); 2.58 (s, 2H); 1.17 (t, 3H); 0.71 (m, 2H); 0.66 (m, 2H). MS (m/z) ES+: 244 (MH+)
Reaction SMILES: [CH3:1][C:2]1([CH:36]=[O:37])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH2:36][OH:37])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)[CH2:3]1
Reactant: CC1(C=O)CCC(c2ccc(OCc3ccccc3)cc2)=C(c2ccc(OCc3ccccc3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(CO)CCC(c2ccc(OCc3ccccc3)cc2)=C(c2ccc(OCc3ccccc3)cc2)C1
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-3,4-di(4-benzyloxy-phenyl)-cyclohex-3-ene carbaldehyde (200 mg, 0.409 mmol) in MeOH (10.0 mL) at −10° C. was added NaBH4 (100 mg, excess). The reaction mixture was stirred 30 min and then quenched with 51% HCl solution (5 mL), extracted with ethyl acetate (50 mL) and dried over MgSO4. The reaction mixture was then concentrated and purified on SiO2 (50% ethyl acetate/hexane) to yield (1-methyl-3,4-di(4-benzyloxy-phenyl)-cyclohex-3-enyl)-methanol.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]#[N:20])=[CH:10]1>>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([NH2:20])=[O:2])=[CH:10]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC(=O)Cc1c[nH]c2ccccc12

Procedure:
The suspension of the bacterial cells (corresponding t 25 to 5.92 mg of the dry cells) obtained in Example 8 was added to 4 ml of the reaction solution containing 10 mM of a potassium phosphate buffer (pH 8.0) and 4 M of 3-indoleacetonitrile, and the reaction was conducted at 25° C. After 24 hours from the initiation of the reaction, 4 M (697 g/lit.) of 3-indoleacetamide was produced with a 100% conversion.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[NH2:41]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([NH:41][C:40]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:38]([O:37][CH3:36])[CH:39]=3)[C:27]=2[S:26][CH:25]=1)=[O:23]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2ncnc3c(C(=O)Nc4cc(C(=O)Nc5cccc(C(F)(F)F)c5)ccc4C)csc23)cc(OC)c1OC

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 3,4,5-trimethoxyaniline to obtain the title compound (see Table 1).