Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.[OH-].[Na+].S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[C:22]1([S:28]([N:13]2[C:14]3[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[CH:12]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc2[nH]cc(CCNC(=O)OC(C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CCNC(=O)OC(C)(C)C)cn2S(=O)(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a stirred two-phase mixture of a solution of the above 3-[2-(tert-butyloxycarbonylamino)ethyl]-5-methoxy-1H-indole in dichloromethane (200 ml) and 50% aqueous sodium hydroxide (50 ml) was added tetrabutylammonium hydrogen sulphate (611 mg, 1.8 mmol) and the mixture was stirred for 10 minutes. Benzenesulphonyl chloride (3.52 ml, 27.6 mmol) was added dropwise uia syringe and the mixture was vigorously stirred for 30 minutes. The mixture was diluted with diethyl ether (500 ml), washed with water (100 ml), brine (2×70 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane-diethyl ether, 90:10) followed by trituration with hexane-diethyl ether (10;1; 100 ml) afforded 1-(benzenesulphonyl)-3-[2-(tert-butyloxycarbonylamino)ethyl]-5-methoxy-1H-indole (7.55 g, 95%) as a white solid; δH (360 MHz, CDCl3) 7.88 (1H, d, J=8.8 Hz), 7.84-7.80 (2H, m), 7.54-7.48 (1H, m), 7.45-7.38 (2H, m), 7.32 (1H, s), 6.96-6.90 (2H, m), 4.55 (1H, br s), 3.82 (3H, s), 3.44-3.36 (2H, m), 2.82 (2H, t, J=6.8 Hz), 1.45 (9H, s).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[C:29]([O:33][C:34]([N:36]([CH2:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[CH2:37][CH3:38])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:45][CH:46]=1)[CH2:37][CH3:38])=[O:35])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(CC)C(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-tert.butoxycarbonyl-N-ethyl-aminomethyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C32H35N3O5
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:23])=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of (2-Amino-phenyl)-phenyl-methanone (5 g, 25 mmol) in DCM (100 mL) is cooled to −10° C., then NBS (4.512 g, 25 mmol) is added in 30 minutes. After the addition the mixture is stirred at −10° C. for 2 h. The mixture is diluted with DCM, washed with salt NaHCO3 (2×100 mL), salt NaCl (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give product (6.3 g), which is used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[CH2:20]([OH:23])[C:21]#[CH:22]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]1([C@@H:12]2[CH2:11][O:10][C:9]([C:3]3[C:2]([F:1])=[C:7]([C:22]#[C:21][CH2:20][OH:23])[CH:6]=[CH:5][CH:4]=3)=[N:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CCO
Reactant: Fc1c(I)cccc1C1=N[C@H](c2ccccc2)CO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1F
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 4,5-dihydro-2-(2-fluoro-3-iodophenyl)-4(R)-phenyloxazole (2.28 g, 6.2 mmol), propargyl alcohol (0.22 g, 12.4 mmol) and bis(triphenylphosphine)-palladium(II) chloride (220 mg, 1.1 mmol) in triethylamine (50 ml), was stirred for 1 h under a nitrogen atmosphere, Cul (420 mg, 2.2 mmol) added and the reaction mixture stirred for a further 16 hours. Insoluble material was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (=1:14) to afford of 3-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)-2-fluorophenyl]-2-propyn-1-ol (1.41 g, 77%) as off-white solids.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:16])=[C:13]([CH3:15])[S:14][C:8]2=[N:7][C:6]=1[CH3:17].Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C[O-].[Na+]>O.CC(C)CC(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:3][CH2:4][C:5]3[C:10](=[O:11])[N:9]4[C:12]([CH3:16])=[C:13]([CH3:15])[S:14][C:8]4=[N:7][C:6]=3[CH3:17])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1nc2sc(C)c(C)n2c(=O)c1CCBr
Agent: Br
Agent: C[O-]
Agent: Cl
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2sc(C)c(C)n2c(=O)c1CCN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A mixture of 5.85 parts of 6-(2-bromoethyl)-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 4 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10 parts of sodium carbonate, 3 parts of a sodium methoxide solution 30% and 240 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water-separator. The reaction mixture was filtered hot over Hyflo and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane (3:1 by volume) yielding 1 part of 6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 159.0° C. (compound 24).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11](Cl)=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C(O[C:23](=[O:38])[CH2:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:10][C:9]=1[NH:18][C:23](=[O:38])[CH2:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C#Cc1ccccc1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J2) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) according to the general procedure M. Obtained as an orange solid (148 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>CN(C=O)C>[CH:3]1([S:9][C:11]2[N:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: SC1CCCCC1
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)nc1SC1CCCCC1
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
1.3 equivalents of NaH (4.9 g, 0.124 mol) were dissolved in 50 mL DMF under a nitrogen atmosphere. After the addition of 1.2 equivalents of cyclohexanethiol (14.2 mL, 0.116 mol), stirring was performed at room temperature for 1.5 h. The resultant suspension was cooled to 10° C. and 1 equivalent of 2-chloro-6-(trifluoromethyl)nicotinonitrile (20 g, 0.096 mol) in 50 mL DMF was added dropwise and stirred for 2 h at room temperature. The reaction mixture was quenched with sat. aq. NH4Cl soln., diluted with 1 l of water and extracted repeatedly with EA (3×200 mL). The combined organic phases were washed with a sat. aq. NaCl soln., dried over MgSO4 and evaporated under a vacuum. Purification performed by column chromatography (silica gel, 100-200 mesh, eluent: 2% EA in hexane) resulted in 26 g (93.8%) of product.
Reaction SMILES: [CH3:1][N:2]([CH:31]([CH3:33])[CH3:32])[C:3]1[C:4]([C:16]2[CH:20]=[CH:19][N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O-:15])=[O:14])=[CH:8][CH:7]=2.[CH3:34]CCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][N:2]([CH:31]([CH3:33])[CH3:32])[C:3]1[C:4]([C:16]2[CH:20]=[CH:19][NH:18][CH:17]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:34])=[O:14])=[CH:8][CH:7]=2
Reactant: CC(C)N(C)c1nc2cc(C(=O)[O-])ccc2nc1-c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3cc[nH]c3)c(N(C)C(C)C)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a solution of 3-[methyl(propan-2-yl)amino]-2-[1-[tris(propan-2-yl)silyl]-1H-pyrrol-3-yl]quinoxaline-6-carboxylate (130 mg, 0.27 mmol) in THF (10 mL) was added TBAF (71 mg, 0.27 mmol) with stirring for 10 min at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (30 mL), and extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solids were collected via filtration. The resulting mixture was concentrated under vacuum to give methyl 3-[methyl(propan-2-yl)amino]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylate (70 mg, 80%) as yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)=[O:23]>>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:18][CH:17]=3)[CH2:12][CH2:13][CH2:14]2)=[O:23])=[CH:26][CH:27]=1
Reactant: CCN(CC)CCCCOc1ccc2c(c1)CCCN2
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Product: CCN(CC)CCCCOc1ccc2c(c1)CCCN2C(=O)Oc1ccc(Br)cc1

Procedure:
In analogy to example 3.9, Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine and 4-bromophenyl chloroformate were converted to yield 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-bromo-phenyl ester as colorless oil, MS: 475 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:18]([C:14]3[O:13][CH:17]=[CH:16][CH:15]=3)=[O:19])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)c3ccco3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole and furan-2-carboxylic acid chloride in pyridine the title compound was obtained as a tan solid (100% yield), MS: m/e=274.1 (M+).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:19]([O-:21])=[O:20])=[C:12]([CH:15]=[C:16](F)[CH:17]=3)[C:13]#[N:14])[CH:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:19]([O-:21])=[O:20])=[C:12]([CH:15]=[C:16]([NH:31][C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH3:30])[CH:17]=3)[C:13]#[N:14])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(F)cc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(C#N)c([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Temperature: 230 °C
Yield: 88.7 %

Procedure:
A mixture of 3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-nitrobenzonitrile (Method 98, 3.50 g, 12.2 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (1.87 g, 13.4 mmol), and DIEA (2.6 ml, 14.6 mmol) in n-BuOH (20 ml) was heated in a sealed tube at 230° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:2) to give the title compound as a yellow solid (4.4 g, 89%). 1H NMR (400 MHz) 12.38 (s, 1H), 10.12 (b, 1H), 8.07 (d, J=6.4 Hz, 1H), 7.34 (m, 2H), 7.16 (m, 2H), 6.89 (b, 1H), 6.77 (s, 1H), 5.63 (m, 1H), 4.55 (m, 1H), 1.90 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.97 (m, 2H), 0.70 (m 2H). MS: Calcd.: 406; Found: [M+H]+ 407.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([NH2:32])[S:31][C:27]=2[CH:26]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:32][C:30]2[S:31][C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:34]=[CH:33][C:28]=3[N:29]=2)=[O:19])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCc3ccccc32)c1
Reactant: COc1ccc2nc(N)sc2c1
Product: COc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCCc5ccccc54)c3)sc2c1

Procedure:
3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (18) (100 mg, 0.32 mmol) was treated with 6-methoxybenzo[d]thiazol-2-amine (47 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide as an off-white solid. Yield: 32 mg (25%). 1H-NMR: 8.48 (s, 1H), 8.40-8.35 (m, 1H), 7.77-7.59 (m, 5H), 7.24-7.18 (m, 1H) 7.11-7.05 (m, 3H), 3.87-3.81 (m, 2H), 2.44 (t, J=6.5 Hz, 2H), 1.68-1.59 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:10])[CH2:6][CH2:5][CH:4]([C:7](O)=[O:8])[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[O:1]=[S:2]1(=[O:10])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3]1
Reactant: O=C(O)C1CCS(=O)(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCC(CO)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
To a solution of 1,1-dioxo-tetrahydro-1lambda*6*-thiophene-3-carboxylic acid (5.0 g) in THF (100 mL) was added LAH (35 mL of 1M THF solution) drop-wise. The mixture was stirred at room temperature for five hours and then cooled in an ice bath. Water (3 mL) and NaOH (6 mL of 15% aqueous solution) were added, and the mixture was stirred a room temperature for 60 hours. The mixture was filtered and the filtrated was concentrated under reduced pressure to give 3.59 g of (1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-yl)-methanol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.Cl.[NH:9]1[CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[N:9]1([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=Cc1ncc[nH]1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1c[nH]c(CN2CCC2)n1
Yield: 61.4 %

Procedure:
To a mixture of 2-imidazolecarboxaldehyde (3.0 g) and azetidine hydrochloride (3.21 g) in anhydrous tetrahydrofuran (180 ml) was added sodium triacetoxyborohydride (9.99 g) followed by glacial acetic acid (1.72 ml). The resultant mixture was stirred at room temperature for 22 h, after which the insoluble material was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue purified using silica SPE (eluting with DCM, methanol, methanol:20% aqueous ammonia) to give the title compound (2.63 g) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10](I)([CH3:12])[CH3:11].C(N(CC)CC)C>CO>[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:12])[CH3:11]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)I
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)C)cc1

Procedure:
A solution of 5 g (40.6 mmol) p-anisidin, 4.1 ml (40.6 mmol) isopropyl iodide and 5.7 ml (40.6 mmol) triethylamine in 40 ml methanol is refluxed for 18 h. The reaction mixture is extracted with diethyl ether/water and the organic layers are evaporated. The crude product is purified by flash chromatography using dichloromethane/MeOH (98:2) as eluent to yield isopropyl-(4-methoxy-phenyl)-amine.
Reaction SMILES: [Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(C2OC=CN=2)C=C(C(N2CCC[C@@H]2COC)=O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[Si]([O:67][C@H:68]([C@H:98]1[CH2:102][C@@H:101]([O:103][CH2:104][CH2:105][CH3:106])[CH2:100][N:99]1C(OC(C)(C)C)=O)[C@@H:69]([NH:79][C:80](=[O:97])[C:81]1[CH:86]=[C:85]([N:87]2[CH2:91][CH2:90][CH2:89][C:88]2=[O:92])[CH:84]=[C:83]([O:93][CH:94]([CH3:96])[CH3:95])[CH:82]=1)[CH2:70][C:71]1[CH:76]=[C:75]([F:77])[CH:74]=[C:73]([F:78])[CH:72]=1)(C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(N2CCCC2=O)C=C(O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].IC(C)C>CN(C=O)C.C(OCC)(=O)C>[F:78][C:73]1[CH:72]=[C:71]([CH2:70][C@H:69]([NH:79][C:80](=[O:97])[C:81]2[CH:86]=[C:85]([N:87]3[CH2:91][CH2:90][CH2:89][C:88]3=[O:92])[CH:84]=[C:83]([O:93][CH:94]([CH3:96])[CH3:95])[CH:82]=2)[C@H:68]([OH:67])[C@H:98]2[CH2:102][C@@H:101]([O:103][CH2:104][CH2:105][CH3:106])[CH2:100][NH:99]2)[CH:76]=[C:75]([F:77])[CH:74]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(OC(C)C)cc(N3CCCC3=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(O)cc(N3CCCC3=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)I
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(OC(C)C)cc(N3CCCC3=O)c2)C1

Procedure:
Step 14 (A): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-isopropoxy-5-(2-oxopyrrolidin-1-yl)benzamido) propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate (Preparation I, 38 mg, 0.05 mmol) in DMF (1 mL) were added cesium carbonate (29 mg, 0.09 mmol) and 2-iodopropane (42 mg, 0.25 mmol) and the reaction mixture was microwaved at 60° C. for 2 h. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 30% to 40% EtOAc/Hexane step gradient) to give 21 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ ppm 0.01 (3H, s), 0.07 (3H, s), 0.86 (9H, s), 0.88 (3H, m), 1.32 (6H, d, J=5 Hz), 1.46-1.54 (11H, m), 2.03-2.21 (4H, m), 2.59 (2H, m), 2.62 (1H, dd, J=10, 15 Hz), 2.94 (1H, m), 3.26-3.36 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.84-3.91 (2H, m), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.11-4.13 (1H, m), 4.55 (1H, m), 4.63 (1H, m), 6.59 (1H, m), 6.78 (2H, d, J=5 Hz), 7.20 (1H, s), 7.33 (1H, s), 7.71 (1H, s), 7.99 (1H, d, J=10 Hz). MS (ESI) (M+H)+ 775.45.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH:10]12[CH2:11][CH:12]([CH:8]=[CH:9]1)[CH:2]1[C:1]([O:6][C:4](=[O:5])[CH:3]21)=[O:7]
Reactant: C1=CCC=C1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(C3)C12

Procedure:
A solution of bicyclo[2. 2. 1]hept-5-ene-2,3-dicarboxylic anhydride in toluene is prepared by reacting 1960 grams (20 moles) of maleic anhydride dissolved in 3000 grams of toluene with 1320 grams (20 moles) of cyclopentadiene at a reaction temperature in the range of from about 70° to 75°C.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2[OH:13])=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl.COC(C)(C)C>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2CCCCC2O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: Cc1ccc(C2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.00 g (15.8 mmol) rac-2-p-tolyl-cyclohexanol in 60 ml dichloromethane were added drop-wise 51.84 g (18.3 mmol) of a 15% solution of Dess-Martin periodinane [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] in dichloromethane, and then drop-wise a solution of 300 μl water in 300 ml dichloromethane within 30 min. The resulting solution was stirred for further 30 min. at ambient temperature. Then the reaction mixture was diluted with 350 ml tert.-butyl methyl ether and evaporated to a quarter of the initial volume. The residue was diluted with 800 ml tert.-butyl methyl ether, washed with a total of 600 ml of a 1:1 mixture of saturated NaHCO3 solution and a 10% Na2S2O3 solution and with brine. The combined aqueous extracts were re-extracted with tert.-butyl methyl ether. The combined organic extracts were washed with brine, died over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography on silica gel with dichloromethane as eluent: 2.39 g rac-2-p-tolyl-cydohexanone as colorless powder: MS (ISP): 189.3 MH+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Cl:14])/[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Cl:14])/[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
(1R,cis,Z) 2,2-dimethyl-3-[2-chloro-3-oxo-3-(1,1-dimethyl-ethoxy)-1-propenyl]-cyclopropane-carboxylic acid prepared as in Step B of Example 34 of European Pat. No. 0050534 and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[2-chloro-3-oxo-3-(1,1-dimethylethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+15.5°±1° (c=1% in chloroform).