Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[NH2:21][C:22]1[C:23]2[C:30]([C:31]#[C:32][C:33]3[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=3)=[CH:29][N:28]([C@@H:43]3[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:45]([C:55]([NH:57][NH:58][C:59](=O)[CH2:60][N:61]([CH3:63])[CH3:62])=[O:56])[CH2:44]3)[C:24]=2[N:25]=[CH:26][N:27]=1.C(OCC)(=O)C>C(#N)C.O>[NH2:21][C:22]1[C:23]2[C:30]([C:31]#[C:32][C:33]3[CH:34]=[C:35]([O:41][CH3:42])[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=3)=[CH:29][N:28]([C@@H:43]3[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[C@H:45]([C:55]4[O:56][C:59]([CH2:60][N:61]([CH3:63])[CH3:62])=[N:58][N:57]=4)[CH2:44]3)[C:24]=2[N:25]=[CH:26][N:27]=1
Reactant: COc1cc(C#Cc2cn([C@H]3C[C@@H](C(=O)NNC(=O)CN(C)C)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#Cc2cn([C@H]3C[C@@H](c4nnc(CN(C)C)o4)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
DIPEA (105 μl) and tosyl chloride (56 mg) were added to a solution of (2S,4S)-tert-butyl 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(2-(2-(dimethylamino)acetyl)hydrazine carbonyl)pyrrolidine-1-carboxylate (100 mg) obtained in Step 1 in acetonitrile (3 ml), and the mixture was stirred at 40° C. for 1 hour. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a light-yellow, amorphous substance (40.5 mg). Physical properties: m/z [M+H]+ 589.2
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 96.5 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)pregna-5,7,16-triene (79.0 mg, 0.0991 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a colorless oil (43.5 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[CH2:17][N:13]2[CH2:14][CH2:15][CH2:16][C@H:12]2[CH3:11])=[O:8])=[CH:9][CH:10]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(Br)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure PP using commercially available 4-bromo benzoic acid, 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine, and thionyl chloride in place of oxalyl chloride. (MS (ES+) 352.3 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[N:6][C:7]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:15])=[N:6][C:7]=1[C:10]1[O:11][CH:12]=[CH:13][N:14]=1
Reactant: Nc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ncco2)c(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.8 %

Procedure:
To a stirred solution of 3-nitro-6-(1,3-oxazol-2-yl)pyridin-2-amine (0.127 g, 0.62 mmol) in dimethylformamide (3 mL) at 0° C. was added N-bromosuccinimide (0.115 g, 0.65 mmol) and the mixture was warmed to room temperature. After 3 days, further N-bromosuccinimide (0.058 g, 0.33 mmol) was added and stirring was continued for 3 hours. The solution was poured into water and the precipitate was filtered, washed with water and dried to give the title compound (0.18 g, 70%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:5]2=[O:22]>[Pd].CO>[NH2:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:14])[N:6]([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)[C:5]2=[O:22]
Reactant: Cc1c(N)c([N+](=O)[O-])cc2c1C(=O)N(C1CCN(C)CC1)C2=O
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)c(N)cc2c1C(=O)N(C1CCN(C)CC1)C2=O
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a suspension of 5-Amino-4-methyl-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (1.7 g, 5.34 mmol) and 10% Pd/C (250 mg) was added MeOH (100 mL) carefully and evacuated in vacuo. The flask was filled with hydrogen under balloon pressure and stirred for 1 h. The reaction mixture was filtered and evaporated in vacuo to afford the crude 5,6-diamino-4-methyl-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione (1.5 g, quant.), which was used as such for further reaction.
Reaction SMILES: [N:1]([C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[Cl:12])=[N+:2]=[N-:3].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.C[O-].[Na+]>C(O)C>[Cl:12][C:5]1[CH:6]=[C:7]([Cl:11])[CH:8]=[C:9]([I:10])[C:4]=1[N:1]1[C:22]([NH2:23])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:3]=[N:2]1
Reactant: COc1ccc(CC#N)cc1
Reactant: [N-]=[N+]=Nc1c(Cl)cc(Cl)cc1I
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3c(Cl)cc(Cl)cc3I)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
To a stirred and ice-cooled solution of 2-azido-1,5-dichloro-3-iodo-benzene (0.500 g, 1.5928 mmol) and 4-methoxyphenylacetonitrile (0.29 g, 1.9114 mmol) in absolute ethanol (6 ml), an ice-cooled solution of sodium methoxide (0.129 g, 2.3892 mmol) in absolute ethanol (4 ml) is added drop-wise and the mixture is allowed to reach room temperature spontaneously overnight. The resulting reaction mixture is evaporated and the gummy residue (0.740 g, 100% mass balance) is purified by column chromatography over silica gel (60-120 mesh) eluting with 0-15% ethyl acetate in hexane, to obtain the title compound as a brown solid (0.072 g, 10% yield). M.p. 72.5-73.6° C. LC-ESI-HRMS of [M+H]+ shows 460.9425 Da. Calc. 460.943317 Da, dev. −1.8 ppm.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[C:3]1([CH3:42])[CH3:41].C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(#N)C.C(OCC)(=O)C>[CH3:50][S:51]([O:1][CH:2]1[C:3]([CH3:42])([CH3:41])[C:4](=[O:40])[N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[CH2:34][C:35]([F:36])([F:38])[F:37])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[CH2:6]1)(=[O:53])=[O:52]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(O)C(C)(C)C2=O)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(OS(C)(=O)=O)C(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (4-(4-((3-(4-hydroxy-3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (40 mg) was dissolved in acetonitrile (2.0 mL), triethylamine (14 μL) and methanesulfonyl chloride (5.7 μL) were added thereto, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, and the mixture was washed three times with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:9]=1
Reactant: O=C(NCCCl)Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1NCCN1c1cccnc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a mixture of 150 g of N-(2-chloroethyl)-N'-(3-pyridyl) urea dissolved in 500 ml of tetrhydrofuran and 500 ml of dimethylformamide, 31.6 g of sodium hydride (60% oily suspension) was added under ice-cooling over 20 minutes. After stirring under ice-cooling for 10 minutes and at room temperature for 2 hours, 10 ml of acetic acid was added and the solvent was distilled off. Saturated saline water and chloroform were added to thr residue and insolubles were separated by filtration. The chloroform layer was washed with sodium hydrogen carbonate solution, dried and the solvent was distilled off. The residue was recrystallized from a mixture of chloroform and hexane to give 108.5 g of 1-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][C@H:20]([CH2:24][O:25][CH3:26])[CH2:19]2)[CH2:10][C@H:9]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([OH:35])[CH:29]=1)=[O:7]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[F:42][C:39]([F:40])([F:41])[C:37]1[CH:36]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:38]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][N:18]2[CH2:23][CH2:22][O:21][C@H:20]([CH2:24][O:25][CH3:26])[CH2:19]2)[CH2:10][C@H:9]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([OH:35])[CH:29]=1)=[O:7]
Reactant: COC[C@@H]1CN(CC#CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(O)c3)C2)CCO1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: COC[C@@H]1CN(C/C=C\CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(O)c3)C2)CCO1
Yield: 66.5 %

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[4-[(2S)-2-(methoxymethyl)-morpholino]-2-butynyl]piperazine (0.33 g) in methanol (10 ml) was hydrogenated over Lindlar catalyst (63 mg). After removal of catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methanol/dichloromethane (1:9) as an eluent. The fractions containing the objective compound were collected and evaporated in vacuo to give (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[(Z)-4-[(2S)-2-(methoxymethyl)morpholino]-2-butenyl]piperazine (0.22 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[N:6]=[C:5]([CH3:7])[CH2:4][S:3]1.[N:9]([O-])=[O:10].[Na+].C(O)(=O)C>O>[N:9](=[C:4]1[S:3][C:2]([CH3:8])([CH3:1])[N:6]=[C:5]1[CH3:7])[OH:10]
Reactant: CC1=NC(C)(C)SC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1=NC(C)(C)SC1=NO
Temperature: 45 °C

Procedure:
30.0 g (0.232 mol) of 2,2,4-trimethyl-3-thiazoline and 17.6 g (0.255 mol) of sodium nitrite are dissolved in 75 ml of water and 26.6 ml (0.464 mol) of acetic acid are added dropwise, with stirring at 45° C. The internal temperature of the reaction mixture is allowed to rise slowly to 10°-15° C., and the mixture is then stirred at this temperature for an additional 2 hours. The product precipitates as ochre-brown crystals and is filtered, washed with water and dried in vacuo. A single recrystallization from chloroform/n-hexane yields 5-oxo-2,2,4-trimethyl-3-thiazoline oxime, m.p. 159°-161° C.
Reaction SMILES: CC(C(CCC1C=CC=CC=1)CC(OCC)=O)C.C(O[C:22](=O)[CH:23]([CH:27]([CH:36]([CH3:38])[CH3:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]([O-:26])=[O:25])C>>[CH3:38][CH:36]([CH:27]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28]1)[CH3:37]
Reactant: CCOC(=O)C(C(=O)[O-])C(CCc1ccccc1)C(C)C
Agent: CCOC(=O)CC(CCc1ccccc1)C(C)C
Product: CC(C)C1CCc2ccccc2C=C1C(=O)O

Procedure:
7-(2-Propyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid was synthesized by the same process as in Reference Example 7, (d), the same process as in Reference Example 1, (b) and (c), and then the same process as in Reference Example 22, (b), except for using monoethyl[3-phenyl-1-(2-propyl)propyl]propanedioate.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C>C(O)C.[OH-].[Na+]>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:24])=[O:3])=[CH:17][CH:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
A solution of 7.7 g of α-[p-(1-cyclohexenyl)-phenoxy]-n-heptanoic acid ethyl ester in 100 ml of ethanol and 70 ml of 2N sodium hydroxide solution is left to stand overnight at room temperature. The bulk of the solvent is then removed in vacuo, the pH adjusted to 3 by adding concentrated by hydrochloric acid, and the residue extracted with ether. The ether phase is washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is crystallised from petroleum ether to yield the α-[p-(1-cyclo-hexenyl)-phenoxy] -n-heptanoic acid of the formula ##STR4## which melts at 78-80° C.
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][C@H:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([I:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[C:14]([CH3:17])([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+]>CO>[I:26][C:21]1[C:22]([O:24][CH3:25])=[CH:23][C:18]([C@@H:13]([OH:12])[C:14]([CH3:17])([CH3:16])[CH3:15])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=1
Reactant: COc1cc([C@@H](OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc([C@@H](O)C(C)(C)C)c([N+](=O)[O-])cc1I
Yield: 98.6 %

Procedure:
A mixture of (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (1.1 g, 2.0 mmol) and K2CO3 (552 mg, 4.0 mmol) in methanol (50 mL) was heated to reflux for one hour, then cooled down, concentrated in vacuo, and diluted with CH2Cl2 (50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield enantiopure (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (720 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H, Ph-H), 7.17 (s, 1H, Ph-H), 5.60 (d, 1H, J=4.0 Hz, PhCH), 3.98 (s, 3H, OCH3), 2.12 (d, 1H, J=4.0 Hz, OH), 0.89 (s, 9H,C(CH3)3).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH3:17][NH:18][CH3:19]>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:18]([CH3:19])[CH3:17])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(N(C)C)C2

Procedure:
Starting from 2.03 g (0.01 mol) of 5-acetylamino-2-tetralone and 2.45 g (0.03 mol) of dimethylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 1.35 g (50.2% of theory) and with a melting point of 199° C. which does not change after recrystallisation from methanol/ether.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([O:10][CH3:11])[CH:4]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]>>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3([C:40]4[C:31](=[CH:32][C:33]5[O:38][CH2:37][CH2:36][O:35][C:34]=5[CH:39]=4)[O:30][CH2:29]3)[C:21]2=[O:41])=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: COc1cc(CCl)ccc1F
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: COc1cc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)ccc1F

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-1-fluoro-2-methoxybenzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(4-fluoro-3-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: mp 161-163° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 7.23-7.15 (m, 2H), 7.05-7.00 (m, 2H), 6.94-6.77 (m, 3H), 6.49 (s, 1H), 6.18 (s, 1H), 5.09-5.04 (m, 1H), 4.97-4.91 (m, 1H), 4.71-4.61 (m, 2H), 4.19-4.08 (m, 4H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.2, 153.6, 150.4, 148.1, 144.7, 141.9, 138.3, 132.2, 128.8, 124.0, 123.6, 121.0, 119.8, 116.1, 112.4, 111.3, 109.2, 99.5, 79.9, 64.5, 63.9, 58.0, 56.2, 43.8; MS (ES+) m/z 433.8 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.O[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:27]=[C:18]1[C:19]2[C:20](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:22])[N:17]1[O:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](O)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
An ice-cold mixture of tert-butyl (cis-3-hydroxycyclopentyl)methylcarbamate 114 (0.19 g, 0.88 mmol), N-hydroxyphthalimide (0.29 g, 1.78 mmol), and triphenylphosphine (0.46 g, 1.75 mmoL) in tetrahydrofuran (10 mL) was treated with diisopropylazodicarboxylate (0.40 g, 1.98 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo to a yellow foam which was purified by chromatography to give 115 (0.19 g, containing DIAD byproduct) as a yellow oil. The mixture was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][OH:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][O:17][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 88.8 %

Procedure:
A solution 58.0 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester, 45.0 g of (1,1-dimethylethyl)dimethylsilylchloride, 69 ml of triethylamine, 1.50 g of 4-(dimethylamino)pyridine and 50 ml of methylene chloride is stirred at room temperature for 18 hours. The resulting solution is washed with water, 2N hydrochloric acid, saturated sodium bicarbonate and sodium chloride. The organic layer is dried and concentrated in vacuo. The residue, dissolved in methylene chloride, is filtered through a silica gel pad and concentrated in vacuo to give 76.5 g of the desired product as a colorless oil.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)[CH2:16][CH3:17].Cl>[Zn].C(OCC)(=O)C>[F:8][C:2]([F:9])([CH:22]([OH:23])[C:21]1[CH:24]=[CH:25][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCCc1ccc(C=O)cc1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1ccc(C(O)C(F)(F)C(=O)OCC)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 4.4 g of well-dried zinc, 10.3 g of ethyl bromodifluoroacetate (e-14) and 25 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 5.0 g of 4-propylbenzaldehyde (e-23) and 50 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 200 ml of 1 N HCl aqueous solution and 200 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of heptane and ethyl acetate (heptane:ethyl acetate=20:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 9.0 g of ethyl 2,2-difluoro-3-hydroxy-3-(4-propylphenyl)propanoate (e-24) was obtained. A yield based on compound (e-23) was 97.8%.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([C:15]1[C:20]([CH3:21])=[C:19]([S:22][CH2:23][CH3:24])[CH:18]=[CH:17][N:16]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[N:6]([CH2:12][C:13]([C:15]2[C:20]([CH3:21])=[C:19]([S:22][CH2:23][CH3:24])[CH:18]=[CH:17][N:16]=2)=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCSc1ccnc(C(=O)CBr)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCSc1ccnc(C(=O)Cn2c(Cl)nc3ccccc32)c1C

Procedure:
2-Chlorobenzimidazole is reacted with 2-bromoacetyl-4-ethylthio-3-methylpyridine in the presence of K2CO3 to give 2-chloro-1-[2-[4-ethylthio-3-methylpyridyl)-2-oxoethyl]benzimidazole. This is reacted with thiourea and treated with NH4OH to give 2-mercapto-1-(2-(2-(4-ethylthio-3-methylpyridyl))-2-oxoethyl)benzimidazole