Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C:12](=[CH2:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O>ClCCl>[C:18]([O:14][C:13](=[O:15])[C:12]([CH2:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[CH2:16])([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(CC(=O)OCc1ccccc1)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C=C(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
To a stirred solution of 2-(benzyloxycarbonylmethyl)propenoic acid (25.0 g, 114.0 mmole) in dichloromethane (200 ml) at -78° C. was added condensed isobutylene (50 ml) and concentrated sulphuric acid (1 ml). The mixture was allowed to warm to room temperature and kept for 72 hours. After this time the solution was washed with 10% sodium carbonate solution (3×200 ml), dried over magnesium sulphate and evaporated to give the required ester as a pale yellow oil (28.4 g, 90%). Found: C,69.60; H,7.35. C16H20O4 requires: C,69.55; H,7.30%.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]#[N:9])#[N:2].[Br:10]Br>[OH-].[Na+]>[Br:10][C:5]1[NH:4][C:3]([C:1]#[N:2])=[C:7]([C:8]#[N:9])[N:6]=1
Reactant: N#Cc1nc[nH]c1C#N
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1nc(Br)[nH]c1C#N

Procedure:
4,5-Dicyanoimidazole (23.6 g) was dissolved in sodium hydroxide solution (0.1N, 500 ml) with stirring and then bromine (36 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature overnight and the resulting solid was filtered, washed with water and dried to give 2-bromo-4,5-dicyanoimidazole m.p. 141°-144°. This compound (20 g) in dimethylformamide (100 ml) was added with stirring to a suspension of sodium hydride (80% dispersion in oil, 3.05 g) in dimethylformamide (100 ml) at room temperature. The mixture was cooled to 5° and chloromethyl 2-trimethylsilylethyl ether (18 ml) was added dropwise with stirring. This mixture was allowed to stand at room temperature overnight and was then poured into water and extracted with ethyl acetate. Evaporation of solvent gave an oil which was purified by column chromatography to give 1-(2-trimethylsilylethoxymethyl)-2-bromo-4,5-dicyano-1H-imidazole m.p.47°-52°.
Reaction SMILES: [Br:1]Br.C([O-])(O)=O.[Na+].[CH3:8][CH:9]([CH3:15])[CH:10]=[CH:11][C:12](=[O:14])[CH3:13]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:11](=[CH:10][CH:9]([CH3:15])[CH3:8])[C:12](=[O:14])[CH3:13]
Reactant: BrBr
Reactant: CC(=O)C=CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(Br)=CC(C)C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of 84 g of bromine in 75 ml of CCl4 was added dropwise to a mixture of 42 g of NaHCO3 and 56 g of 5-methyl-3-hexen-2-one in 175 ml of CCl4 at 0° C. while stirring in the course of 2 hours. The reaction mixture was stirred for a further hour at 0° C. and then filtered off and evaporated down. The residue was taken up in 150 ml of a 1:1 mixture of ethanol and water, to which 63 g of NaHCO3 had been added. The mixture was heated to reflux while stirring for 2 hours. After cooling, it was poured out into ice-water. This mixture was extracted three times with pentane. This extract was washed twice with water, dried over MgSO4, filtered off and evaporated down. The residue was distilled, 41 g of 3-bromo-5-methyl-3-hexen-2-one (E) being obtained, b.p. 62°-82° C./2 kPa.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[O:30]1[C:34]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)=[CH:33][N:32]=[CH:31]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:39][C:38]2[CH:40]=[CH:41][C:35]([C:34]3[O:30][CH:31]=[N:32][CH:33]=3)=[CH:36][CH:37]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Nc1ccc(-c2cnco2)cc1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2cnco2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(oxazol-5-yl)aniline in step 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:28]=1.C(N(CC)CC)C>CS(C)=O.O>[F:22][C:20]([F:23])([F:21])[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:9]=[C:8]([CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:4]2[CH2:5][CH2:6][N:1]([C:34]([NH:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:2][CH2:3]2)=[N:13][CH:14]=1
Reactant: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.6 %

Procedure:
To a solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(2,2,2-trifluoroethoxy)pyridine (0.14 g, 0.38 mmol) in DMSO (3 mL) was added phenyl pyridin-3-ylcarbamate (0.082 g, 0.38 mmol) followed by triethylamine (0.235 mL, 1.692 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% acetone, 70% hexane) to give the title compound (0.13 g, 70%). 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.30 (d, J=7.2 Hz, 1H), 8.22 (d, J=4.4 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.32 (m, 4H), 7.02 (d, J=7.5 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.39 (s, 1H), 4.33 (q, J=7.8 Hz, 2H), 3.65 (m, 2H), 3.55 (m, 2H), 2.60 (m, 2H), 2.47 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 158.96, 154.56, 154.45, 150.43, 143.12, 140.48, 138.89, 137.80, 136.56, 134.41, 129.49, 127.96, 125.08, 124.74, 123.80, 121.02, 118.77, 112.57, 67.33, 67.05, 45.75, 44.70, 35.74, 29.16; m/z (485.1, M+ H+); HPLC: 93.6%.
Reaction SMILES: ClCCl.[C:4]1([CH2:22][OH:23])[S:5][CH:6]=[C:7]2[C:13]=1[C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[S:10][C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=1>C(OCC)C>[C:4]1([CH:22]=[O:23])[S:5][CH:6]=[C:7]2[C:13]=1[C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[S:10][C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=1
Reactant: OCc1scc2c1-c1ccccc1Sc1ccccc1-2
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1scc2c1-c1ccccc1Sc1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a dichloromethane solution of the alcohol 15 (3.0 mmoles in 40 ml) dipyridine-chromium-(VI)-oxide (pyridinyl dichromate, PDC, 0.006 mole) was added. The reaction mixture was stirred at room temperature for 18 hours. Diethyl ether (50 ml) was added to the reaction mixture and the thus diluted reaction mixture was purified on a Florisil column to give a yellow crystal product.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20][CH2:21][CH3:22]>>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH3:22])=[C:13]([Cl:12])[C:18]=1[Cl:19])=[O:6]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCOc1cccc(Cl)c1Cl
Product: CCOc1ccc(C(=O)c2ccccc2O)c(Cl)c1Cl

Procedure:
4-(2-Hydroxybenzoyl)-2,3-dichlorophenetole was prepared by reaction of 2-methoxybenzoyl chloride and 2,3-dichlorophenetole; m.p. of crude product 112°-120° C.
Reaction SMILES: FC(F)(F)C([O:5][CH:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C:12]3=[CH:13][CH2:14][C:15]2=[O:25])[CH2:7]1)=O.[OH-].[Na+]>O1CCCC1.CO.O>[OH:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C:12]3=[CH:13][CH2:14][C:15]2=[O:25])[CH2:7]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CC(OC(=O)C(F)(F)F)CC[C@@]43C)C1=CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)C1=CCC2=O
Yield: 97.9 %

Procedure:
3-Trifluoroacetoxyandrost-5(6),14-dien-17-one (15 mg) in tetrahydrofuran (3 ml) and methanol (2 ml) was treated with 2 N aqueous sodium hydroxide (1 ml) at 0° for 3 min. The solution was diluted with water (15 ml), the organic solvents were evaporated off in vacuo, and the residue was extracted with ether to give the title compound (11 mg), which crystallized from acetone-hexane as prisms (8 mg), m.p. 161°-164°, identical [IR and t.l.c. (ethyl acetate-hexane 1:3)] with an authentic sample. Two recrystallizations raised the m.p. to 165°-168°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: Nc1nccc(Cl)n1
Solvent: C1COCCO1
Product: Nc1nccc(N2CCc3ccccc32)n1
Yield: 89.2 %

Procedure:
A suspension of 2-amino-4-chloropyrimidine (1.3 g; 10 mM) in dioxan (30 ml) was treated with indoline (2.4 g; 20 mM) and the mixture was heated for 18 hours at 95°-100° C. The precipitated product was separated from the cooled mixture by filtration and suspended in a mixture of 2-propanol (30 ml) and a solution of potassium hydroxide flake (6 g) in water (10 ml). This mixture was stirred and heated at 95°-100° C. for one hour. The hot 2-propanol solution was separated from the aqueous layer and allowed to cool. The solid product was recrystallised from 2-propanol to give 2-amino-4-(indolin-1-yl)pyrimidine as a solid (1.9 g, 89.6%), m.p. 177°-179° C.; microanalysis, found: C,62.2; H,6.2; N,23.8%; C12H12N4.H2O requires: C, 62.6; H,6.1; N,24.3%.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:26])[CH2:23][C:24]#[N:25])[CH:19]=[CH:20][CH:21]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]([OH:26])[CH2:23][C:24]#[N:25])[CH:19]=[CH:20][CH:21]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCC(O)c1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaBH(OAc)3 (7.84 g, 36.99 mmol) was added to a solution of aniline 12 (2.0 g, 12.33 mmol) and benzaldehyde (1.3 g, 12.33 mmol) in DCM. The resulting mixture was stirred at RT for 5 h and quenched with saturated aqueous NaHCO3. Organic layer was washed with water followed by brine and dried over anhydrous Na2SO4. Organic layer was concentrated under reduced pressure. Purification by flash chromatography (40% to 50% EtOAc—hexanes gradient) gave 3-(3-(benzylamino)phenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (2.61 g, 83%); 1H NMR (400 MHz, DMSO-d6) δ 7.36-7.29 (m, 4H), 7.23-7.19 (m, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.54 (d, J=7.6 Hz, 1H), 6.44 (dd, J=1.6, 8.0 Hz, 1H), 6.27 (t, J=6.0 Hz, 1H), 5.79 (d, J=4.4 Hz, 1H), 4.72-4.68 (m, 1H), 4.25 (d, J=6.0 Hz, 2H), 2.82-2.67 (m, 2H).
Reaction SMILES: [OH-].[Na+].[CH:3]([S:6][C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)([CH3:5])[CH3:4].[CH:14](Cl)([F:16])[F:15]>O1CCOCC1>[CH:3]([S:6][C:7]1[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][N:8]=1)([CH3:5])[CH3:4]
Reactant: FC(F)Cl
Reactant: CC(C)Sc1ncccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Sc1ncccc1OC(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
In the course of 15 minutes, 464 ml of 30% aqueous sodium hydroxide solution are added dropwise to a solution of 118.4 g of 2-isopropylthio-3-hydroxypyridine in 560 ml of dioxane. Then in the course of 2 hours, at a temperature of 80° C., 121 g of Freon-22 are introduced and the reaction mixture is stirred for a further 90 minutes. The reaction mixture is cooled to room temperature and then extracted with a mixture of 2500 ml of ice water and 1000 ml of methylene chloride and the phases are washed four times with 50 ml of methylene chloride each time and once with 100 ml of ice water. The combined organic phases are then dried over sodium sulfate and concentrated by evaporation in vacuo. Purification by silica gel chromatography with ethyl acetate/n-hexane 1:9 as eluant yields 105.7 g of 2-isopropylthio-3-difluoromethoxypyridine in the form of an oil having an nD21 of 1.5088.
Reaction SMILES: [N:1]([CH:4]([C@H:7]1[CH2:11][CH2:10][CH2:9][O:8]1)[CH2:5][CH3:6])=[N+]=[N-].[H][H]>CCO.CC(O)=O.[Pd]>[O:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[C@H:4]([NH2:1])[CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCC(N=[N+]=[N-])[C@H]1CCCO1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC[C@@H](N)C1CCCO1

Procedure:
A solution of (2R)-2-(1-azidopropyl)tetrahydrofuran (1.9 g, 12.24 mmol, 1 equiv) in EtOH/AcOH (105 ml of a 100:5 mixture) and 10% Pd/C CATCart (12.24 mmol, 1 equiv) was placed under a positive pressure of hydrogen for 8 hours. The product mixture was concentrated in vacuo and diluted with DCM. The mixture was passed down a 10 g SCX-2 cartridge (resin loading 0.67 mmol/g), eluting with methanol followed by 2M ammonia in EtOH. The appropriate fractions were concentrated in vacuo to afford the title compound. 1.0 (3H, t, CH3), 1.3 (1H, m), 1.6 (2H, m), 1.9 (3H, m), 2.6 (0.5H, m, CHNH2 of one diastereomer), 2.8 (0.5H, m, CHNH2 of one diastereomer), 3.6 (1H, m, CHO), 3.75 (1H, m, CHO), 3.85 (1H, m, CHO).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(OCC)(=O)C.CO>[CH3:8][C:7]1[S:6][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:4][C:3]=1[CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: Cc1sc(N2CCCCC2)nc1CCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOP(=O)(Cc1nc(N2CCCCC2)sc1C)OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 46.7 %

Procedure:
A mixture of 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperidine (2.7 g) and triethyl phosphite (1.5 g) was stirred at 160° C. for 20 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:1, v/v), then ethyl acetate-methanol (10:1, v/v) to give diethyl {[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methyl}phosphonate as a brown oil (1.4 g, yield 35%). NMR (CDCl3) δ: 1.29 (6H, t, J=7.1 Hz), 1.53-1.74 (6H, m), 2.24 (3H, d, J=4.1 Hz), 3.10 (2H, d, J=20.9 Hz), 3.28-3.46 (4H, m), 4.00-4.21 (4H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]2)[C:22]1=[O:41]>>[NH2:8][C:6]1[S:7][C:3]([CH2:2][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:33]4=[CH:34][C:35]5[O:39][CH2:38][O:37][C:36]=5[CH:40]=[C:32]4[O:31][CH2:30]3)[C:22]2=[O:41])=[C:4]([C:9]([F:12])([F:11])[F:10])[N:5]=1
Reactant: Nc1nc(C(F)(F)F)c(CCl)s1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: Nc1nc(C(F)(F)F)c(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)s1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(chloromethyl)-4-(trifluoromethyl)thiazol-2-amine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-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′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (4.0%) as a colorless solid: mp 165-167° C.; 1H NMR (300 MHz, DMSO-d6) δ7.39 (br, 2H), 7.32 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=6.7 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.69 (s, 1H), 6.12 (s, 1H), 5.91 (s, 2H), 5.02 (ABq, 2H), 4.70 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 167.9, 155.9, 148.9, 142.2, 141.8, 134.7 (q, 1JCF=135 Hz), 132.1, 129.5, 124.5, 123.9, 123.8 (m), 119.9, 109.2, 103.2, 101.9, 93.9, 80.2, 57.8, 40.9; MS (ES+) m/z 462.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(N(CC)CC)C.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[O:11][CH3:12])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 41.1 %

Procedure:
To a stirred solution of 0.406 g of 4-chloro-2-methoxybenzoyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. An additional 0.406 g of 4-chloro-2-methoxybenzoyl chloride and 0.346 g of triethylamine is added and stirring is continued for 2 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a residue which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.320 g of the desired product as a white crystals, m.p. 222°-224° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15]C(OC)=O)=[CH:10][C:9]=1[N:20]1[C:24](=[O:25])[CH:23]([CH:26]([CH3:28])[CH3:27])[O:22][C:21]1=[O:29].[Cl-].[NH4+]>CO>[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[N:20]1[C:24](=[O:25])[CH:23]([CH:26]([CH3:27])[CH3:28])[O:22][C:21]1=[O:29]
Reactant: COC(=O)Oc1cc(N2C(=O)OC(C(C)C)C2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC(C)C1OC(=O)N(c2cc(O)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Potassium carbonate (3.04 g, 22.0 mmol) was added to a solution of 3-(2'-fluoro-4'-chloro-5'-methoxycarbonyloxyphenyl)-5-isopropyl-1,3-oxazolidine-2,4-dione (15.2 mg, 44.0 mmol) in dry methanol (150 ml) and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added and the product was extracted with ether. The ether layer was dried and the solvent was then distilled under reduced pressure to give a pale yellow oily product. The product was purified by silica gel column chromatography (eluent: ethyl acetate/hexane×1/3) to give 3-(2'-fluoro-4'-chloro-5'-hydroxyphenyl)-5-isopropyl-1,3-oxazolidine-2,4-dione (10.5 g, yield 83%). The phenol derivative thus obtained (700 mg, 2.43 mmol) was dissolved in acetonitrile (30 ml). To the solution was added aryl bromide (2 ml) and potassium carbonate (340 mg) and the mixture was stirred for 3 hours under reflux. After completion of the reaction, the solvent was distilled under reduced pressure. After addition of 1N hydrochloric acid, the product was extracted with ether. The organic layer was dried and the solvent was distilled under reduced pressure to give a pale yellow oily product. The product was purified by silica gel column chromatography (eluent: ethyl acetate/hexane×1/10) to give a pure product of 3-(2'-fluoro-4'-chloro-5'aryloxyphenyl)-5-isopropyl-1,3-oxazolidine-2,4-dione [Compound 7] (540 mg, yield 68%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7].S(Cl)([Cl:13])=O>>[Br:1][CH2:2][CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([Cl:13])=[O:7]
Reactant: CC(C)(CCBr)CC(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)(CCBr)CC(=O)Cl
Yield: 89 %

Procedure:
5-Bromo-3,3-dimethylpentanoic acid (40 g, 0.192 mol) was converted into the corresponding acid chloride by heating it on a water bath with thionyl chloride (29.6 g, 1.3 equivalents). The title compound was obtained by vacuum distillation as a colourless liquid, 38.8 g (89% yield), b.p. 77° C./0.75 mm Hg. 1H NMR (CDCl3) δ3.40 (2H, t), 2.85 (2H, s), 2.00 (2H, t), and 1.10 (6H, s).
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:10][C:11](=[O:14])[NH:12][NH2:13])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([NH:12]/[N:13]=[CH:4]/[C:3]([CH3:5])=[CH2:2])=[O:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=C(C)C=O
Reactant: CC(C)(C)OC(=O)NN
Product: C=C(C)/C=N/NC(=O)OC(C)(C)C

Procedure:
B-23a is prepared analogously to B-19a starting from methacroleine (1.18 ml, 14.3 mmol) and tert-butylcarbazate (1.89 g, 14.3 mmol). Yield: 2.61 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH:13]([O:15][CH3:16])[CH2:12][CH2:11][NH:10]1.CO[CH2:19][CH:20]1CCC(C2C=CC=CC=2OC)[NH:21]1.COCC1CCC(C2C=CC=CC=2OC)N1CCN>>[NH2:21][CH2:20][CH2:19][N:10]1[CH2:11][CH2:12][CH:13]([O:15][CH3:16])[CH2:14][CH:9]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COCC1CCC(c2ccccc2OC)N1
Reactant: COc1ccccc1C1CC(OC)CCN1
Agent: COCC1CCC(c2ccccc2OC)N1CCN
Product: COc1ccccc1C1CC(OC)CCN1CCN

Procedure:
2-(2-Methoxyphenyl)4-methoxypiperidine was converted to the title compound in two steps by the same procedures as the transformation of 2-methoxymethyl-5-(2-methoxyphenyl)-tetrahydropyrrole to 2-methoxymethyl-5-(2-methoxyphenyl)-1-(2-aminoethyl)-tetrahydropyrrole as described above in Preparations 23 and 24. 1H NMR (CDCl3, 400 MHz) δ:3.80 (3H, s, OMe), 3.31 (3H, s, OMe).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(O)cc1

Procedure:
A solution of the title D compound, 2-[(4-benzyloxy-benzenesulfonyl)-(t-butoxycarbonyl)-amino]-4-chloro-benzoic acid methyl ester (2.45 g, 4.61 mmol) in 30 mL of EtOAc containing 1.2 g of 10% palladium on carbon is shaken under 50 psi of hydrogen at RT overnight. The mixture is then filtered and concentrated to give 2-[(4-hydroxybenzene-sulfonyl)-(t-butoxycarbonyl)amino]4-chloro-benzoic acid methyl ester as a white foam.