Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[O:38][CH2:37][CH2:36][N:35]1[C:33](=[O:34])[C:5]1[C:6]([OH:32])=[C:7]3[C:13]4[C:14]([C:16]5[C:27](=[O:28])[C:26]6[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([OH:29])[CH:25]=6)[O:20][C:17]=5[C:18](=[O:19])[C:12]=4[CH:11]=[CH:10][C:8]3=[CH:9][C:4]=1[CH2:3]2)=[O:15].[CH:39]12CC(C=C1)C1C(OC(=O)C21)=O.NC1C=CC=CN=1.CN(C1C=CC=CN=1)C.CC1(O)C2CC3CC(CC1C3)C2>C(OCC)(=O)C.O.O1CCCC1>[CH3:1][C:2]12[O:38][CH2:37][CH2:36][N:35]1[C:33](=[O:34])[C:5]1[C:6]([OH:32])=[C:7]3[C:13]4[C:14]([C:16]5[C:27](=[O:28])[C:26]6[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([O:29][CH3:39])[CH:25]=6)[O:20][C:17]=5[C:18](=[O:19])[C:12]=4[CH:11]=[CH:10][C:8]3=[CH:9][C:4]=1[CH2:3]2)=[O:15]
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Reactant: COc1cc2oc3c(c(=O)c2cc1O)C(=O)c1c(ccc2cc4c(c(O)c12)C(=O)N1CCOC1(C)C4)C3=O
Agent: CC1(O)C2CC3CC(C2)CC1C3
Agent: CN(C)c1ccccn1
Agent: Nc1ccccn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2oc3c(c(=O)c2cc1OC)C(=O)c1c(ccc2cc4c(c(O)c12)C(=O)N1CCOC1(C)C4)C3=O
Temperature: 23 °C

Procedure:
16.42 parts of the compound (II-167-a) (5-norbornene-2,3-dicarboxylic acid anhydride, Wako Pure Chemical Industries, Ltd.) and 53.29 parts of tetrahydrofuran were charged, stirred at 23° C. to dissolved. To the obtained mixture, 2.44 parts of amino pyridine was added at 23° C., and stirred. To the obtained mixture, 2.44 parts of dimethylamino pyridine was added at 23° C., and stirred for 30 minutes at 50° C. To the obtained mixture, a mixture of 16.63 parts of 2-methyl-2-adamantanol and 53.29 parts of tetrahydrofuran was added in the form of drops over 1 hour, and stirred for 10 hours at 50° C. To the obtained mixture, 30 parts of ion-exchanged water and 60 parts of ethyl acetate were added to wash, and separated to collect an organic layer. To the obtained organic layer, 30 parts of ion-exchanged was added to wash, and separated to collect an organic layer. This washing with water operation was repeated three times. The obtained organic layer was concentrated to obtain a concentrate. The concentrate was column-fractionated under the condition below, whereby giving 25.2 parts of the compound (II-167-b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[CH2:10]1N2CN3CN(C2)CN1C3.Cl.[OH-:21].[Na+]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:8])[C:3]=1[OH:9])[CH:10]=[O:21]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Oc1c(F)cccc1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 2,6-difluorophenol (5.00 g, 38.43 mmol) and hexamethylenetetramine (HMTA) (5.93 g, 42.30 mmol) in trifluoroacetic acid (TFA) (50 ml) was heated under reflux 16 h. The reaction mixture was cooled to room temperature, poured on to HCl (150 ml 4 M) and stirred for 3 hours and brought to pH 3 via the addition of NaOH solution (5 M). The organic phase was extracted in to diethyl ether (4×100 ml), the combined ethereal extracts dried (MgSO4) and the solvent removed in vacuo. The residue were purified by column chromatography [silica gel, eluted with hexane:EtOAc, 4:1] providing white solid (6.1 g, 38 mmol, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(-c3cc[n+]([O-])cc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
A suspension of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (0.500 g, 0.0014 mol) in dimethoxyethane (15 mL) and water (30 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.631 g, 0.00155 mol), sodium carbonate (0.374 g, 0.0035 mol) and tetrakis(triphenylphosphine)palladium (0) (0.163 g, 0.00014 mol) at 80° C. for 18 hours. The solid was filtered and washed with water. The solid was slurried in ethyl acetate for 18 hours and filtered, washing with ethyl acetate. The solid was dried in vacuo to give crude 4-[4-amino-3-(3-methoxy-4-[(1-methyl-1H-2-indolyl)-carbonyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.523 g, 0.0010 mol) as a brown solid:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: C=CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 70.8 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 5.5 mg (0.0458 mMol) allyl chloroformate, 9.7 mg (71%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH:26]([OH:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH:26]([OH:28])[CH3:27])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Product: CC(O)CNC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 43 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using (rac)-1-amino-2-propanol instead of ethanolamine, to the title compound (100 mg, 43%) which was obtained as a colourless gum. MS: m/e=388.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10]C=2)=[C:3]1[C:14]([O:16][CH3:17])=[O:15].ClCC(=O)CC(OC)=O.C1(N=C=O)C=CC=CC=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][N:43]=2)[C:38]([CH:45]=O)=[CH:37]1.N1CCCCC1>CO>[NH:36]1[C:44]2=[N:43][CH:42]=[CH:41][CH:40]=[C:39]2[C:38]([CH:45]=[C:6]2[O:5][C:4]([N:7]3[CH2:8][CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:3]([C:14]([O:16][CH3:17])=[O:15])[C:2]2=[O:1])=[CH:37]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)C1=C(Nc2ccccc2)OCC1=O
Agent: COC(=O)CC(=O)CCl
Solvent: CO
Solvent: O=C=Nc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C1=C(N2CCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.6 %

Procedure:
To a solution of methyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in methanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration, then purified by preparative HPLC, collected former fraction to afford the titled compound as solid (0.0075 g, y. 11%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:25]([F:28])([F:27])[F:26])=[C:9]([CH:24]=1)[O:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.[OH-].[Na+]>[NH:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][O:10][C:9]1[CH:24]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2)c1
Reaction time: 0.83 h

Procedure:
To a solution of (R)-2-(5-acetylamino-2-trifluoromethyl-phenoxymethyl)-1-(tert-butoxycarbonyl)pyrrolidine (1.34 g, 3.33 mol) in 10 mL CH2Cl2 at RT was added 5 mL TFA. The reaction was stirred for 50 min, neutralized with saturated aqueous NaHCO3, and diluted with CH2Cl2 and 2N NaOH. The layers were separated, and the organic layer was brine-washed. The aqueous layers were back-extracted 4 times with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)=[C:6]([CH3:16])[CH:5]=[N:4]1)[CH3:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:64]/[C:65](/[C:69](/[C:72]([F:75])([F:74])[F:73])=[CH:70]\[CH3:71])=[CH:66]/[CH:67]=C)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>>[O:63]=[C:54]1[C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:61](=[O:62])[N:53]1[CH2:52][C@@H:51]([NH:50][C:13]([C:10]1[S:11][CH:12]=[C:8]([C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[CH3:16])[CH:9]=1)=[O:15])[CH2:64][C:65]1[CH:66]=[CH:67][CH:71]=[CH:70][C:69]=1[C:72]([F:74])([F:75])[F:73]
Reactant: C=C/C=C(C[C@H](N)CN1C(=O)c2ccccc2C1=O)\C(=C/C)C(F)(F)F
Reactant: CCn1ncc(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a mixture of 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (240 mg, 1.02 mmol) and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (Pybrop) (568 mg, 1.22 mmol) was added DIPEA (1.77 ml, 10.16 mmol). After 10 min, 2-{(2S,4Z)-2-amino-4-[(1E)-1-(trifluoromethyl)-1-propen-1-yl]-4,6-heptadien-1-yl}-1H-isoindole-1,3(2H)-dione (425 mg, 1.22 mmol) was added. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (365 mg, 63%) as a white solid: LC-MS (ES) m/z 567 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([OH:20])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C[CH2:24][CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]2[CH2:17][O:19][C:23]([CH3:24])([CH3:22])[O:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Reactant: C1CCOC1
Product: CC1(C)OC[C@H](Cc2ccc(OCc3ccccc3)cc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of (S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (3.1 g, 11.38 mmol) in tetrahydrofuran (50 mL) was treated with a solution of borane tetrahydrofuran complex in tetrahydrofuran (1.0 M, 22.7 mL, 22.76 mmol) at 0° C. The mixture was allowed to slowly warm to room temperature and stirred at this temperature for 2 h. The resulting mixture was carefully quenched with 1N aqueous sodium hydroxide and treated with ethyl acetate. The layers were separated and the aqueous layer extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was immediately treated with excess acetone dimethyl ketal and a catalytic amount of p-toluene sulfonic acid. The mixture was treated with ethyl acetate and water. The aqueous layer made basic with solid potassium carbonate (pH=9), and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo which afforded (S)-4-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolane (3.1 g, 91%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[F:22]
Reactant: NCc1ccccc1F
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=c1c2cc(F)ccc2nc(CNCc2ccccc2F)n1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.20 g, 0.66 mmol), 2-fluorobenzylamine (0.038 mL, 0.33 mmol), and acetic acid (0.19 mL, 3.3 mmol) in dichloroethane (10 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.350 g, 1.65 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature and stirred 16 hours. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (30 g) with elution proceeding as follows: 30% ethyl acetate/hexane (100 mL), nil; (50 mL), unweighed impurity; (100 mL), nil; (125 mL), unweighed impurity; (150 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; (450 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-2-[(2-fluoro-benzylamino)-methyl]-3H-quinazolin-4-one as a pale pink solid which had: mp 140° C.; 1H NMR δ 7.89 (dd, J=3, 8 Hz, 1H), 7.76 (dd, J=4, 9 Hz, 1H), 7.58 (dd, J=2, 8 Hz, 1H), 7.53-7.41 (m, 4H), 7.35-7.30 (m, 2H), 7.07 (t, J=8 Hz, 1H), 6.99 (t, J=10 Hz, 1H), 3.89 (ABq, Δv1-3=21 Hz, J=13 Hz, 2H), 3.46 (ABq, Δv1-3=31 Hz, J=17 Hz, 2H); APCI MS m/z=412 (P+1).
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1.[CH2:29]([OH:32])[CH2:30][OH:31].[OH-].[K+].O>ClCCl>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[OH:31][CH2:30][CH2:29][O:32][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Reactant: OCCO
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCOc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Temperature: 120 °C
Yield: 91.6 %

Procedure:
A round bottom flask was charged with 0.2 g (0.438 mmol) of 9-(4-fluoro-phenyl)-thianthrenium hexafluorophosphate, and 5.0 g of ethylene glycol. The mixture was heated up to 120° C. and stirred until complete dissolution. 50 mg of potassium hydroxide were added to this solution; the solution was stirred for 1 hour and then poured into water. Dichloromethane was added and the organic layer separated, washed with water and dried (Na2SO4). After drying the solvent was removed under vacuum to give a white solid (0.2 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=O.CN(C(ON1N=[N:30][C:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:39](N(CC)C(C)C)(C)[CH3:40]>CN(C=O)C>[ClH:1].[N:29]12[CH2:28][CH2:27][CH:26]([CH2:39][CH2:40]1)[C@@H:25]([NH:30][C:12]([C:3]1[S:4][C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[C:2]=1[Cl:1])=[O:14])[CH2:24]2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1sc2cc(F)ccc2c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1sc2cc(F)ccc2c1Cl

Procedure:
191.1 mg (0.83 mmol) of 3-chloro-6-fluoro-1-benzothiophene-2-carboxylic acid, 150.0 mg (0.75 mmol) of R-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamine and 3.0 ml of DMF are reacted according to the general procedure (variant B). The reaction mixture is purified by preparative HPLC. The product is dissolved in 4M HCl in dioxane, then reconcentrated and dried under high vacuum. 223.3 mg (77.4% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([NH2:13])[C:10](=[CH2:12])[CH3:11]>>[CH:1](=[N:13][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC=O
Reactant: C=C(C)CN
Product: CCCCCCC=NC=C(C)C

Procedure:
The N-heptylidene-(2-methylpropenylamine) was prepared from heptanal and methallylamine, with subsequent isomerisation of the reaction product with potassium tert.-butylate; boiling point 54° C./5 Pa; nD20 =1.4662.
Reaction SMILES: [CH2:1]([OH:21])[C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:20].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:22]1([O:19][C:12]2[CH:13]=[CH:14][C:15]3[C@@H:16]4[C@H:7]([C@H:6]5[C@@:2]([CH2:18][CH2:17]4)([CH2:1][OH:21])[C@@H:3]([OH:20])[CH2:4][CH2:5]5)[CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: OC[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC[C@]12CC[C@@H]3c4ccc(OC5CCCC5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
350 mg. of 1,3,5(10)-estratriene-3,17β,18-triol in 10 ml. of ethanol is heated for 5 hours to the boiling point under N2 with 0.5 ml. of cyclopentyl bromide and 0.5 g. of potassium carbonate. After the mixture has been worked up and purified analogously to Example 18, 3-cyclopentyloxy-1,3,5(10)-estratriene-17β,18-diol is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2cc(Cl)ccc2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CSc1nc2cc(Cl)ccc2[nH]1
Reaction time: 0.83 h

Procedure:
8.89 g of 6-chloro-2-mercaptobenzimidazole was dissolved in 150 ml of dimethylformamide, followed by the addition of 6.65 g of potassium carbonate and 6.15 g of methyl iodide under cooling with ice. The obtained mixture was stirred at that temperature for 50 minutes, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated in a vacuum to give crude 6-chloro-2-methylthiobenzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].N1C=CC=CC=1>C(Cl)Cl>[CH3:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH:17][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A solution of 3,4-dimethoxybenzoyl chloride (11.5 g) in methylene chloride (100 ml) was added dropwise to a stirred mixture of 2-methyl-5-nitroaniline (8.74 g), pyridine (18.6 ml) and methylene chloride (200 ml) and the mixture was stirred at ambient temperature for 18 hours. The mixture was washed with 2M hydrochloric acid and with water, dried over magnesium sulphate, filtered and evaporated to dryness. The resultant solid was dried under vacuum at 60° C. to yield N-(2-methyl-5-nitrophenyl)-3,4-dimethoxybenzamide (15.9 g); m.p.>300° C.; NMR: (CDCl3) 2.43 (s, 3H), 3.94 (m, 6H), 6.93 (m, 1H), 7.38 (m, 2H), 7.51 (m, 1H), 7.75 (broad s, 1H), 7.94 (d, 1H), 8.89 (broad m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][NH:13][CH2:12]2)[O:8][N:7]=1.C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=3)[CH2:14][N:13]([C:36]([O:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:37])[CH2:12]2)[O:8][N:7]=1
Reactant: COCCOc1noc(C2CNCC(c3ccc(CC(F)(F)F)cc3)C2)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 32 mg (0.08 mmol) of the compound from Example 66A in dichloromethane (1.0 ml) was admixed with 0.04 ml (29 mg, 0.29 mmol) of triethylamine and then, at 0° C., 17 mg (0.08 mmol) of 4-nitrophenyl chloroformate were added. The mixture was stirred at 0° C. for 2 h, then warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 50.5 mg (79% of theory, purity 70%)
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Cl-].[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:19][C:18]=2[CH:42]=1)#[N:13].C1CCN2C(=NCCC2)CC1>O1CCCC1.C(O)C>[OH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[CH:22][C:20]2[O:21][C:17]3[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:42][C:18]=3[CH:19]=2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Reactant: O=Cc1ccc(CO)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc2oc(C=Cc3ccc(CO)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 189.6 %

Procedure:
911 mg of 4-hydroxymethylbenzaldehyde and 2.0 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride were dissolved in a solvent mixture of 10 ml of tetrahydrofuran and 10 ml of ethanol, followed by the addition of 845 mg of 1,8-diazabicyclo[5.4.0]-7-undecene and by subsequent stirring at room temperature for 1 hour. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography, thereby obtaining 2.3 g of 2-[2-(4-hydroxymethyl-phenyl)vinyl]-5-benzofurancarbonitrile as a mixture of E and Z forms. 2.3 g of the thus obtained E/Z mixture was dissolved in a solvent mixture of 10 ml of tetrahydrofuran and 10 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure for 7 hours in the presence of 800 mg of palladium oxide.1H2O.barium sulfate. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an elution solvent to obtain 835 mg of 2-[2-(4-hydroxymethylphenyl)ethyl]-5-benzofuran-carbonitrile as crystals.