Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:28]1(I)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC(C)=O>CN(C)C=O>[CH:28]1([N:16]2[CH:17]=[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)=[N:15]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)c1c[nH]nc1-c1ccc(Oc2ccccc2)cc1
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cn(C2CCCC2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
To tert-Butyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (15.6 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride, 60% in mineral oil (20.8 μg, 0.52 mmol). After the gas evolution ceased (about 5 minutes), cyclopentyl iodide (59 μL, 0.51 mmol) was added dropwise and the mixture was stirred for 16 hours at room temperature. EtOAc was added and the crude mixture was washed with a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc (3 times). The combined organic extracts were washed with water and brine. The organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with petroleum ether/DCM) to afford the title compound as a white solid (0.131 g, 69% yield). MS (ES+) m/e=405. 1H NMR (CDCl3) δH 1.51 (9H, s), 1.70-1.80 (2H, m), 1.85-2.00 (2H, m), 2.02-2.13 (2H, m), 2.18-2.30 (2H, m), 4.71 (1H, quint.), 7.06 (4H, d), 7.12 (1H, t), 7.35 (2H, t), 7.76 (2H, d), 7.95 (1H, s).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)[S:9][CH:10]=1.C(O)(=O)C.O1CCCC1>O>[CH:2]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)[S:9][CH:10]=1)=[O:1]
Reactant: CC(=O)Nc1nc(C=Cc2cc(C3OCCO3)cs2)cs1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc(C=Cc2cc(C=O)cs2)cs1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 92.8 %

Procedure:
To N-(4-{2-[4-(1,3-dioxolan-2-yl)thiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (1.418 g, 4.398 mmol) were added acetic acid (16.8 ml), tetrahydrofuran (5.6 ml) and water (5.6 ml), and the mixture was stirred at 55° C. for 2.5 hr. The reaction mixture was concentrated, and diisopropyl ether was added. The precipitated solid was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give N-{4-[2-(4-formylthiophen-2-yl)vinyl]-1,3-thiazol-2-yl}acetamide (1.136 g, 4.081 mmol, yield 92.8%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]([C:10]1[C:11]([CH3:18])=[C:12]([CH:16]=[O:17])[NH:13][C:14]=1[CH3:15])=[O:9]>C1COCC1>[CH3:18][C:11]1[C:10]([C:8](=[O:9])[CH2:7][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:14]([CH3:15])[NH:13][C:12]=1[CH:16]=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)CCl
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Diethylamine (5 ml) was added to a solution of 4-(2-Chloroacetyl)-3,5-dimethylpyrrole-2-carboxaldehyde (1 g, 5 mmol) in THF (20 ml). The mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure and the residue was treated with water, NaHCO3 (5%) and extracted with dichloromethane. After drying and filtering, the solvent was removed and the residue was used without further purification.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:22][C:21]([CH2:24][OH:25])([OH:23])[CH2:20]3)=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1>CN(C)C=O>[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:20][C:21]([CH2:24][OH:25])([OH:23])[CH2:22]3)=[N:17][C:18]=2[I:1])[CH:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: OCC1(O)CC(c2ncc3c(Cl)nccn23)C1
Solvent: CN(C)C=O
Product: OCC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 60 °C

Procedure:
Under inert atmosphere N-iodosuccinimide (3.6 g, 0.016 mol) and 3-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethyl-cyclobutanol (3.16 g, 0.012 mol) were dissolved in N,N-dimethylformamide (30 mL) and heated at 60° C. for 3.0 hours. The reaction mixture was then concentrated in vacuo to a dark oil and purified by HPFC Jones 20 g silica gel column, eluting with 5% MeOH: CH2Cl2 to yield a light brown fluffy solid which was triturated with diethyl ether and hexanes to afford the title compound; MS (ES+): m/z 379.85 (100) [MH+], 381.80 (30) [MH+++]; HPLC: tR=2.30 min (OpenLynx, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:7])([O-:3])=[O:2].C([Al](CC(C)C)CC(C)C)C(C)C.C[O:26][C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:11][C:10]1[CH:9]=[CH:8][C:6]([NH:7][C:27](=[O:26])[C:28]2[CH:29]=[CH:30][C:31]([CH2:34][N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:32][CH:33]=2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To a solution of 10.95 g (72 mmol) of 3-nitro-4-methyl-aniline in 80 ml of toluene is added a solution of triisobutylaluminium (28% in hexane), 66.5 ml (61 mmol) over a period of 30 min at 0° C. followed by the addition of a solution of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (14.9 g, 60 mmol) in toluene (30 ml) during 1 hour at 0° C. under an atmosphere of argon. After stirring for 12 h at room temperature an other portion of triisobutylaluminium (66.5 ml (61 mmol) is added to the dark brown reaction mixture. The mixture is stirred for additional 6 h, then 2 additional small portions of triisobutylaluminium (each 18 ml, 18 mmol) are added and stirring is continued for several hours at room temperature. After acidic and basic workup with sulfuric acid and NaOH the combined organic toluene phases are evaporated in vacuo to give a brown crude product which was crystallized from t-butyl methyl ether to give the title compound as brownish yellow crystals: first crop (11.65 g), sec. crop (3.8 g) and a third crop (1.2 g). in summary 16.65 g (75.3%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]=[C:4]1OC)[CH3:2].[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[NH:12])[CH3:2]
Reactant: [Cl-]
Reactant: CCC1CCCN=C1OC
Reactant: [NH4+]
Solvent: CO
Product: CCC1CCCNC1=N
Product: Cl

Procedure:
The product of EXAMPLE 154 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30]C(OC(C)(C)C)=O)[C:10](=[O:29])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]3[CH:27]=[CH:26][NH:25][C:24]3=[O:28])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[C:39]([N:46]1[CH2:49][CH:48]([C:50]([OH:52])=O)[CH2:47]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30][C:50]([CH:48]2[CH2:47][N:46]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:49]2)=[O:52])[C:10](=[O:29])[N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]3[CH:27]=[CH:26][NH:25][C:24]3=[O:28])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2-n2cc[nH]c2=O)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3-n3cc[nH]c3=O)CC2)C1
Yield: 76 %

Procedure:
The title compound was prepared according to the procedure described in Example 10 (Step b) using N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]-piperidyl)ethyl) (tert-butoxy)carboxamide (Example 18 Step b) (0.227 g, 0.433 mmol) and satd HCl in EtOAc (20 mL), followed by Boc-azetidine-3-carboxylic acid (PepTech Corporation) (0.105 g, 0.52 mmol), EDC (Advanced ChemTech) (0.125 g, 0.65 mmol), HOBT (Novabiochem) (0.058 g, 0.433 mmol) and TEA (Aldrich) (0.058 mL, 0.433 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (100% EtOAc then 1:9 MeOH:EtOAc) provided the title compound as a white foam (0.2 g). MS (ESL pos. ion) m/z: 608 (M+1). Calc'd for C32H38ClN5O5: 607.26.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[B:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[Li:22]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[B-:6]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1.[Li+:22]
Reactant: [Li]c1ccco1
Reactant: c1coc(B(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: [Li+]
Product: c1coc([B-](c2ccco2)(c2ccco2)c2ccco2)c1

Procedure:
The trifurylboron is further dissolved in dry tetrahydrofuran (30 ml), one equivalent of 2-furyllithium is added dropwise to the mixture of 0° C. under nitrogen. The precipitate formed is filtered and dried to obtain pure lithium tetra(2-furyl)borate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([OH:7])=[O:6].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:29](O)[CH3:30]>>[CH2:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:19])(=[O:20])[NH2:18])[C:10]=1[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:5]([O:7][CH2:29][CH3:30])=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1N1CCOCC1
Reactant: CCO
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1cc(NCc2ccccc2)c(N2CCOCC2)c(S(N)(=O)=O)c1
Reaction time: 24 h

Procedure:
A mixture of 3-amino-4-morpholino-5-sulphamyl-benzoic acid (3 g), benzyl bromide (4 g), and anhydrous ethanol (45 ml) was refluxed. After 24 hours and again after 48 hours a solution of benzyl bromide (1.5 g) in anhydrous ethanol (5 ml) was added during 4 hours. After the second addition, the refluxing was continued for 24 hours. The reaction mixture was cooled, and the precipitated ethyl 3-benzylamino-4-morpholino-5-sulphamyl-benzoate was collected by suction and recrystallized from ethanol, after which the compound was obtained with a melting point of 185-186°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:9][CH2:8]1.[O:18]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21](=[O:22])[C:20]([C:29](O)=[O:30])=[C:19]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C1C=CC=CN=1)C.CS(Cl)(=O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:29]([C:20]2[C:21](=[O:22])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:18][C:19]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])[CH2:11][CH2:12]1
Reactant: O=C(O)c1c(-c2ccccc2)oc2ccccc2c1=O
Reactant: NCCCCN1CCN(c2ccccn2)CC1
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(NCCCCN1CCN(c2ccccn2)CC1)c1c(-c2ccccc2)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
3.6 g of the 4-[4-(2-pyridyl)-piperazin-1-yl]butylamine obtained above were added to a reaction mixture cooled to -2020 C. which contained, in 100 ml of absolute dichloromethane, a mixed anhydride produced in a manner analogous to Example 1 (a) from 4.0 g flavone-3-carboxylic acid, 3.367 g dimethylaminopyridine and 1.28 ml methanesulfonyl chloride. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for two hours. Subsequently the reaction mixture was worked up analogously to Example 3, and the resulting title compound was recrystallized from ethylacetate. There were obtained 4.7 g 3-{4-[4-(2-pyridyl)-piperazin-1-yl]-butylaminocarbonyl}flavone.
Reaction SMILES: [I-].C([Si:7]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35]C=2)[CH2:12][CH2:11][CH:10]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][CH2:8]1)CCCC.[CH:39]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([O:53][Si](C(C)(C)C)(C)C)=[C:49]([F:61])[CH:48]=2)=[CH:43][CH:42]=1)=O.Br[CH2:63][C:64]([F:67])([F:66])[F:65]>>[CH2:33]([Si@H:7]1[CH2:8][CH2:9][C@H:10]([CH2:13][CH2:39][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:63][C:64]([F:67])([F:66])[F:65])=[C:49]([F:61])[CH:48]=3)=[CH:45][CH:46]=2)[CH2:11][CH2:12]1)[CH2:38][CH2:37][CH2:36][CH3:35]
Reactant: FC(F)(F)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)cc2)cc1F
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [I-]
Product: CCCCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(OCC(F)(F)F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 56 was repeated using (4-pentyl-4-phenyl-4-silacyclohexyl)methyltriphenylphosphonium iodide, 4'-formyl-3-fluoro-4-(t-butyldimethylsiloxy)biphenyl and 1-bromo-2, 2,2-trifluoroethane, thereby obtaining the intended compound.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].F[C:11](F)(F)[C:12]1([C:15]2[CH:16]=[C:17]([NH2:27])[N:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=C[CH:21]=3)[N:19]=2)[CH2:14][CH2:13]1.[N:30]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.ClCCl>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:27][C:17]1[N:18]([C:20]2[CH:21]=[N:30][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:19]=[C:15]([C:12]2([CH3:11])[CH2:13][CH2:14]2)[CH:16]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Add a solution of 2,2,2-trichloroethylchloroformate (1.80 g, 8.5 mmol) in THF (10 mL) dropwise to an ice-salt cooled solution of 5-(1-trifluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (2.29 g, 8.1 mmol) and pyridine (0.9 mL, 11 mmol) in THF (30 mL) at −15° C. Stir at −15° C. for 0.5 hours and then 22° C. for 1 hour, then distribute the reaction mixture between dichloromethane (50 mL) and a saturated aq. sodium bicarbonate solution (50 mL). Isolate the aqueous phase and extract twice with dichloromethane (25 mL each). Dry the combined organic phases over sodium sulfate and concentrate. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to give a white solid (2.46 g, 66% yield). MS(ES+): m/z=457.2 [M+H].
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+].[CH2:18]([S:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24](N)[CH:23]=1)[CH:19]=[CH2:20]>O.CO.C(O)(=O)C>[CH2:18]([S:21][C:22]1[CH:27]=[CH:26][C:25]2[NH:28][C:8]([NH:9][C:12](=[O:13])[O:14][CH3:15])=[N:10][C:24]=2[CH:23]=1)[CH:19]=[CH2:20]
Reactant: C=CCSc1ccc(N)c(N)c1
Reactant: CSC(=N)N
Reactant: COC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C=CCSc1ccc2[nH]c(NC(=O)OC)nc2c1
Reaction time: 0.17 h

Procedure:
To a mixture of 5.7 g of 2-methyl-2-thiopseudourea sulfate in 3.4 ml of water there is added at 0° 3.6 ml of methyl chloroformate. The mixture is stirred for 10 minutes at this temperature. Then, there is added dropwise 7.6 ml of 25% NaOH. The temperature is kept below 25° and the mixture is stirred for 10 minutes. Then, 3.8 ml of acetic acid is added and again the temperature is kept below 25°. After a stirring period of 10 minutes, there is added the total of 4-(2-propenylthio)-o-phenylenediamine from Example 1B dissolved in 10 ml of methanol and the mixture is refluxed for one hour. The resulting solid is filtered off, washed with water and dried to yield 4 g. Crystallization from acetonitrile furnishes the analytically pure title compound, m.p. 197°-198°.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)[O:17][C:10]=23)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([C:24]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[O:25])=[CH:20][CH:19]=5)[O:17][C:10]=34)[C:2]=2[CH3:1])=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1c(N)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12

Procedure:
The compound was synthesized according to the procedure M using 2-methyl-3-{2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furo[3,2-b]pyridin-7-yl}aniline (50 mg, 0.13 mmol) and 4-tert-butylbenzoyl chloride (27.21 mg, 0.14 mmol). The title compound was obtained as white solid (6.00 mg, 9%). HPLC (method F): 100%, RT=4.714 min. MS: m/z=558 [M+H]+, RT=4.85 min.
Reaction SMILES: [BH4-].[Na+].[C:3]([C@:5]12[CH2:29][C:28](=[O:30])[CH2:27][CH2:26][C@:25]1([CH3:31])[C:24]1[CH2:23][CH2:22][C@@:21]3([CH3:32])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:8]=1[CH2:7][CH2:6]2)#[N:4].Cl>C(O)C>[C:3]([C@:5]12[CH2:29][C@@H:28]([OH:30])[CH2:27][CH2:26][C@:25]1([CH3:31])[C:24]1[CH2:23][CH2:22][C@@:21]3([CH3:32])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:8]=1[CH2:7][CH2:6]2)#[N:4].[C:3]([C@:5]12[CH2:29][C@H:28]([OH:30])[CH2:27][CH2:26][C@:25]1([CH3:31])[C:24]1[CH2:23][CH2:22][C@@:21]3([CH3:32])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:8]=1[CH2:7][CH2:6]2)#[N:4]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@]1(C#N)CC3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@@H](O)C[C@]1(C#N)CC3
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@]1(C#N)CC3
Reaction time: 4 h

Procedure:
327 mg sodium borohydride are added to a solution of 1.76 g 5-cyano-5α-cholest-8-en-3-one in 200 ml ethanol at room temperature. The reaction mixture is stirred for 4 hours. After addition of hydrochloric acid (1 N) the resulting mixture is extracted with dichloromethane. The organic layer is separated, dried over anhydrous sodium sulphate and filtered. After evaporation of the solvent the residue is chromatographed with a mixture of hexane and ethyl acetate to give 0.36 mg 5-cyano-5α-cholest-8-en-3β-ol and 1.00 g 5-cyano-5α-cholest-8-en-3α-ol as white solids.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2N[CH2:14][CH2:13][CH2:12]3)[CH2:3]1.N1CC(OC2C=CC=C3C=2N(C(C2C=CC=CC=2)C2C=CC=CC=2)CC=C3)C1>>[ClH:1].[CH2:12]1[C:11]2[C:16](=[C:7]([O:6][CH:4]3[CH2:5][NH:2][CH2:3]3)[CH:8]=[CH:9][CH:10]=2)[CH2:14][CH2:13]1
Reactant: c1cc2c(c(OC3CNC3)c1)NCCC2
Agent: C1=Cc2cccc(OC3CNC3)c2N(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Product: c1cc2c(c(OC3CNC3)c1)CCC2

Procedure:
8-(3-Azetidinyloxy)-1,2,3,4-tetrahydroquinoline hydrochloride, mp >250° C. starting from 8-(3-Azetidinyloxy)-1-(diphenylmethyl)-quinoline.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([NH:20][CH3:21])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:20]([C:19]2[CH:22]=[CH:23][C:16]([O:15][C:14]([F:13])([F:24])[F:25])=[CH:17][CH:18]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CN(c1ccc(OC(F)(F)F)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-trifluoromethoxy-N-methylaniline (20 μL, 0.302 mmol) by a procedure similar to example 1b and was isolated as white powder (22 mg, 44%). 1H NMR (CDCl3): 7.93 (dd, J=8.4, and 0.6 Hz, 1H), 7.61 (ddd, J=8.4, 4.5 and 1.2 Hz, 1H), 7.29-7.22 (m, 4H), 7.06 (ddd, J=8.4, 4.5 and 1.2 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 3.65 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[H][H]>CO.[Pt](=O)=O>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2ccccc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: Cc1nccc2c1CCCC2
Yield: 100.2 %

Procedure:
A solution of 1-methylisoquinoline (1.0 g) in methanol (30 ml) was saturated with gaseous hydrogen chloride at room temperature. The mixture was treated with platinum(IV) oxide (0.2 g). The mixture was vigorous stirred under hydrogen atmosphere at room temperature until hydrogen absorption was stopped. The reaction mixture was filtered off to remove the catalyst. The filtrate was concentrated in vacuo and the residue was taken up with water. The mixture was alkalized with sodium carbonate and the resultant precipitate was extracted with isopropyl ether. The extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-methyl-5,6,7,8-tetrahydroisoquinoline (1.03 g) as a brown oil. 1H NMR (CDCl3, δ): 1.6-2.0 (4H, m), 2.42 (3H, s), 2.5-2.9 (4H, m), 6.82 (1H, m), 8.16 (1H, m)
Reaction SMILES: N[C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[ClH:19].C(O)(=O)C.N([O-])=O.[Na+]>O.C(Cl)(Cl)Cl>[Cl:19][C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccc(F)cc1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(Cl)nc1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of 10.5 g (0.05 mole) of ethyl p-fluorobenzoylacetate, 6.7 g (0.05 mole) of sulfuryl chloride and 30 ml. of chloroform was held at reflux for 18 hours and cooled. The chloroform solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 10.8 g (88%) of ethyl 2-chloro-(p-fluoro)-benzoylacetate as an oil. A mixture of 10.8 g (0.0441 mole) of ethyl 2-chloro-(p-fluoro)benzoylacetate, 3.36 g (0.0441 mole) of thiourea, 20 ml. of water and 10 ml. of ethanol was held at reflux for 3 hours. Ethanol was removed under reduced pressure. The residue was made basic with saturated sodium bicarbonate. The solid was filtered, washed with water and recrystallized from ethanol to give 8.9 g (76%) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate as white prisms, m.p. 205°-208° C. To 4.0 g (0.015 mole) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate was added 30 ml. of concentrated hydrochloric acid and 30 ml. of glacial acetic acid. The carboxylate did not dissolve completely. To this mixture was added 30 ml. of chloroform. The carboxylate dissolved gradually into the chloroform solution. the reaction mixture was cooled to 0°-5° C. with an ice bath. To the above mixture was added with vigorous stirring 4.0 g (0.058 mole) of sodium nitrite. The reaction mixture was stirred at 5°-10° C. for 30 minutes and poured into a solution of 1.48 g (0.0150 mole) of cuprous chloride in 20 ml. of concentrated hydrochloric acid. After the gas evolution subsided, the reaction mixture was diluted with water. The chloroform layer was separated and the aqueous layer was extracted with chloroform. The combined chloroform solution was washed with water followed by saturated sodium bicarbonate, dried (MgSO4) and concentrated under reduced pressure. The residual solid was recrystallized from ethanol to give 3.3 g (77%) of ethyl 2-chloro-4-(p-fluorophenyl)-5-thiazolecarboxylate as orange needles, m.p. 113°-114° C.