Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10](=[O:14])([O:12][CH3:13])N.ClC1C=C(NC(NC2C=CC(Cl)=C(Cl)C=2)=O)C=CC=1Cl.CO>ClC1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:14])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(N)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C(Nc1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)c(Cl)c1
Solvent: Clc1ccccc1
Solvent: CO
Product: COC(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 6 h

Procedure:
648 g of 3,4-dichloroaniline, 360 g methyl carbamate, 280 g N,N'-bis-(3,4-dichlorophenyl)-urea, 385 g methanol and 1600 g chlorobenzene were reacted in the apparatus described in Example 1 for 6.0 hours at 200° C. After the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and analyzed by high pressure liquid chromatography (HPLC). A yield of 990 g (80% of the theoretical yield) of N-(3,4-dichlorophenyl)-carbamic acid-methyl ester was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CCC1.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][N:57]([CH3:60])[C@H:56]([CH3:61])[CH2:55]2)[CH2:51]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:50]4[CH2:53][CH:52]([N:54]5[CH2:59][CH2:58][N:57]([CH3:60])[C@H:56]([CH3:61])[CH2:55]5)[CH2:51]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Reactant: C[C@@H]1CN(C2CNC2)CCN1C
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(N4CC(N5CCN(C)[C@H](C)C5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (20.0 mg, 0.0347 mmol) described in Production Example 1-1-6 and NMP (2.0 mL) was added a mixture (59.0 mg) of (2R)-4-(azetidin-3-yl)-1,2-dimethylpiperazine and benzylbenzene described in Production Example 5-3 at room temperature. The resultant mixture was irradiated with a microwave at 140° C. for 12 hours. The reaction mixture was cooled to room temperature, and then water was added thereto, the resultant solution was extracted with ethyl acetate, and an organic layer was washed with water and then with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) and then further purified by NH silica gel thin-layer chromatography (ethyl acetate) to give the title compound (10.8 mg, yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccncc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and isonicotinic acid as starting materials, MS (LC/MS): 408.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[CH2:34][CH2:35][N:31]([CH3:30])[C:32]4=[O:36])=[CH:7][C:6]=3[N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N(C)S(C)(=O)=O)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3N(C)S(C)(=O)=O)CC2)c(C)c1
Yield: 70.4 %

Procedure:
Using N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-N-methylmethanesulfonamide (130 mg) described in Preparation Example 227 and 1-methylimidazolidin-2-one (27 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (95 mg) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl.O>[CH2:24]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C=C2/C(=N/OCc3ccccc3)CCc3ccccc32)cc1
Temperature: 97.5 °C
Reaction time: 48 h
Yield: 81.9 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (25 mg, 0.076 mmol), benzyl bromide (0.022 ml, 0.18 mmol) and potassium carbonate (0.032 g, 0.23 mmol) were added into dimethylformamide (1.0 ml). Then, the solution was stirred at 95-100° C. for 48 hours, and cooled to room temperature. Again, water and dichloromethane were added, and an organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to remove organic solvent. The residue was purified through silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3, v/v). As a result, 26 mg of the present compound (productive yield 82%) was obtained as a white solid crystal.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[N:3]1.[CH3:32][S:33]([CH:36]=[CH2:37])(=[O:35])=[O:34]>C(#N)C>[CH3:1][N:2]1[C:10]2=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:24][CH2:25]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)=[N:7][C:6]([C:30]#[N:31])=[C:5]2[N:4]=[N:3]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: C=CS(C)(=O)=O
Solvent: CC#N
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(CCS(C)(=O)=O)CC4)c(C(F)(F)F)c3)cc21

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]-triazolo[4,5-c]pyridine-4-carbonitrile (50 mg) and methylsulfonylethene (0.051 ml) were combined in acetonitrile (3 ml) and the reaction mixture microwaved at 120° C. for 20 minutes. The reaction mixture was concentrated under vacuum and the resulting solid suspended in methanol and filtered off to afford the title compound (43.8 mg).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO.[OH-].[Na+]>C(O)(=O)C.O>[CH:8](=[N:6][OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: ON=Cc1ccccc1
Temperature: 10 °C
Yield: 95 %

Procedure:
943 g. (5.75 moles) of hydroxylamine sulfate are placed in a 12 liter flask with 1166 g. (11 moles) of benzaldehyde, 250 ml. of methanol and 5900 ml. of water. The mixture is stirred and chilled to 10° C. in an ice bath. Add 960 g. (12 mole) of 50% sodium hydroxide is added to the mixture gradually over a period of one hour while the temperature of the mixture is maintained below 25° C. with cooling. The mixture is stirred until the reaction is complete (approximately one hour). The mixture is neutralized to pH 7.0 with acetic acid. The lower oxime layer is separated and the aqueous layer is extracted with 2 liters of toluene. The oxime layer and toluene extract are washed twice with 1 liter of water. The toluene is stripped and 1307 g. of the oxime at 98% purity for a 95% yield is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:15][C:16]1[O:17][CH2:18][C@@:19]2([N:41]=1)[C:32]1[CH:31]=[C:30]([C:33]3[CH2:34][CH2:35][O:36][CH2:37][CH:38]=3)[CH:29]=[C:28]([F:39])[C:27]=1[O:26][C:25]1[C:20]2=[CH:21][C:22]([OH:40])=[CH:23][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:40][C:22]2[CH:21]=[C:20]3[C:25]([O:26][C:27]4[C:28]([F:39])=[CH:29][C:30]([C:33]5[CH2:34][CH2:35][O:36][CH2:37][CH:38]=5)=[CH:31][C:32]=4[C@@:19]43[CH2:18][O:17][C:16]([NH2:15])=[N:41]4)=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Cl)n1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(Oc3cccc(Cl)n3)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 100 °C
Yield: 34.1 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-6-fluoropyridine (88 mg, 0.67 mmol), cesium carbonate (0.027 mL, 0.33 mmol) and (S)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (82 mg, 0.22 mmol, prepared as described in Method BB40 and Example 2 but using 4-bromo-2-fluorophenol and 2-bromo-5-methoxybenzoic acid) in DMF (0.8 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor at 100° C. for 35 min. Then it was heated at 120° C. for 5 min. The crude material was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 35% to 65% to provide (S)-7′-(6-chloropyridin-2-yloxy)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2-amine (36 mg, 0.075 mmol, 33.7% yield) as a off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6](=[C:8]1[S:12]C(=S)N[C:9]1=[O:14])[CH3:7])([OH:3])=O.C([OH:21])C.O>>[CH3:7][C:6]1[C:5]2[C:4](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1](=[O:3])[S:12][C:8]=1[C:9]([OH:21])=[O:14]
Reactant: CCO
Reactant: CC(=C1SC(=S)NC1=O)c1ccccc1C(=O)O
Solvent: O
Product: Cc1c(C(=O)O)sc(=O)c2ccccc12

Procedure:
4-Methyl -2- thiaisocoumarin -3- carboxylic acid mp. (EtOH-H2O) 250.5°-251.5° (lit mp. 243°-5°), (Found: C, 60.40; H, 3.98; S, 14.80 C11H8SO3 requires C, 59.99; H, 3.66; S, 14.56) was prepared from 5- (o-carboxy-α-methylbenzylidene) rhodanine by an analogous procedure to that described in Example 12.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:8]2([CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][C:15]([F:21])([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].Cl.[CH3:25][C:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[F:21][C:15]1([C:18](=[O:19])[NH:30][C:26]2([CH3:25])[CH2:29][CH2:28][CH2:27]2)[CH2:16][CH2:17][N:12]([CH:10]2[CH2:11][C:8]3([CH2:22][CH2:23][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]3)[CH2:9]2)[CH2:13][CH2:14]1
Reactant: CC1(N)CCC1
Reactant: CCOC(=O)N1CCC2(CC(N3CCC(F)(C(=O)O)CC3)C2)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC2(CC(N3CCC(F)(C(=O)NC4(C)CCC4)CC3)C2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
Crude 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-4-fluoropiperidine-4-carboxylic acid was suspended in thionyl chloride (3 mL) and the reaction was stirred at 90° C. for 2 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.196 g, 1.62 mmol) and DIPEA (0.523 g, 0.71 mL, 4.05 mmol) were added, the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 6% MeOH in DCM]) to give ethyl 2-{4-fluoro-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.09 g, 28%) as a pale yellow gum as a mixture of diastereomers.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:40][CH:41]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([CH2:51][CH2:52][N:53]3[CH2:58][CH2:57][NH:56][CH:55]([CH3:59])[CH2:54]3)[CH:48]=2)[C:43](=[O:60])[O:42]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:40][CH:41]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([CH2:51][CH2:52][N:53]3[CH2:58][CH2:57][N:56]([C:13](=[O:15])[CH2:12][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:11][CH:10]=4)[CH:55]([CH3:59])[CH2:54]3)[CH:48]=2)[C:43](=[O:60])[O:42]1
Reactant: CC1CN(CCc2ccc3c(c2)CC(C)OC3=O)CCN1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1Cc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4)C(C)C3)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [4-(1H-tetrazol-1-yl)phenyl]acetic acid (101 mg, 0.49 mmol) in DCM (1271 μl) was treated with HATU (189 mg, 0.49 mmol) at room temp. After 5 minutes a solution of of 3-methyl-6-[2-(3-methylpiperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one (110 mg, 0.38 mmol) and DIEA (167 μl, 0.954 mmol) in DCM (1271 μl) was added and the reaction allowed to stir overnight at room temp. The reaction was quenched with water and SPE purification gives crude product which was purified via reverse phase HPLC (5-85% gradient elution ACN/H2O with 0.5% TFA) to obtain 3-methyl-6-[2-(3-methyl-4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one. LC-MS (IE, m/z): 475 [M+1]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH:21]([CH3:59])[C:22]([CH3:58])([CH3:57])[O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[C:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]=[C:31]2[CH2:55][CH3:56])=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>O>[CH2:55]([C:31]1[N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([CH3:58])([CH3:57])[CH:21]([OH:20])[CH3:59])=[CH:29][CH:28]=2)[C:35](=[O:36])[C:34]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[C:50]3[NH:51][C:4](=[O:7])[O:5][N:3]=3)=[CH:42][CH:43]=2)=[C:33]([CH2:52][CH2:53][CH3:54])[N:32]=1)[CH3:56]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(C)O[Si](C)(C)C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylpropoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.87 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (12 mL). N,N′-carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (2.5 mL and 1.0 M tetrahydrofuran solution) were added, and the mixture was stirred for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.O>C(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C:12]3[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(F)cc1

Procedure:
4-Fluorobenzylamine (20 g, 160 mmol) in 10 mL CH2Cl2 was added to phthalic anhydride (5 g, 34 mmol) in 20 mL glacial acetic acid. The reaction was stirred at 100° C. for 4 h as water was collected with a Dean-Stark trap. Solvent was evaporated and the product was obtained by crystallization from ethanol (7.5 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[N:3]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[ClH:1].[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=3)[N:3]=2)[CH2:35][CH2:34]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: FC(F)(F)c1cc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)ccc1Cl
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNCc3ccc(Cl)c(C(F)(F)F)c3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
The operation is carried out as in Stage 3 of Example 7 starting from 320 mg of the product obtained in Stage 1 above and 770 mg of trans-1,4-diaminocyclohexane and the reaction medium is heated to approximately 140° C. for 3 hours. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 85/25/1.5 salification is carried out with 1.4N HCl/EtOH, followed by filtering, washing with 5 ml EtOH then drying at ˜50° C. In this way 166 mg of expected product is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@H:16]1[CH2:20][CH2:19][C@H:18]([C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[NH:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].C(O)C>CO>[CH2:8]([CH:16]1[CH2:20][CH2:19][CH:18]([CH:21]([OH:31])[C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[NH:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccc2c(c1)OCO2)[C@H]1CC[C@H](CCc2ccccc2)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccc2c(c1)OCO2)C1CCC(CCc2ccccc2)N1

Procedure:
2-[phenethyl]-5-[(3,4-methylenedioxy)benzoyl]pyrrolidine trifluoroacetate (XIV) is reduced with metal borohydride, preferably with sodium borohydride, in a lower alcohol, preferably ethanol or methanol, at -10° to +20° C. The solvent is removed, the aqueous residue is diluted with the solution of base, preferably saturated sodium carbonate, and the product is extracted to organic halogenated solvent, preferably dichloromethane, to result in ±trans erythro 2-[phenethyl]-5-[(3,4-methylenedioxy)-α-hydroxybenzyl]pyrrolidine compound (XV). ##STR16##
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([Cl:8])=[O:7])=[N:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>O1CCOCC1>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: O=C(Cl)c1ccon1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)c4ccon4)CC3)nc(N)c2cc1OC
Product: Cl
Reaction time: 64 h

Procedure:
A solution of isoxazole-3-carbonyl chloride (0.753 g., 0.0057 mole) in dioxane (20 ml.) was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.66 g., 0.0057 mole) in dioxane (60 ml.). The mixture was stirred at reflux for 30 minutes, then at room temperature for 64 hours. Filtration gave the title compound which was recrystallized from methanol (1.81 g., 75% yield). The product had a m.p. of 268°-273° C. with decomposition.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][Si:6]([CH3:19])([CH3:18])[CH2:7][CH2:8][O:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16]O>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:16][C:12]1[N:11]([CH2:10][O:9][CH2:8][CH2:7][Si:6]([CH3:19])([CH3:18])[CH3:5])[CH:15]=[CH:14][N:13]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOCn1ccnc1CCl
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A solution of thionyl chloride (0.87 mL, 12.0 mmol, 3.0 eq) in chloroform (8 mL) was cooled to 0° C. and treated with a solution of [1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol (0.92 g, 4.0 mmol, 1.0 eq) in chloroform (2 mL). The clear solution was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The solvent was removed and the product was sequentially slurried and concentrated using chloroform, toluene and cyclohexane to give 2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole hydrochloride as a beige solid (1.1 g, 97%): 1H NMR (300 MHz, DMSO-d6) δ 7.85 (d, 1H, J=1.9 Hz), 7.70 (d, 1H, J=1.9 Hz), 5.62 (s, 2H), 5.14 (s, 2H), 3.57 (t, 2H, J=8.3 Hz), 0.90 (t, 2H, J=8.3 Hz), −0.02 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 142.1, 123.2, 120.2, 76.5, 66.8, 31.7, 17.3, −1.4.