Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[N:8]1([C:6]2[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=[C:2]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=3)[N:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1nc(-c2ccccc2)cc(N2CCOCC2)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(Nc2nc(-c3ccccc3)cc(N3CCOCC3)n2)cc1

Procedure:
A sample of (4-morpholin-4-yl-6-phenyl-pyrimidin-2-yl)-(4-trifluoromethoxy-phenyl)-amine was prepared from 4-(2-chloro-6-phenyl-pyrimidin-4-yl)-morpholine (0.3 g, 1.04 mmol) and 4-trifluoromethoxy phenylamine (0.14 mL, 1.04 mmol) according to a procedure analogous to that described above in Example 48.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][C:8]2([CH3:15])[CH3:14].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>>[CH3:14][C:8]1([CH3:15])[C:7]2[C:12](=[C:3]([CH2:2][O:1][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)[CH:4]=[CH:5][CH:6]=2)[NH:11][C:10](=[O:13])[CH2:9]1
Reactant: C1=COCCC1
Reactant: CC1(C)CC(=O)Nc2c(CO)cccc21
Product: CC1(C)CC(=O)Nc2c(COC3CCCCO3)cccc21

Procedure:
Analogously to Example 129g, 2.5 g of 8-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one and 2.28 ml of 3,4-dihydro-2H-pyran are reacted. The title compound is obtained as a light brown oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=4.28.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.[C:16]([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CC(C)=O.CCOCC>[C:16]([S:24][CH2:25][CH2:26][C:27]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Reactant: O=C(Cl)CCSC(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(SCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1

Procedure:
11.3 g of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid and 13.2 g of thriethylamine are dissolved in 200 ml of dehydrated acetone and 11.7 g of S-benzoyl-3-mercaptopropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour. 4 N Hydrochloric acid in ether is added to this mixture and the precipitate is filtered. The filtrate is concentrated in vacuo and the obtained oil is dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the titled compound, yield 12 g (58%), mp. 100.5°-101° C. (dec.) (ethyl acetatebenzene), [α]D26 +130.8° (c=1.0, methanol).
Reaction SMILES: CN(C=O)C.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>CCOCC>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1
Reactant: COCCCBr
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCn1cc(C=O)c2ccccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a DMF (0.1 M) solution of indole-3-carbaldehyde (1 eq) was added sodium hydride (60% (w/w) dispersion in oil, 1.1 eq.) at 0° C. followed by 1-bromo-3-methoxypropane (1.5 eq.). The reaction mixture was stirred at 50° C. for 4 h. The mixture was then diluted with ether, washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 1:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26]([NH:28][NH2:29])=[O:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6](/[C:8](=[N:29]/[NH:28][C:26](=[O:27])[C:25]2[CH:30]=[CH:31][CH:32]=[C:23]([S:20]([N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)(=[O:21])=[O:22])[CH:24]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 20 %

Procedure:
1-(5-chloro-2-nitrophenyl)ethanone (30 mg, 0.150 mmol) and 3-(morpholinosulfonyl)benzohydrazide (42.9 mg, 0.150 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2), afforded the product (E)-N′-(1-(5-chloro-2-nitrophenyl)ethylidene)-3-(morpholinosulfonyl)benzohydrazide (15 mg, 0.030 mmol, 20.09% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.20 (m, 1H), 8.07 (m, 1H), 7.88 (m, 1H), 7.66 (m, 1H), 7.51 (m, 2H), 7.39 (m, 1H), 3.69 (m, 4H), 2.99 (m, 4H), 2.29 (s, 3H). Mass [M+H]+:468.0
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14]C)[CH2:12]C)=[O:7])=[C:4]([O:19][CH2:20][CH2:21][NH2:22])[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:22][CH2:21][CH2:20][O:19][C:4]1[CH:3]=[C:2]([NH2:1])[C:17]([Cl:18])=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:14])[CH3:12])=[O:7])(=[O:25])[CH3:24]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCN
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NCCOc1cc(N)c(Cl)cc1C(=O)NCCN(C)C
Reaction time: 0.05 h
Yield: 54.1 %

Procedure:
To a solution of 4-amino-2-(2-aminoethoxy)-5-chloro-N-[2-(diethylamino)ethyl]benzamide (780 mg, 2.4 mmoles) (prepared in Example 47) in methylene chloride was added acetic anhydride (245 mg, 2.4 mmoles) and the mixture stirred for 3 minutes. This was concentrated in vacuo and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase was concentrated and the residue flash-chromatographed on silica using methylene chloride:methanol:ammonia (100:4:0.5) solvent system. The appropriate fractions were combined and concentrated in vacuo. The residue was recrystallized from methylene chloride-ether to give 445 mg of the title compound as a white solid, mp. 143°-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17](OC)[CH2:16][CH2:15][C@H:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([C:24]#[N:25])(C)C.B(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:24]#[N:25])[CH2:16][CH2:15][C@H:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H]1CCC(OC)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC(C#N)N1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of ethyl(2S)-N-tert-butoxycarbonyl-5-methoxyprolinate (4.10 g, 15.81 mmol) in CH2Cl2 (40 mL) at −50° C. was added trimethylsilyl cyanide (6.3 mL, 47.4 mmol) and BF3 etherate (5.60 mL, 47.4 mmol). The mixture was stirred from −50° C. to −30° C. for 2.0 h before it was quenched with saturated NaHCO3. The organic layer was separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over MgSO4. Filtration, evaporation of solvent and flash column chromatography (hexane/ethyl acetate, 3:1) gave separated cis and tran isomers (2.20 g). 1HNMR (300 MHz, CDCl3) δ isomer 1: 4.68 (dd, J=4.0, 2.0 Hz) and 4.55 (t, J=5.4 Hz) for 1H, 4.40 (t, J=7.7 Hz) and 4.26 (t, J=6.9 Hz) for 1H, 3.79 (s, 3H), 2.42–1.98 (m, 4H), 1.52 (s) and 1.44 (s) for 9 H; isomer 2: 4.78 (dd, J=8.8, 1.5 Hz) and 4.67 (d, J=8.0 Hz) for 1H, 4.45 (d, J=8.8 Hz) and 4.34 (d, J=8.0 Hz) for 1H, 3.75 (s) and 3.73 (s) for 3H, 2.56–2.12 (m, 4H), 1.52 (s) and 1.43 (s) for 9H; CIMS 255 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:15])([CH3:14])[C:12](=O)[NH:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:13]2([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC1(C)C(=O)NCC(=O)N1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNCCN1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of 1-(4-chlorophenyl)-6,6-dimethylpiperazine-2,5-dione (0.9 g, 3.56 mmol) in THF (100 mL) at 0° C., was added LiAlH4 (0.54 g, 14.2 mmol) portionwise. The reaction was stirred at 0° C. for 0.5 h, the reaction was warmed to rt and stirred for 1 h. The reaction was carefully quenched with water, diluted with EtOAc, and added solid NaHCO3. The solution was stirred, filtered, and concentrated to give to give 1-(4-chlorophenyl)-2,2-dimethylpiperazine (0.76 g, 3.38 mmol, 95% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH:5][N:4]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:19][C:20]1[CH:21]=[C:22]([N:5]2[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:7][C:3]([C:2]([F:1])([F:17])[F:18])=[N:4]2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)nn1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a mixture tert-butyl (3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (251 mg, 0.946 mmol, 1 equiv.), 3,5-difluorophenylboronic acid (299 mg, 1.89 mmol, 2 equiv.) and copper acetate (258 mg, 1.49 mmol, 1.5 equiv.) in dichloromethane (14 mL) was added pyridine (151 mg, 0.151 mL, 1.89 mmol, 2 equiv) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with dichloromethane (250 mL) and the solvent of the filtrate was evaporated to give tert-butyl (1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (214 mg, 60%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>C1COCC1.B.CSC>[F:15][C:12]([F:13])([F:14])[CH2:11][N:8]1[CH2:9][CH2:10][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:6][CH2:7]1
Reactant: O=C(N1CCC2(CC1)OCCO2)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: FC(F)(F)CN1CCC2(CC1)OCCO2
Yield: 100.8 %

Procedure:
In the solution of 1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2,2,2-trifluoroethanone (20 g, 83.7 mmol) in THF, borane-methyl sulfide complex (83.7 ml, 2M solution in THF) was added at 0° C. After refluxing the reaction mixture for 12 h, the reaction was cooled and quenched with MeOH. After removal of THF, the residue was extracted with ethyl acetate and washed with brine, dried with MgSO4 and concentrated to give 8-(2,2,2-trifluoroethyl)-1,4-dioxa-8-aza-spiro[4.5]decane (19 g) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:22]([C:24]2[CH:25]=[N:26][C:27]3[N:28]([N:30]=[CH:31][C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH:29]=2)=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:22]([C:24]2[CH:25]=[N:26][C:27]3[N:28]([N:30]=[CH:31][C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH:29]=2)=[O:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNC(=O)c2cnc3c(-c4cccc(Cl)c4)cnn3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1N1CCNCC1)c1cnc2c(-c3cccc(Cl)c3)cnn2c1
Yield: 89.8 %

Procedure:
A solution of N-{2-(4-t-butoxycarbonyl piperazino)phenyl}methyl 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-6-amide (300 mg) and trifluoroacetic acid (0.42 ml) in chloroform (6 ml) was heated at reflux over 6 hours. The reactant was cooled, and ice and a 2N aqueous sodium hydroxide solution (3 ml) were added, and thereafter extracted with chloroform. The organic layer was dried with magnesium sulfate, and thereafter the solvent was distilled under a reduced pressure. The residue was purified by an alumina column chromatography, and thereafter recrystallized from tetrahydrofuran-diisopropyl ether to yield N-(2-piperazinophenyl)methyl 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-6-amide (220 mg, 90%). mp: 185-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C:24]#[N:25]>>[CH3:13][O:12][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[O:10][CH3:11])[N:1]=[C:24]([NH2:25])[C:23]([CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH3:14])=[CH:4]2
Reactant: COc1cc(N)c(C=O)cc1OC
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2cc(OC)c(OC)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4,5-dimethoxybenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[F:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23](SC)=[N:24][CH:25]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:23]2[NH:22][C:21](=[O:28])[C:20]([CH2:19][C:18]3[CH:29]=[CH:30][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:25][N:24]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Yield: 71.9 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.88 g) and 5-(4-fluorobenzyl)-2-methylthio-4-pyrimidone (0.75 g) were refluxed in pyridine (3 ml) for 24 hours. The pyridine was removed in vacuo and the residue triturated with ethanol (5 ml) giving a colourless solid. The solid was recrystallised from methanol giving 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(4-fluorobenzyl)-4-pyrimidone (0.96 g) m.p. 172°-3° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10]([C@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:11]>CCOCC>[CH:10]([C@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:11]
Reactant: CON(C)C(=O)[C@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C=O
Temperature: 0 °C
Yield: 99.5 %

Procedure:
Lithium aluminum hydride (1 M in THF, 5.3 ml, 5.3 mmol) was added to a solution of (3R)-tert-butyl 3-(methoxy(methyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.7 g, 5.0 mmol theory) in ether (16 ml) stirring at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the reaction was slowly quenched with water (0.40 ml). Sodium hydroxide (1N, 0.80 ml) followed by water (0.60 ml) were then added and the resultant gelatinous precipitate was filtered through Celite® rinsing with ether and THF. The filtrate was evaporated and the residue transferred to a separatory funnel with EtOAc. Washing with brine and drying with MgSO4 afforded crude product (1.3 g, 100% yield) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CN(C=O)C>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]([CH3:14])[C:7]2[CH:6]=[C:5]([Cl:9])[N:4]=[C:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)cc(N(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Temperature: 100 °C
Yield: 17.6 %

Procedure:
To a stirred solution of methyl 3,4,6-trichloropyridine-2-carboxylate (310 mg, 1.29 mmol) in DMF (5 ml) was added TEA (359 μl, 2.58 mmol) followed by tert-butyl 4-(methylamino)piperidine-1-carboxylate (276 mg, 1.29 mmol) and the reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then cooled to room temperature and poured onto water (50 ml), followed by extraction of the product into TBME (3×50 ml), washing of the combined organics with brine (50 ml), drying with Na2SO4 and evaporation. The crude product was then purified over a 10 g silica Isolute column eluting with a gradient of 0% to 50% EtOAc in heptane to afford the title compound as a white solid (95 mg, 18%). LC-MS 95%, 2.29 min (3.5 minute LC-MS method), m/z=418.1/419.8, 1H NMR (500 MHz, Chloroform-d) δ 6.87 (s, 1H) 4.12-4.34 (m, 2H) 3.99 (s, 3H) 3.69-3.80 (m, 1H) 2.79 (s, 3H) 2.64-2.77 (m, 2H) 1.75 (br. s., 4H) 1.48 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:13]([OH:15])=O)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][N:4]=1.F[B-](F)(F)F.C(OC([C:26](=NOC(N(C)C)=[N+](C)C)[C:27]#[N:28])=O)C.C(NCC)C>CN(C=O)C>[CH2:27]([NH:28][C:13]([C:9]1[CH:10]=[C:11]([CH3:12])[C:6]2[N:7]([C:3]([NH2:2])=[N:4][N:5]=2)[N:8]=1)=[O:15])[CH3:26]
Reactant: Cc1cc(C(=O)O)nn2c(N)nnc12
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(C)c2nnc(N)n2n1
Reaction time: 2 h
Yield: 38.9 %

Procedure:
3-Amino-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid hydrochloride (W1.141; 300 mg) was dissolved in DMF (6 ml) and admixed with O-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU; 429 mg) and diethylamine (573 mg). After 2 h, the DMF was drawn off and the residue was purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). The product was taken up with water and freeze-dried. In order to remove residual diethylamine, the mixture was chromatographed using a short column (dichloromethane/methanol 95:5). 112 mg of the title compound were obtained, which was still contaminated with diethylamine.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.[ClH:20]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:20].[CH3:18][C:11]1([CH3:19])[CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[C:14](=[O:17])[CH2:13][CH2:12]1
Reactant: CC1(C)CCC(=O)C2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(=O)C2CNCC21
Temperature: 60 °C

Procedure:
A mixture of 2.31 g of (3aRS,7aRS)-2-benzyl-7,7-dimethyl-4-perhydroisoindolone and 9.96 cm3 of 1N hydrochloric acid in 25 cm3 of anhydrous ethanol is heated to 60° C. with stirring; 0.11 g of 20% palladium hydroxide on charcoal is added and the reaction mixture is then hydrogenated, with stirring, at a temperature of 60° C. and at atmospheric pressure. After reaction for 6 hours, the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 2.17 g of (3aRS,7aRS)-7,7-dimethyl-4-perhydroisoindolone hydrochloride are obtained, in the form of a pink oil containing ethanol.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[CH:4](=[O:8])[CH2:5][CH2:6][CH3:7].[CH2:9]=[O:10]>>[CH2:4]([C:5]([CH2:1][OH:3])([CH2:9][OH:10])[CH2:6][CH3:7])[OH:8].[CH:1]([O-:3])=[O:2]
Reactant: CCCC=O
Reactant: C=O
Agent: O=C[O-]
Product: CCC(CO)(CO)CO

Procedure:
In the process of the invention, n-butyraldehyde is firstly reacted with formaldehyde in the presence of a base. This reaction can be carried out in one or more stages. In the single-stage variant, the starting materials are reacted directly to form trimethylolpropane and a formate salt. In a two-stage variant, n-butyraldehyde and formaldehyde are firstly reacted in the presence of catalytic amounts of base to form 2,2-dimethylolbutanal, purification or separation steps are carried out if desired and only then is the 2,2-dimethylolbutanal reacted with further formaldehyde in the presence of stoichiometric amounts of base to form trimethylolpropane and formate salt.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:23])[CH3:24])[C:12]([C@H:25]([C:34]3[CH:35]=[CH:36][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=3)[OH:26])=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: CC(C)c1ccc([Mg]Br)cc1
Product: CC(C)c1ccc([C@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC2(CCC2)C3)cc1

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 4-isopropylphenylmagnesiumbromide.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)[CH:15]=[C:14]2[CH:29]=[C:30]1[S:34][C:33](=[O:35])[NH:32][C:31]1=[O:36]>>[C:1]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)[CH:15]=[C:14]2[CH:29]=[C:30]1[S:34][C:33](=[O:35])[NH:32][C:31]1=[O:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)c(C=C1SC(=O)NC1=O)cn2Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Product: O=C1NC(=O)C(=Cc2cn(Cc3ccc(Cl)c(Cl)c3)c3ccc(NC(=O)c4ccccc4)cc23)S1

Procedure:
The title compound was prepared by General Procedure 7 with benzoyl chloride and the amino compound from Example 47 as reactants. Nmr and ms data were consistent; ms m/e 523 (M+1). HPLC (System 1): purity greater than 80%.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:34]=[CH:33][C:20]3[CH2:21][CH:22]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:27])[N:24]([CH3:26])[CH2:25][C:19]=3[CH:18]=2)=O)=CC=1)([O-])=O.[H][H]>[Pd].CCO>[NH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:34]=[CH:33][C:20]2[CH2:21][CH:22]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:27])[N:24]([CH3:26])[CH2:25][C:19]=2[CH:18]=1
Reactant: [H][H]
Reactant: COC(=O)CC1Cc2ccc(OCCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cc2CN(C)C1=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1Cc2ccc(OCCCN)cc2CN(C)C1=O
Reaction time: 18 h
Yield: 92.6 %

Procedure:
A mixture of methyl (±)-8-[3-(4-nitrobenzyloxycarbonylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (1.4 g, 3 mmol), 10% palladium on charcoal (0.55 g, 0.6 mmol), and EtOH (20 mL) was stirred at RT under a balloon of hydrogen. After 18 hr, the mixture was filtered and the filtrate was concentrated to give the title compound (0.89 g, 99%) as a tan solid: MS (ES) m/e 321.4 (M+H)+.