Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26](O)=[O:27])=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:62][CH2:63][C@@H:64]([OH:73])[CH2:65][N:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]2[N:10]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:26]([NH:62][CH2:63][C@@H:64]([OH:73])[CH2:65][N:66]4[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]4)=[O:27])=[C:21]4[C:25]=3[O:24][CH2:23][CH2:22]4)[N:8]=[CH:7][C:6]=2[N:5]([CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: CN1CCN(C[C@H](O)CN)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H](O)CN4CCN(C)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
7-[[(7R)-7-Ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (150 mg, 0.36 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (117 mg, 0.36 mmol) were dissolved in 30 mL of anhydrous dichloromethane followed by the addition of diisopropylethylamine (0.1 mL, 0.80 mmol) and (2R)-1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 20e (63 mg, 0.36 mmol) successively. The reaction solution was stirred for 2 hours. The resulting solution was added with 30 mL of saturated sodium carbonate solution and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]-2,3-dihydrobenzofuran-4-carboxamide 33 (78 mg, yield: 40.0%) as a white solid.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:30])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)=[O:6])#[N:2].N1CCCCC1.O.C(Cl)Cl.CO>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:30])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CO
Product: N#CCNC(=O)C1(N)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
FMOC-1-amino-cyclohexanecarboxylic acid cyanomethyl-amide (248 mmol) is dissolved in DMF (200 ml), piperidine (248 mmol) is added and the mixture is stirred at RT for 2 hours. The reaction mixture is poured into water (3000 ml) and stirred for 30 minutes. The suspension is filtered and the filtrate is acidified with HCl 4N and than extracted with ethyl acetate. NaOH 1N is added to make the water phase basic and the mixture is extracted three times with ethyl acetate. The organic fractions are dried over sodium sulfate and the solvent is evaporated. The residue is dried (vacuum) to yield a pale yellow oil. Rf=0.26 (CH2Cl2/MeOH=95:5).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:11](=[O:18])[O:10][CH:9]1[CH2:19][O:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](/[C:8](=[CH:9]/[CH2:19][O:20][CH3:21])/[CH2:17][C:12]1([C:11]([OH:18])=[O:10])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCC1OC(=O)C2(CCCC2)CC1C(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC/C=C(\CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 29 %

Procedure:
To a solution of the product from stage b) above (6.11 g, 20.49 mmol) in toluene (50 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.7 ml, 24.58 mmol), and the resultant solution was then heated at reflux under nitrogen for 5 h. The solution was then cooled to room temperature and the solvent was removed under reduced pressure. To the resultant residue was then added deionised water (100 ml) and the mixture was then extracted with tert-butyl methyl ether (30 ml). The phases were then separated and the aqueous phase was acidified to pH 2 with hydrochloric acid (15 ml of a 2 M solution) and then extracted with tert-butyl methyl ether (2×30 ml). The combined organic extracts were then washed with water (30 ml) and then brine (30 ml) and dried over magnesium sulfate. The solvent was then removed under reduced pressure to give the crude title compound (6.29 g), which was then crystallised from heptane (15 ml) at 0° C. The resultant solid was collected by filtration was then washed with ice-cold heptane (2×5 ml) to give the title compound as a white solid (1.79 g, 6.0 mmol, 29%, E-isomer assigned on basis of chemical shifts); 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 1.45-1.70 (m, 6H), 2.05-2.10 (m, 2H), 2.74 (s, 2H), 3.36(s, 3H), 4.09 (d, 2H), 6.75 (t, 1H); 13C NMR (100 MHz, CDCl3) δ: 23.9, 28.0, 34.1, 35.0, 55.0, 58.6, 69.2, 80.8, 132.7, 139.1, 167.1, 183.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(2S,4R)-4-Fluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.87 g, 13.1 mmol) was dissolved in 45 mL of CH2Cl2. The mixture was cooled down to 0° C., and methanesulfonyl chloride (2.55 mL, 32.8 mmol) and triethylamine (4.56 mL, 32.8 mmol) were added. The mixture was allowed to warm to RT and stirred for 1.5 h. The mixture was quenched with a saturated aqueous solution of NaHCO3, extracted twice with CH2Cl2, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAC 3:7) to afford the desired material. TLC, Rf (c-hexane/EtOAc 1:1)=0.4; MS: 320.0 [M+Na]+, 198.1 [MH−Boc]+, 617.2 [2M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:11]([S:14](Cl)(=[O:16])=[O:15])([CH3:13])[CH3:12]>ClCCl>[CH:11]([S:14]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:16])=[O:15])([CH3:13])[CH3:12]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
Add 4-methoxy-benzylamine (11.7 m, 89.5 mmol) to a solution of isopropyl sulfonyl chloride (5.0 mL, 44.74 mmol) in dichloromethane (100 mL) and stir for 18 hours at ambient temperature. Wash solution with 1 N hydrochloric acid (3×100 mL), dry with magnesium sulfate and concentrate. Purify on silica gel with hexane/ethyl acetate mixtures to give 4.73 g (43%) of the title compound as a white solid. MS(ES−): m/z=242.1 (M−H)−
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH:10]([F:12])[F:11])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>CCCCCC>[CH2:26]([O:25][C:23]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[C:3]=1[O:9][CH:10]([F:11])[F:12])=[O:24])[CH3:27]
Reactant: Nc1cccc(F)c1OC(F)F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1cccc(F)c1OC(F)F)C(=O)OCC
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 22.4 g (0.127 mole) of 3-fluoro-2-difluoromethoxyaniline obtained as described above and 27.4 g (0.127 mole) of diethyl ethoxymethylenemalonate was heated at 120° C. for 5 hours. The mixture was cooled to room temperature, n-hexane was added thereto, and the mixture was filtered. Products collected by filtration was washed with n-hexane and dried to obtain 37.5 g of N-(2,2-diethoxycarbonylvinyl)-3-fluoro-2-difluoromethoxyaniline as white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1)[CH:17]=[CH2:16]
Reactant: CSc1ncc(O)cn1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cnc(SC)nc1
Reaction time: 2 h

Procedure:
4.5 g of 5-hydroxy-2-methylthiopyrimidine, 9.0 g of potassium carbonate and 3.9 g of allyl bromide are together refluxed in 50 ml of acetone, with stirring, for 41/2 hours. The inorganic salts are removed by filtration, and the filtrate is concentrated under reduced pressure. The oil remaining yields, from petroleum ether, 5-allyloxy-2-methylthiopyrimidine, m.p. 41°-42°.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=3)[O:10][C:9](=[O:19])[CH:8]=2)[N:6]=1.[NH2:20][C:21]1[O:25][C:24]([C:26]([OH:33])([CH2:31][CH3:32])[C:27]([F:30])([F:29])[F:28])=[N:23][N:22]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[OH:33][C:26]([C:24]1[O:25][C:21]([NH:20][CH2:17][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[CH:8][C:9](=[O:19])[O:10]3)=[CH:15][CH:14]=2)=[N:22][N:23]=1)([C:27]([F:29])([F:28])[F:30])[CH2:31][CH3:32]
Reactant: CCC(O)(c1nnc(N)o1)C(F)(F)F
Reactant: Cc1nc(-c2cc(=O)oc3cc(C=O)ccc23)cs1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(O)(c1nnc(NCc2ccc3c(-c4csc(C)n4)cc(=O)oc3c2)o1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(2-methyl-1,3-thiazol-4-yl)-2-oxo-2H-chromene-7-carbaldehyde (0.200 g, 0.74 mmol) and 2-(5-amino-1,3,4-oxadiazol-2-yl)-1,1,1-trifluorobutan-2-ol (0.202 g, 0.96 mmol) in toluene (2 ml) was added PPTS (0.019 g, 0.07 mmol). The reaction mixture was heated under reflux with a Dean-Stark trap for 6 h. After evaporation, the residue was diluted in EtOH (2 ml), cooled to 0° C. and sodium borohydride (28 mg, 0.74 mmol) was added. After 15 min, the reaction was quenched with a saturated solution of NH4Cl, extract with EtOAc then washed with water and brine. The solvent was evaporated and the residue chromatographed on silica gel (chloroform-ethanol, 95:5) to give the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.27 (d, 1H), 8.09 (s, 1H), 7.45 (m, 3H), 6.66 (s, 1H), 6.08 (s, 1H), 4.7 (d, 2H), 2.83 (s, 3H), 2.22 (m, 1H), 2.10 (m, 1H), 0.98 (m, 3H).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:12]=2[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:22]([CH2:29][C@H:30]1[O:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:2]([N:9]([CH2:31][C@H:30]([OH:32])[CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:12]=2[CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Under nitrogen, to a solution of N-benzyl-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine hydrochloride (300 mg) and (2S)-1-phenoxy-2,3-epoxypropane (193 mg) in dichloromethane (10 ml) was added ytterbium(III) trifluoromethanesulfonate (61 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S)-1-[N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (340 mg).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[N:10]=[C:9]([SH:14])[N:8]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>O>[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[N:10]=[C:9]([S:14][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[N:8]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CSc2nc(O)cc(O)n2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
A DMF (500 ml) solution of 4,6-dihydroxy-2-mercaptopyrimidine (50 g, 346 mmol), triethylamine (62.7 ml, 450 mmol), 4-methoxybenzyl chloride (52.8 ml, 381 mmol) was heated and stirred at 100° C. for 1 hour 45 minutes. The reaction solution was poured into water and stirred for a while, and the precipitated crystals were collected by filtration and air-dried to obtain 75.2 g (82% yield) of 4,6-dihydroxy-2-(4-methoxybenzylsulfanyl)pyrimidine.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([SH:12])[S:10][CH:11]=1)=[O:5])C.[OH-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:19][N:20]1[CH2:25][CH2:24][O:23][C@@H:22]([CH2:26][NH:27][C:28](=[O:31])[CH2:29]Cl)[CH2:21]1.CCCCCCC>O.C(O)(C)(C)C.COC(C)(C)C>[C:4]([CH2:6][C:7]1[N:8]=[C:9]([S:12][CH2:29][C:28]([NH:27][CH2:26][C@@H:22]2[O:23][CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:16]([Cl:15])[CH:17]=3)[CH2:21]2)=[O:31])[S:10][CH:11]=1)([OH:3])=[O:5]
Reactant: CCOC(=O)Cc1csc(S)n1
Reactant: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Solvent: O
Product: O=C(O)Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Ethoxycarbonylmethyl-2-mercaptothiazole (70.14 g) was dissolved in a mixed solution of water (300 ml) and tert-butanol (250 ml), sodium hydroxide (29.46 g) was added on a water bath, and the mixture was stirred for 1.5 hr. To the reaction mixture was added a solution of (2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}chloroacetamide obtained in the above-mentioned 1-1 in tert-butyl methyl ether, and the mixture was stirred at 65° C. for 6 hr. n-Heptane (50 ml) and water (50 ml) were added to the reaction mixture, and the mixture was cooled to room temperature. The reaction mixture was stood still and partitioned, and the aqueous layer was further washed with a mixed solvent of tert-butyl methyl ether (200 ml)/n-heptane (20 ml). 6N Hydrochloric acid (60 ml) was added to the aqueous layer, and the mixture was extracted with ethyl acetate (750 ml) and further extracted twice with a mixed solvent of ethyl acetate (175 ml)/tert-butanol (20 ml). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (181 g) of compound 1-2.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([CH3:18])=[CH:9][C:10](=[O:17])[N:11]3[CH2:14][CH:15]=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C.ClCCl>[CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([CH3:18])=[CH:9][C:10](=[O:17])[N:11]3[CH2:14][CH2:15][N:41]3[CH2:42][CH2:43][CH:38]([N:30]([CH2:29][C:27]4[CH:26]=[CH:25][C:24]5[O:19][CH2:20][CH2:21][O:22][C:23]=5[CH:28]=4)[C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:39][CH2:40]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(CC=O)c2cc(C3CC3)ccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C3CC3)ccc12
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To 1.5 mL of dichloromethane solution containing 53 mg of (7-cyclopropyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde, 77 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 15 μL of acetic acid were added, and stirred for 10 min. To the reaction mixture, 70 mg of sodium triacetoxyborohydride was added, and stirred for 30 min. Water, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was neutralized with aqueous saturated sodium hydrogen carbonate solution, thereafter extracted with ethyl acetate. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:2], to give 99 mg of tert-butyl (1-(2-(7-cyclopropyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C:8]1=[O:13].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:14][N:2]([CH3:1])[CH2:3][C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])[C:8]1=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CC#CCN1CC[C@@H](O)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC#CCN1CC[C@@H](OS(C)(=O)=O)C1=O

Procedure:
A solution of 0.4 g of (R)-1-[4-(dimethylamino)-2-butynyl]-3-hydroxy-2-pyrrolidinone, 0.6 ml of triethylamine and 0.3 ml of methane sulfonyl chloride in 10 ml of dichloromethane was stirred at 0° C. for 1 hour. Saturated aqueous sodium carbonate was added and the mixture separated. The aqueous portion was washed with dichloromethane. The organic layer and wash were combined, washed with sodium chloride solution, dried and evaporated. The residue was evaporated from 10 ml of toluene. The residual oil was purified by chromatography (silica gel), giving 0.4 g of (R)-1-[4-(dimethylamino)-2-butynyl]-3-[(methane sulfonyl)oxy]-2-pyrrolidinone as a colorless oil.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]1.[C:13]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCCC1>[CH3:12][C:11]1[N:7]([CH2:6][C:13]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[CH:9][CH:10]=1
Reactant: O=C1CCCCCCC1
Reactant: Cc1ccnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccnn1CC1(O)CCCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of n-butyllithium (10 mL, 2.5M) in tetrahydrofuran (20 mL) was added 1,5-dimethyl-1H-pyrazole (2.0 g) in tetrahydrofuran (10 mL) dropwise via syringe. After 1 hour, cyclooctanone (2.63 g) in tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature. The mixture was quenched by the addition of saturated ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with additional ethyl acetate. The combined organics were dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH2:22])[CH2:17]2)[CH:13]=[CH:14][CH:15]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([NH:22][CH:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=2)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc([C@H]2CCC[C@H](N)C2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc(C2CCCC(NC(C)=O)C2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
Acetic anhydride (1 ml) and pyridine (0.5 ml) were added to (trans)-3-(3-methoxyphenyl) cyclohexylamine (10 mg) and the mixture was stirred at 50° C. for 2 hours. The reaction solution was poured into glacial sodium bicarbonate water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate water and saturated saline and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 8 mg of N-acetyl-N-[3-(3-methoxyphenyl)cyclohexyl]amine (53.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:13]=[C:14]1[CH2:31][CH2:30][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15]1.O>CCOCC>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C:17]2([CH2:30][CH2:31][C:14]([OH:13])([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:15][CH2:16]2)[CH2:18][CH2:19]1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1cccnc1)CC2
Reaction time: 0.33 h
Yield: 50 %

Procedure:
3-Bromopyridine (14.9 mmol, 1 equiv.) was dissolved in ether (50 ml) and added dropwise at −78° C. to a solution of n-BuLi (16.5 mmol, 1.17 M solution in ether, 1.1 equiv.). The mixture was stirred for 20 minutes. tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (stage (iv) Amine F-40) (7.49 mmol) was then dissolved in ether (90 ml) and added slowly. The reaction mixture was stirred for a further hour at −78° C. Distilled water was added and the mixture was thawed to 25° C. The phases were separated, and the organic phase was washed with saturated NaCl solution (30 ml), dried over Na2SO4 and concentrated. The crude product was taken up in ethyl acetate (10 ml) and a solid was precipitated with hexane (30 ml). The solid was filtered off and dried under a high vacuum to yield the desired product. Yield: 50%
Reaction SMILES: [C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH2:11][CH:10]1[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([N:29]1C2C(=CC(Cl)=CC=2)C(=O)CC1C)(=O)[C:22]1C=CC=C[CH:23]=1.ClC1C2C(=CC=CC=2)N=CC=1.C(N)C#C>ClC(Cl)C.C1(C)C=CC=CC=1.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-].C(N(CC)CC)C>[CH3:20][CH:10]1[CH2:11][C:12](=[N:29][CH2:21][C:22]#[CH:23])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CC1CC(=O)c2cc(Cl)ccc2N1C(=O)c1ccccc1
Reactant: CC1CC(=O)c2ccccc2N1C(=O)c1ccccc1
Agent: [Ti+4]
Agent: C#CCN
Agent: Clc1ccnc2ccccc12
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CCN=C1CC(C)N(C(=O)c2ccccc2)c2ccccc21
Temperature: -5 °C

Procedure:
To a solution of 1-benzoyl-2-methyl-2,3-dihydro-1H-quinolin-4-one (corresponds to a compound of general formula (3b) wherein R3 is phenyl, R4 is CH3 and R5, R6, R7, R8 are H, prepared as disclosed in example 46, according to protocol B, starting from 4-chloro-quinoline, (0.3 g), triethylamine (0.92 g), propargyl amine (0.125 g) in dichloroethane (20 ml), cooled at −5° C. in an ice/sodium chloride bath, a solution of titanium chloride in toluene 1 mol/l was dropwise added for 10 minutes. The mixture was stirred over night at room temperature and then washed with dichloromethane and an aqueous solution of potassium carbonate. The organic layer was separated, dried over sodium sulfate and the solvent was removed under reduced pressure to give (2-methyl-4-prop-2-ynylimino-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (brown oil) (0.5 g) which was not purified, but directly used in the next step