Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:26])[C@@H:15]([NH:16][C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:27][F:28])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[F:28][CH2:27][C:9]1[CH2:10][S:11][C@@H:12]2[C@H:15]([NH:16][C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14](=[O:26])[N:13]2[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C1=C(CF)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CF)CS[C@H]12
Reaction time: 0.5 h

Procedure:
A mixture of 45 mg of 3-fluoromethyl-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid tert.-butyl ester and 2 ml of trifluoroacetic acid is left to stand for 30 minutes at room temperatur. The trifluoroacetic acid is then removed under reduced pressure and the residue is washed with acetone/ethyl ether mixture to give 3-fluoromethyl-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid as an amorphous powder; thin layer chromatogram on silica gel (system: chloroform/methanol 1:1): Rf~0.50; ultraviolet absorption spectrum (ethanol): λmax : 259μ (ε=5300); infrared absorption spectrum (nujol): characteristic bands at 3.02μ; 5.60μ; 5.78μ; 6.06μ and 6.51μ.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[CH:14]=[O:15].Cl[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>O1CCCC1.CCCCCC>[O:15]1[CH:14]([CH:8]2[CH2:9][CH:10]3[CH2:13][CH:7]2[CH:12]=[CH:11]3)[CH:17]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: O=CC1CC2C=CC1C2
Reactant: CC(C)(C)OC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1OC1C1CC2C=CC1C2
Reaction time: 1 h
Yield: 94.9 %

Procedure:
In a nitrogen atmosphere, a solution of 112 g of potassium tert-butoxide in 400 g of dry tetrahydrofuran was added dropwise over 2 hours to a mixture of 122 g of 5-norbornene-2-carbaldehyde, 151 g of tert-butyl chloroacetate, and 500 g of dry tetrahydrofuran at 0-5° C. After one hour of stirring, 400 g of water was added to stop the reaction. The organic layer obtained by hexane extraction was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by vacuum distillation yielded 224 g (yield 95%) of tert-butyl 2,3-epoxy-3-(5-norbornen-2-yl)propionate as a fraction having a boiling point of 92-94° C./53 Pa.
Reaction SMILES: [CH2:1]([N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1)[CH2:2][CH3:3].S(=O)(=O)(O)[OH:21].N>>[CH2:1]([N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:18])=[O:21])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCN=C(N)Nc1ccnc(CCCCC#N)n1
Reactant: O=S(=O)(O)O
Agent: N
Product: CCCN=C(N)Nc1ccnc(CCCCC(N)=O)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 5-(4-[2-propylguanidino]pyrimid-2-yl)valeronitrile (0.25 g.) and concentrated sulphuric acid (2 ml.) was stirred at ambient temperature for 3.5 hours. The reaction mixture was cooled in an ice bath and basified by careful dropwise addition of concentrated aqueous ammonia (s.g. 0.880). The resulting white precipitate was collected, washed with water and allowed to dry. The solid was purified by medium pressure chromatography on silica gel using CHCl3 /MeOH/aqueous ammonia (s.g. 0.880) 8:2:0.3 v/v/v as eluant to give 5-(4-[2-propylguanidino]pyrimid-2-yl)valeramide (0.15 g.), m.p. 212°-214°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:12]1(=[O:24])(=[O:23])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][NH:15][CH2:14][CH2:13]1>>[O:23]=[S:12]1(=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]([C:2]2[N:3]=[C:4]([NH:3][CH2:4][CH2:5][CH2:6][NH2:7])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: O=S1(=O)CCNCc2ccccc21
Product: NCCCNc1nc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccsc12

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichlorothieno[3,2-d]pyrimidine and propane-1,3-diamne, followed by reaction with 2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 404, 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.04 (d, J=7.3 Hz, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.46-7.57 (m, 2H), 7.34-7.42 (m, 1H), 7.10 (d, J=5.3 Hz, 1H), 5.19 (br. s., 2H), 3.76 (br. s., 2H), 3.44-3.54 (m, 4H), 3.00 (t, J=6.1 Hz, 2H), 1.88 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22].[F-].[K+].CC#N>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([F:23])([F:24])[F:22])=[C:15]([F:14])[CH:16]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(N)c(F)c(-c2ccc(C(F)(F)F)c(F)c2)n1
Temperature: 115 °C
Yield: 70.3 %

Procedure:
To a 5 mL microwave vial was added methyl 4-amino-6-chloro-5-fluoropicolinate (500 mg, 2.44 mmol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (851 mg, 2.93 mmol), potassium fluoride (KF; 369 mg, 6.35 mmol), and PdCl2(PPh3)2 (172 mg, 0.24 mmol). Subsequently, CH3CN (3.0 mL) and H2O (3.0 mL) were added, and the reaction vial was sealed and heated in a Biotage microwave at 115° C. for 20 min. The reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×2 mL). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified using a Teledyne ISCO purification system with a gradient eluent system of EtOAc and hexanes to yield the title compound as a yellow solid (570 mg, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dt, J=12.3, 6.2 Hz, 3H), 7.52 (d, J=6.4 Hz, 1H), 6.80 (s, 2H), 3.86 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −59.96, −59.99, −115.69, −144.18, −144.20; ESIMS m/z 333.21 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)[CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: CI
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCN(C)C(=O)OC(C)(C)C)ccc1F
Reaction time: 1 h

Procedure:
To a solution of [2-(4-fluoro-3-methoxyphenyl)ethyl]carbamic acid t-butyl ester (795 mg) in N,N-dimethylformamide (6 mL) was added 60% sodium hydride (154 mg) at room temperature. After stirring for 1 hour, methyl iodide (0.55 mL) was added dropwise and the solution was stirred for 14 hours. Water was added cautiously by small amounts, and after extraction with ethyl acetate, the solution was washed with water and saturated sodium chloride water. The residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (506 mg) was obtained as a colorless oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30](C(OCC5C=CC=CC=5)=O)[CH2:29][CH2:28]4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCC3CCN(C(=O)OCc4ccccc4)CC3)C2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCC3CCNCC3)C2)CC1
Reaction time: 60 h
Yield: 32.5 %

Procedure:
To benzyl 4-(2-{(3R)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperidin-1-yl}ethyl)piperidine-1-carboxylate (805 mg) was added 4M HCl in dioxane (5 ml). After removal of the solvent, 1-methyl-2-pyrrolidinone (5 ml) and zinc bromide (20 mg) were added, the mixture purged with Argon, 10% Pd/C (100 mg) added and stirred under hydrogen for 60 hours. Catalyst was filtered off through Celite, fresh catalyst and zinc bromide added and stirring continued for a further 48 hours under hydrogen. After filtration, the mixture was purified on a SCX2.50 g column, eluting sequentially with isohexane, ethyl acetate, 50% ethyl acetate/MeOH, MeOH and finally with 10% ammonia in MeOH to give the title compound (205 mg, 34%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([NH:1][CH2:2][CH2:3][CH:4]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(CCN)C(c2ccc(Cl)c(Cl)c2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(2-aminoethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (125 mg) in THF (2.5 mL) were added triethylamine (0.134 mL) and acetyl chloride (0.046 ml), and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (121 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][N:11]([S:26]([CH3:25])(=[O:28])=[O:27])[C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)C=Cc1cc(Br)ccc1CN2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)N1Cc2ccc(Br)cc2C=Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A solution of 9-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (30 mg, 0.09 mmol) (prepared in a manner analogous to that described for Example 1F) in dichloroethane was treated with pyridine (0.02 mL, 0.27 mmol) and methanesulfonyl chloride (0.009 mL, 0.12 mmol). The reaction mixture was stirred at room temperature for two hours then concentrated, diluted with MeOH and filtered. The crude product was purified by preparative reversed-phase HPLC to afford Example 330A (16 mg). HPLC Rt=3.66 min. m/z=398 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.C([O-])(O)=O.[Na+].CO.[Br:19]Br>O>[Br:19][C:7]1[C:2]([Cl:1])=[N:3][C:4]([O:10][CH3:11])=[N:5][C:6]=1[O:8][CH3:9]
Reactant: BrBr
Reactant: COc1cc(Cl)nc(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(Cl)c(Br)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
In a 250 mL round bottom flask, 4-chloro-2,6-dimethoxy-pyrimidine (3.25 g, 18.65 mmol) and NaHCO3 (3.6 g, 42.9 mmol) was charged with MeOH and water (1:1 ratio, 160 mL). Bromine (1.44 mL, 27.97 mmol) was added to the mixture dropwise (in 1 hour). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated down. Ethyl acetate was added, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) to give white solid (4.06 g, 86%). LC-MS shows 255.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 4.07 (s, 3H), 3.98 (s, 3H); 13C NMR (300 MHz, CDCl3): δ 168.27; 162.79; 160.38; 97.08; 55.78; 55.70.
Reaction SMILES: [C:1]([C:5](=[CH:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19](F)[CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=O)[CH2:2][CH3:3].S(O)(O)(=O)=O.[CH3:31][O:32][C:33](=[NH:35])[NH2:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[F:23][C:21]1[CH:22]=[C:17]([CH:16]2[NH:35][C:33]([O:32][CH3:31])=[N:34][C:1]([CH2:2][CH3:3])=[C:5]2[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH:18]=[CH:19][C:20]=1[F:24]
Reactant: COC(=N)N
Reactant: CCC(=O)C(=Cc1cc(F)c(F)c(F)c1)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Temperature: 70 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
A suspension of benzyl 2-propionyl-3-(3,4,5-trifluorophenyl)-2-propenoate (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol), NaHCO3 (16.3 g, 130.2 mmol) in DMF (190 mL) was stirred at 70° C. for 20h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4×100 mL), brine (200 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (SiO2, EtOAc/Hexane, 10%-30%) to afford benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate as a colorless oil (10.6 g, 58% yield). The product was directly used in the next step after 1H NMR spectroscopy which showed it to be a mixture of amine/imine tautomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: C1CNCCN1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine (Aldrich) to give the title compound. LC-MS: 581.2 [(M+H)+]
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:14][NH:15][CH2:16][CH2:17][OH:18]>C(O)(C)C.CCOCC>[CH3:14][N:15]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17][OH:18]
Reactant: CNCCO
Reactant: CCCCCCCCCCCCI
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCCCCCCCCCCN(C)CCO
Yield: 97.5 %

Procedure:
A solution of iodododecane (18.1 g, 61.09 mmol) and 2-(methylamino)ethanol (23.0 g, 0.3 mol) in isopropanol (75 ml) was heated under reflux for 3 h. The cooled mixture was diluted with ether (500 ml), washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure and distillation of the residue under vacuum gave 14.5 g (97%) of N-methyl-N-dodecylethanolamine as a clear oil: b.p. 100-111° C./0.3 torr (bulb to bulb distillation, air bath temperature).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5](I)[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH: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)=[O:19])=[CH:13][CH:12]=1.[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH:33]=[CH2:34])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH: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)=[O:19])=[CH:13][CH:12]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
In 2 mL of dimethylformamide, 158 mg (0.28 mmol) of 1-[4-(6-amino-8-iodopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea was dissolved, and 262 mg (0.82 mmol) of vinyltributyltin and 20 mg (0.01 mmol) of tetrakistriphenylphosphine palladium was added thereto and the mixture solution was stirred at 95° C. for three hours. The reaction solution was concentrated and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 122 mg (93%) of a target product as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9](OC(C)(C)C)=O)[CH2:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:9][N:6]1[CH2:7][CH2:8][CH:3]([CH:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH2:1])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(C(N)c2ccccc2)CC1
Yield: 63.3 %

Procedure:
Intermediate XXXI, e.g. tert-butyl 4-[amino(phenyl)methyl]piperidine-1-carboxylate (1.0 g, 3.44 mmol) was dissolved in dry THF (50 mL). LiAlH4 (261 mg, 6.89 mmol) was added in portions. The reaction was heated under reflux overnight. As the reaction was completed, it was quenched with dropwise addition of water (5 mL), followed by NaOH 1N (5 mL) and H2O (5 mL). The suspension thus obtained was extracted with ethyl acetate, dried over MgSO4 and evaporated, affording the crude product. It was further purified by flash chromatography (DCM/MeOH 20:1 with 2% NH4OH) to give the tertiary amine XXXII, e.g., 1-(1-methylpiperidin-4-yl)-1-phenylmethanamine (444.6 mg, 63% yield).
Reaction SMILES: C[C:2]12[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:6](=[O:12])[O:5][C:3]2=[O:4].[CH3:13]C1CCC2C(OC(=O)C2C1)=O>[Ni]>[CH3:13][CH:11]1[CH2:10][CH2:9][CH2:8][CH:7]2[C:6]([O:5][C:3](=[O:4])[CH:2]12)=[O:12]
Reactant: CC12CCCCC1C(=O)OC2=O
Reactant: CC1CCC2C(=O)OC(=O)C2C1
Agent: [Ni]
Product: CC1CCCC2C(=O)OC(=O)C12

Procedure:
The aforesaid methylhexahydrophthalic anhydride which was liquid at ordinary temperatures was a mixture of 70% by weight of 4-methylhexahydrophthalic anhydride which was liquid at ordinary temperatures and was obtained by hydrogenating 4-methyl-Δ4 -tetrahydrophthalic anhydride at 150° C. in the presence of Raney nickel catalyst and 30% by weight of 3-methylhexahydrophthalic anhydride which was liquid at ordinary temperatures and was obtained by hydrogenating 3-methyl-Δ4 -tetrahydrophthalic anhydride in the same manner as described above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[S:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:22][C:21]1[CH:20]=[C:19]([O:23][CH:35]2[CH2:36][CH2:37][S:32][CH2:33][CH2:34]2)[CH:18]=[C:17]([CH3:24])[C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=2)[CH:11]=1
Reactant: OC1CCSCC1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OC4CCSCC4)cc3C)c2)cc1F
Yield: 85.9 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (0.50 g, 1.18 mmol), tetrahydro-2H-thiopyran-4-ol (0.15 g, 1.30 mmol) and triphenylphosphine (0.31 g, 1.30 mmol) in tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (40% toluene solution, 0.70 mL, 1.53 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 19 hrs., and an equivalent amount of the aforementioned reagents (tetrahydro-2H-thiopyran-4-ol, triphenylphosphine and diethyl azodicarboxylate) were added. The mixture was further stirred at the same temperature for 6 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give the title compound (0.53 g, yield 91%) as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=[O:28])([CH3:25])([CH3:24])[CH3:23].O>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[C:18]([CH:11]1[C:10](=[O:21])[C@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
Triethylamine (3 mL, 21.5 mmol) was added dropwise to a cooled (0° C.) solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 1.50 g, 7.0 mmol) in dichloromethane (18 mL), yielding a thick suspension. This was stirred for 3 min and then N′-(2-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 29; 1.20 g, 5.3 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and stir for 2.5 h. The mixture was added to water (50 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine (30 mL), dried (magnesium sulfate), filtered, evaporated, and dried under high vacuum at room temperature for 30 min to give N′-(2-fluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (2.67 g, 124% of the expected amount) as an orange foam. This was used directly in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Br.Br.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C=O>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:17][CH2:16]1
Reactant: c1ccc2sc(NCC3CCNCC3)nc2c1
Reactant: BrCC1COc2ccccc2O1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCC(CN1CCC(CNc3nc4ccccc4s3)CC1)O2
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 3.8 parts of 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin, 6.3 parts of N-(4-piperidinylmethyl)-2-benzothiazolamine dihydrobromide, 10 parts of sodium carbonate, 0.1 parts of sodium iodide and 68 parts of N,N-dimethylformamide was stirred for 48 hours at 70° C. The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The oily residue was crystallized from acetonitrile, yielding 2.8 parts of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-2-benzothiazolamine; mp. 139.9° C. (compound 1).