Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:25]([O:29][C:30]([N:32]([CH3:49])[C@H:33]([C:46](O)=[O:47])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[C:51]1([CH2:57][CH2:58][CH2:59][NH:60][C:61](=[O:68])[C@@H:62]([CH2:64][CH2:65][S:66][CH3:67])[NH2:63])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[C:25]([O:29][C:30]([N:32]([CH3:49])[C@H:33]([C:46]([NH:63][C@@H:62]([C:61]([NH:60][CH2:59][CH2:58][CH2:57][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:68])[CH2:64][CH2:65][S:66][CH3:67])=[O:47])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[CH:37][CH:36]=1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: CSCC[C@@H](N)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)N(C)C(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Temperature: -20 °C

Procedure:
Diisopropylethylamine (0.90 ml.), then diphenylphosphinyl chloride (1.23 g.), were added to a solution of N-(tert-butyloxycarbonyl)-O-(tert-butyl)-N-methyl-L-tyrosine (1.76 g.) in tetrahydrofuran (15 ml.) maintained at -20° C., and the mixture was stirred for ten minutes. A solution of N-(3-phenylpropyl)-D-methioninamide hydrochloride (1.58 g.) and diisopropylethylamine (0.90 ml.) in tetrahydrofuran (10 ml.) was then added. The mixture was stirred for one half hour at -20°, one hour at 0° C. and overnight at room temperature, then filtered and stripped of solvent. A solution of the residue in ethyl acetate (100 ml.) was washed with water, aqueous citric acid, water again, aqueous sodium bicarbonate and water again, dried and stripped of solvent. Purification of the residue by high pressure liquid chromatography on silica gel (350 g.) using hexane-ethyl acetate (2:1) as the eluant afforded in fractions 6-7 (k'=8-14) [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-N-methyl-L-tyrosyl]-N-(3-phenylpropyl)-D-methioninamide as a clear gum (2.1 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:16]([CH3:18])[CH3:17])[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[ClH:1].[CH2:19]([C:10]1([OH:15])[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[N:16]([CH3:18])[CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C(c1cccc(Cl)c1)C1CCCCC1=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C(c1cccc(Cl)c1)C1CCCCC1(O)Cc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.8 %

Procedure:
2.0 g (7.5 mmole) of the 2-[(3-chlorophenyl)dimethylaminomethyl]cyclohexanone prepared according to Example 42 were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 4.5 ml (9.0 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran) and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.61 g of crude base (97.0% of theory) were obtained, from which 1.24 g of 1-benzyl-2-[(3-chlorophenyl)dimethylaminomethyl]cyclohexanol hydrochloride (41.8% of theory) having a melting point of 161° C.-163° C. were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.CN(C(ON1N=[N:25][C:20]2C=C[CH:23]=[N:24][C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[O:35]=[C:36]1[NH:44][C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[C:37]21[CH2:52][C:51]1[C:46](=[CH:47][CH:48]=[C:49]([NH:53][C:54]3[N:59]=[CH:58][N:57]=[C:56]([C:60](O)=[O:61])[CH:55]=3)[CH:50]=1)[CH2:45]2>CN(C=O)C>[NH:24]1[C:19]2[CH2:9][CH2:7][N:3]([C:60]([C:56]3[N:57]=[CH:58][N:59]=[C:54]([NH:53][C:49]4[CH:50]=[C:51]5[C:46](=[CH:47][CH:48]=4)[CH2:45][C:37]4([C:38]6[C:39](=[N:40][CH:41]=[CH:42][CH:43]=6)[NH:44][C:36]4=[O:35])[CH2:52]5)[CH:55]=3)=[O:61])[CH2:4][CH2:6][C:20]=2[N:25]=[CH:23]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2nc[nH]c2CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.2 equivalents (12 μmol) of the amine derivative, 3.4 equivalents DIPEA (34 μmol) and 1.2 equivalents (12 μmol) HATU were added to 4.10 mg (10 μmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride in 0.32 mL DMF and the mixture was shaken overnight at 80° C. The reaction mixture was evaporated down in the vacuum centrifuge at 60° C. The following compounds were able to be synthesised analogously to this working method:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][CH2:28][C@@:29]1([OH:58])[C:34](=[O:35])[O:33][CH2:32][C:31]2[C:36]([N:38]3[C:50](=[CH:51][C:30]1=2)[C:49]1N=C2C(C(CC[Si](C)(C)C)=CC=C2)=C[C:40]=1[CH2:39]3)=[O:37]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:27][CH2:28][C@@:29]1([OH:58])[C:34](=[O:35])[O:33][CH2:32][C:31]2[C:36]([N:38]3[C:50](=[CH:51][C:30]1=2)[C:49]1[C:40](=[C:8]([CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:39]3)=[O:37]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CC[Si](C)(C)C)cccc3nc2-1
Reactant: C[Si](C)(C)CCC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
To a solution of 1-(2-amino-phenyl)-3-trimethylsilanyl-propan-1-one (3) (34 mg) and CDE ring moiety (4) (24 mg) in acetic acid (0.5 mL) and toluene (1 mL) was added p-toluenesulfonic acid (1 mg). The reaction solution was stirred for 20 hours at 100° C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and the residue was washed with hexane (10 mL), water (10 mL), and a mixture of acetone (5 mL) and hexane (5 mL). The yellow solid was evaporated to dryness in vacuo to yield 39 mg (98% Yield) of BNP1350 (Karenitecin; Cositecan; 7-(2′-trimethylsilyl)ethyl camptothecin; IUPAC Nomenclature: (4S)-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3′:4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])C.C(O)=O>O>[CH:27]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: c1ccccc1
Solvent: O
Solvent: O=CO
Product: O=CNNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
To a suspension of 2.88 parts of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide with 100 parts by volume of dry benzene is added about 1 part offormic acetic anhydride, prepared from 10.2 parts of acetic anhydride and 4.6 parts of formic acid. The reaction mixture is stirred until no evidence of starting material is detected, at which time 100 parts of water is added with vigorous stirring. Stirring is continued for about 1 hour, at the end of which time the mixture is filtered and the resulting product is dried to afford 1-formyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, melting at about 177°-181°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:5][C:6](=[O:8])[CH:7]=1.O.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:5][C:6](=[O:8])[C:7]=1[N:16]=[O:17]
Reactant: Nc1cc(=O)[nH]c(C2CCCCC2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(C2CCCCC2)[nH]c(=O)c1N=O
Temperature: 70 °C

Procedure:
A mixture of 4-amino-2-cyclohexylpyrimid-6-one (18 g.) and water (150 ml.) was stirred and heated to 70° C, and treated slowly with sodium nitrite (8 g.), followed by an excess of glacial acetic acid. The mixture was stirred for a further 1 hour and the blue solid (25 g.) filtered off and used directly for the next stage. A sample recrystallised from glacial acetic acid gave pure 4-amino-2-cyclohexyl-5-nitrosopyrimid-6-one, m.p. 233°-234° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5]([CH3:8])([CH3:7])[N:6]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:1][C:2]2[O:3][CH2:4][C:5]([CH3:8])([CH3:7])[N:6]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1=NC(C)(C)CO1
Product: CC1(C)COC(C=Cc2ccc(Cl)cc2)=N1

Procedure:
2-(2-p-Chlorophenylethenyl)-4,4-dimethyl-2-oxazoline (P-1581) was synthesized from 2,4,4-trimethyl-2-oxazoline and p-chlorobenzaldehyde.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][C:17](=[O:22])[C:18](OC)=[O:19])[CH2:10][C:9]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C1(C)C=CC=CC=1>[CH:1]1([O:7][N:8]2[C:13]([CH3:14])([CH3:15])[CH2:12][CH:11]([NH:16][C:17]([C:18]([NH:28][CH2:27][CH2:25][OH:26])=[O:19])=[O:22])[CH2:10][C:9]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: NCCO
Solvent: Cc1ccccc1
Product: CC1(C)CC(NC(=O)C(=O)NCCO)CC(C)(C)N1OC1CCCCC1
Yield: 63.9 %

Procedure:
A mixture of 9.1 grams (26.7 mmol) of methyl N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)oxamate, 1.8 grams (29.4 mmol) of ethanolamine and 35 ml of toluene is heated at reflux for 30 minutes. Methanol is removed from the reaction mixture by fractional distillation. The reaction mixture is poured into ethyl acetate (125 ml) to afford 6.3 grams (64% yield) of the title compound as a white solid melting at 190°-1920° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[C:11]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])=[O:13])=[C:5]2[N:4]=1.CN(C=O)C.O=S(Cl)[Cl:37]>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[C:10]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[C:11]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])=[O:13])=[C:5]2[N:4]=1
Reactant: COc1ccncc1NC(=O)c1c(NC(=O)C(F)(F)F)nn2ccc(CO)nc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccncc1NC(=O)c1c(NC(=O)C(F)(F)F)nn2ccc(CCl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude 5-(hydroxymethyl)-N-(4-methoxy-3-pyridyl)-2-[(2,2,2-trifluoroacetyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide prepared in step 2 above (50 mg, 0.1219 mmol) and DMF (44.55 mg, 47.19 μL, 0.6095 mmol) were suspended in dry DCM (1.25 mL). SOCl2 (72.51 mg, 44.46 μL, 0.6095 mmol) was added dropwise and the resulting mixture was stirred at RT for ˜2 h. The bright yellow suspension was filtered and the collected solid was washed with DCM (1 mL) and ether (3×1 mL) to give a light yellow powder (49.6 mg). LC-MS (M+H)+ 429.1; 1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.60 (s, 1H), 9.63 (s, 1H), 9.50 (d, J=7.1 Hz, 1H), 8.71 (d, J=6.4 Hz, 1H), 7.80 (d, J=6.6 Hz, 1H), 7.62 (d, J=7.1 Hz, 1H), 5.07 (s, 2H), 4.34 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([NH:31][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CNCCCSc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
In 150 ml of methylene chloride were dissolved 5.22 g (30.8 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.16 ml (37.0 mmol) of triethylamine, methanesulfonyl chloride [2.86 ml (37.0 mmol)] was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried. Then the solvent was distilled off. 2.62 ml (24.0 mmol) of benzylamine was added to the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 1.0 g of the desired compound (yield: 16.1% yellow oil)
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.[P:24](=[O:32])(Cl)([S:27][CH2:28][CH2:29][CH3:30])[O:25][CH3:26].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:24](=[O:32])([S:27][CH2:28][CH2:29][CH3:30])([O:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)[O:25][CH3:26]
Reactant: CCCSP(=O)(Cl)OC
Reactant: Oc1cc(Cl)c2nc3ccccc3cc2c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OC)Oc1cc(Cl)c2nc3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-4-chloroacridine (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-methyl S-propyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-methyl O-(4-chloroacridin-2-yl) S-propyl phosphorothioate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([Cl:16])[N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2cc(Br)c(Cl)cc2n1
Product: Clc1ncc2cc(Br)c(Cl)cc2n1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of 6-bromo-7-chloroquinazolin-2-ol (6.0 g, 23 mmol) in phosphorus oxychloride (50 mL) was refluxed for 5 hours. The reaction was cooled to room temperature, and most of phosphorus oxychloride was removed under reduced pressure. The residue was dropwise added to ice water (500 mL), and the resulting precipitate was collected by the filtration to give the title compound as a yellow solid (3 g, 48%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[F:23].C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.C(O)(=O)C>[CH2:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH:11]1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(F)C1
Reactant: O=Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzaldehyde (34.0 g, 0.321 mol) was added to a solution of tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate, 2.7 (70 g, 0.32 mol) and acetic acid (10 mL) in ethanol (500 mL) and stirred for 30 min at room temperature. Sodiumcyanoborohydride (26.23 g, 0.417 mol) was added and stirred for 3 h. Reaction was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (2×250 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a minimum amount of dichloromethane (200 mL) and pH adjusted to 3-4 by adding aqueous citric acid (124 g, 0.645 mol in 1000 mL water). Layers were separated and aqueous layer was washed with dichloromethane (3×250 mL). Separated aqueous layer pH was then adjusted to 9-10 by using saturated Na2CO3 and extract with diethyl ether (2×500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product which was purified by as light yellow oil. The residue was purified by silica gel chromatography by eluting with 10-15% EtOAc/hexane to provide the desired product tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.8 (51 g, 51.52% yield). 1HNMR (400 MHz, CDCl3): δ 7.39-7.29 (m, 5H), 4.44-4.35 (m, 0.5H), 4.32-4-10 (m, 1.5H), 3.98-3.85 (m, 2H), 3.80 (d, 1H), 2.97-2.77 (m, 4H), 2.04-1.93 (m, 1H), 1.46 (s, 9H); LCMS: 92.34%, m/z=309.2 (M+1); HPLC: 95.46%; Chiral HPLC: 47.2% at 9.56 min. and 48.3% at 12.34 min. Column. AG/Chiral Pak AD-H/03, n-Hexane/EtOH (80:20).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[CH2:13]([CH:16]([CH3:20])[CH:17](O)[OH:18])[CH2:14][CH3:15].C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]([F:11])([F:12])[C@H:3]1[CH2:4][CH2:5][C@H:6]([CH:9]2[O:18][CH2:17][CH:16]([CH2:13][CH2:14][CH3:15])[CH2:20][O:10]2)[CH2:7][CH2:8]1
Reactant: CCCC(C)C(O)O
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1COC([C@H]2CC[C@H](C(F)(F)F)CC2)OC1

Procedure:
A mixture of 0.02 mol of trans-4-trifluoromethyl-1-formylcyclohexane (prepared as in Example 3), 0.02 mol of 2-propylpropanediol, 30 ml of toluene and 0.5 g of pTsOH (sic) is heated for 4 hours on a water separator. The pure product is obtained after customary work-up and crystallization.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11].S(OC)(O[CH3:21])(=O)=O>[OH-].[K+]>[CH3:21][O:11][C:10]1[C:9]([CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[F:1]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(Oc2ccccc2F)c1O
Agent: [K+]
Agent: [OH-]
Product: COc1c(C)cccc1Oc1ccccc1F
Yield: 80.7 %

Procedure:
Aqueous solution (50 ml) of potassium hydroxide (10.4 g) was added portionwise to a mixture of 6-(2-fluorophenoxy)-o-cresol (13.5 g) and dimethyl sulfate (15.5 g) with stirring under ice-cooling, and the mixture was refluxed under heating for an hour. After cooling, the reaction mixture was extracted with n-hexane, and the extract was washed with 10% aqueous sodium hydroxide and water, dried and then evaporated. The residue was purified by column chromatography (silica gel, benzene.n-hexane) to give oily 2-fluorophenyl 2-methoxy-3-methylphenyl ether (11.6 g).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[S:13][C:12](C(N)=O)=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].C[N:26](C)C=O>>[CH3:21][N:20]([CH3:22])[CH:19]=[N:26][C:12]1[S:13][C:9]([CH2:8][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1ccc(CN2CCCCCC2)s1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ccc(CN2CCCCCC2)s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3.72 g (15.65 mmol) of 5-[(hexahydro-1H-azepin-1-yl)methyl]thiophene-2-carboxamide was dissolved in 30 ml of N,N-dimethylformamide, 3.4 ml (25.6 mmol) of N,N-dimethylformamide dimethylacetal was added, and the mixture was stirred at 80° C. for 4 hours. The reaction solution was concentrated under a reduced pressure, and the resulting residue was dissolved in chloroform, washed with water and then dried over anhydrous magnesium sulfate. By evaporating the solvent, 3.82 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5].[BH4-].[Na+].[CH:33](OCC)(OCC)OCC>C(O)C.ClCCl>[Br:30][C:27]1[CH:28]=[CH:29][C:2]([NH:1][CH3:33])=[C:3]([CH:26]=1)[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CNc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-{N-(2-amino-5-bromobenzoyl)glycyl}aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1042) (50 mg, 0.10 mmol) in triethyl orthoformate (6.5 mL) was stirred at 150° C. for 17 h. Concentration afforded a yellow solid. To a solution of the yellow solid in ethanol (3 mL) was added sodium borohydride (7.6 mg, 0.2 mmol) and the mixture was stirred at room temperature for 14 h. A resulting white precipitate was resolved in di-chloromethane and the solution was washed with 1 N aqueous NaOH (2 mL). The organic layer was separated, dried over K2CO3, filtered and evaporated. Column chromatography (SiO2, 20% MeOH/CHCl3) gave 4-[N-{5-bromo-2-(methylamino)benzoyl}glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compound No. 1427) (40 mg, 80%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 505 (C23H28BrClF6N4O2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[CH:17](=O)[CH2:18][CH:19]([CH3:21])[CH3:20]>C([O-])(O)=O.[Na+]>[CH2:17]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CC=O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: CC(C)CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 1-(4-nitrophenyl)piperazine (5.00 g, 24.1 mmol, 1.0 eq), sodium triaectoxyborohydride (10.23 g, 48.3 mmol, 2 eq), and isovaleraldehyde (4.16 g, 5.18 mL, 48.3 mmol) is stirred at RT for 48 h. The reaction mixture is transferred to a separatory funnel and the solution washed with 10% aqueous NaCl solution (2×50 mL) (gas evolution). A yellow precipitate formed in the separatory funnel DCM (50 mL) was added followed by a saturated aqueous solution of NaHCO3 (50 mL) and the precipitate dissolved. The phases are separated and DCM phase is again washed with saturated aqueous solution of NaHCO3 (50 mL). The combined aqueous NaHCO3 extracts are extracted with DCM (2×50 mL), the combined DCM extracts are dried over MgSO4, filtered through a filtration tube, and the solvent is evaporated to provide a viscous oil that partially solidified on standing. The residue is triturated with hexanes (25 mL) and resulting slurry stirred at room temperature for 48 h. The precipitate which forms is collected by filtration, washed with hexanes (2×25 mL), dried briefly on the frit, and then dried under vacuum for 48 h to provide 1-isopentyl-4-(4-nitrophenyl)piperazine as a yellow solid (5.15 g, 77% recovery, 92% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product was used in the next step without further purification. LCMS-ESI (m/z): calcd for C15H23N3O2, 277; [M+H]+ found, 278.