Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[C:49]1([CH:55]([CH3:59])[C:56]([OH:58])=O)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:56](=[O:58])[CH:55]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH3:59])[CH2:47][CH2:48]1)[CH2:4][CH2:3]2
Reactant: CC(C(=O)O)c1ccccc1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(C)c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (4.1 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using 2-phenylpropionic acid as the acylating agent. LCMS: m/e 774.9 (M+H)+, 3.87 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=7.0 Hz, 2H), 7.41-7.31 (m, 2H), 7.29-7.22 (m, 3H), 7.18 (dd, J=8.2, 3.1 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.77 (s, 1H), 4.67 (s, 1H), 4.11 (quin, J=6.4 Hz, 1H), 3.89-3.44 (m, 4H), 2.99-2.92 (m, 1H), 2.86-2.67 (m, 3H), 2.67-2.57 (m, 1H), 2.51 (d, J=13.7 Hz, 2H), 2.46-2.27 (m, 2H), 2.21-2.09 (m, 2H), 2.07-1.85 (m, 4H), 1.80-1.15 (m, 16H), 1.74 (s, 3H), 1.40 (d, J=6.7 Hz, 3H), 1.09 (d, J=8.5 Hz, 3H), 1.07 (d, J=13 Hz, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[C:31](OCC)(=[O:34])[NH:32][NH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.[H-].[Na+]>C(O)CCC>[CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[N:6]3[C:31](=[O:34])[NH:32][N:33]=[C:7]3[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)C=C(c1ccc(-n3c(C)nc4cnccc43)cc1)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,3-dihydro-7,8-dimethyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (411 mg, 1.0 mmol), ethyl carbazate (210 mg, 2 mmol) and p-toluenesulphonic acid (10 mg) in n-butanol (5 ml) was stirred overnight at reflux. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (etuting with dichloromethane/methanol=9:1). The intermediate carbazate was then dissolved in dry tetrahydrofuran (5 ml) and cyclised by the addition of sodium hydride (60% dispersion in oil, 40 mg, 1 mmol) and stirring for 3 hours at room temperature. The mixture was partitioned between 2N hydrochloric acid (5 ml) and ethyl acetate (20 ml). The aqueous phase was neutralised with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate:tetrahydrofuran=1:1 (2×30 ml). The extracts were combined, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with dichloromethane:methanol=10:1). The product was further purified by recrystallisation from methanol/dichloromethane to give a white solid, (85 mg, 20%), m.p.>325° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[N:26]1([CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3([C:48]([OH:50])=O)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C)C=O>[N:51]1([C:48]([C:42]2([C:39]3[CH:40]=[CH:41][C:36]([O:35][CH2:34][CH2:33][CH2:32][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[CH:37][CH:38]=3)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:50])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CCOCC1)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.5 mmol) was added to a solution of 4-[4-(3-Morpholin-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid hydrochloride (160 mg, 0.4 mmol), morpholine (54 μL, 0.6 mmol) and Hunig's base (180 μL, 1 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between 2M NaOH solution (20 mL) and DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume) to provide the title compound (182 mg, 100%) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 1.93-2.04 (m, 4H), 2.20 (m, 2H), 2.42-2.55 (m, 6H), 3.22-3.43 (br m, 8H), 3.72 (t, 4H), 3.79 (m, 2H), 3.90 (m, 2H), 4.00 (t, 2H), 6.88 (d, 2H), 7.17 (d, 2H). LRMS APCI+ m/z 419 [MH]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[CH:2]=[CH2:3].C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36]>ClCCl>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]([NH:12][S:37]([C:32]2[CH:33]=[CH:34][C:35]([F:36])=[C:30]([F:29])[CH:31]=2)(=[O:39])=[O:38])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(C)N)ccc1-c1cc(F)ccc1OC
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1cc(C(C)NS(=O)(=O)c2ccc(F)c(F)c2)ccc1-c1cc(F)ccc1OC
Reaction time: 8 h

Procedure:
A mixture of 3′-allyl-4′-hydroxyacetophenone (0.352 g, 2.0 mmol), N-phenyl-bis(trifluoromethane) sulfonimide) (0.710 g, 2.0 mmol) and potassium carbonate (0.830 g, 6.0 mmol) in tetrahydrofuran (3.0 ml) was heated in a microwave oven at 120° C. for 10 min. The resultant mixture was treated with 5-fluoro-2-methoxyphenyl boronic acid (0.680 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.060 g, 0.05 mmol) and dimethylformamide (1.0 ml) and heated in a microwave oven at 120° C. for 10 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 9:1 heptane/ethyl acetate. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone. A solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone (0.319 g, 1.1 mmol), sodium cyanoborohydride (0.140 g, 2.2 mmol) and ammomium acetate (1.7 g, 22 mmol) was stirred under nitrogen at ambient temperature for 72 h, evaporated to dryness under reduced pressure and partitioned between dichloromethane and brine. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. To a solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (19.0 mg, 0.07 mmol) in dichloromethane (1 ml) was added triethylamine (6.7 mg, 0.07 mmol) and 3,4-di-fluorophenyl sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight and the solvent evaporated. The residue was purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound. 1H NMR (400 MHz, CDCl3): δ 7.52-7.42 (m, 2H), 7.13 (q, 1H), 7.04-6.90 (m, 4H), 6.88-6.83 (m, 1H), 6.77 (q, 1H), 5.67 (dt, 1H), 4.99-4.82 (m, 3H), 4.57 (dq, 1H), 3.71 (s, 3H), 3.09 (br s, 2H), 1.51 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:22][CH:23]4[CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NC1Cc2ccccc2C1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](CNC1Cc2ccccc2C1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-aminoindan in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=419.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:25][O:26]C(C)(C)C)[CH2:10][C:11]1([OH:24])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C>[CH2:1]([O:8][CH:9]([CH2:25][OH:26])[CH2:10][C:11]1([OH:24])[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OCC(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)OCc1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(O)(CC(CO)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
2.36 g of tert-butyl 4-[2-(benzyloxy)-3-(tert-butoxy)propyl]-4-hydroxy-1-piperidinecarboxylate was dissolved in 40 ml acetonitrile, 426 mg of cerium ammonium nitrate was added thereto, and the mixture was stirred at room temperature overnight. Silica gel was added to the reaction solution, and then it was evaporated. It was purified by adsorptive silica gel charged in a non-adsorptive silica gel column with hexane-ethyl acetate to give 547 mg of tert-butyl 4-[2-(benzyloxy)-3-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:7]=[CH:8][CH2:9][CH:10]=1)[C:4]([OH:6])=[O:5]>C1C2C(CCCC2)CCC1.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC1=CCC=CC1C(=O)O
Agent: *O[SiH2]*
Solvent: C1CCC2CCCCC2C1
Solvent: CCCCCC
Product: Cc1ccccc1C(=O)O
Yield: 95.5 %

Procedure:
To a suspension of 2-methyl-l,4-dihydrobenzoic acid (0.085 g, 0.50 mmol; 81% pure, from Aldrich Chemical Company) in decalin (5 mL) under a nitrogen atmosphere was added the polysiloxane matrix material containing a homogeneous dispersion of metal particles (0.100 g as prepared according to Example 1). The solution was heated to reflux for 19 hours. On cooling the reaction mixture was diluted with hexane (25 mL) and extracted with aqueous sodium hydroxide (5%) solution (2×5 mL). The basic aqueous solution was acidified and extracted with chloroform (3×4 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of solvent on rotary evaporator gave 2-methylbenzoic acid (0.065 g. 96%). IR(KBr) 3600-2000 (br), 2923, 1694, 1300, 920,731 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.03 (ddd, J=8.5, 3.0, 1.5 Hz, 1 H), 7.42 (td, J=8.5, 1.5 Hz, 1H), 7.26 (td, J=8.5, 1.5 Hz, 1 H), 7.22 (dd, J=8.5, 1.5 Hz, 1 H), 2.64 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[CH2:16][Cl:15])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4-bromoaniline (1.72 g, 10 mmol) was dissolved in 50 mL dichloromethane. Pyridine (cat.) was added and then 2-chloroacetyl chloride (800 uL, 10 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hr. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to give the intermediate 7a (1.03 g, 4 mmol, 42% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.24 (broad s, 1H), 7.54-7.44 (m, 4H), 4.21 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:10]/[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C(C)=O)cc1
Product: COc1ccc(C(=O)/C=C/N(C)C)cc1
Yield: 88 %

Procedure:
The title compound was prepared in 88% yield from 1-(4-methoxyphenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.88-3.06 (6H, br s), 3.85 (3H, s), 5.71 (1H, d, J=12.0 Hz), 6.91 (2H, d, J=8.8 Hz), 7.84 (1H, d, J=12.0 Hz), 7.91 (2H, d, J=8.8 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH:3]=O.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].N1CCCCC1>C(O)(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:5])[CH:3]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(C)C=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=CC(C)C)C(=O)OCC
Yield: 90.4 %

Procedure:
A mixture of 69.80 g of 2-methylpropanal, 77.30 g of diethyl malonate, 2.06 g of benzoic acid, 2.47 cm3 of piperidine and 100 cm3 of toluene is stirred at reflux for 15 hours. After cooling, 100 cm3 of toluene are added. The solution is washed in succession twice with 100 cm3 of distilled water, twice with 100 cm3 of 1M hydrochloric acid and 100 cm3 of saturated aqueous sodium carbonate solution. The organic phase is dried over anhydrous sodium sulphate and concentrated. The residue obtained is distilled under reduced pressure (117° C./10 torr) to obtain 93.44 g of the expected product in the form of a colourless oil.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([N:23]1[CH2:22][CH2:21][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])[CH2:25][CH2:24]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccccc2Cl)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(2-chlorophenyl)piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: O=C(O)CC1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (77 mg, 68%), MS (ISP) m/z=453.4 [(M+H)+], mp 181° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[C:3]1=[O:16].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][C:32]2([F:38])[F:37])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][N:34]([CH:2]3[CH2:6][CH2:5][N:4]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=4)[C:3]3=[O:16])[CH2:33][C:32]2([F:38])[F:37])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Reactant: FC1(F)CNCCC1c1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(CN2CCC(N3CCC(c4ccc(OCc5ccccc5)cc4)C(F)(F)C3)C2=O)cc1F
Temperature: 120 °C

Procedure:
To a mixture of 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (0.51 g, 1.8 mmol, Intermediate 6) and 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (0.3 g, 1 mmol, from step C) was added triethylamine (0.69 mL, 4.9 mmol) and the resulting mixture was heated in a sealed tube at 120° C. for 1 h. The reaction mixture was allowed to cool and then diluted with water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue (0.45 grams, 64%, mixture of 4 diastereoisomers) was used directly in the next step without further purification, LCMS (method P) RT 1.19 min, m/z 509 (M+H+).
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O.C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1O
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Piperidine (0.25 mL, 2.5 mmol) was added to a suspension of 3-hydroxy-4-methoxybenzaldehyde (0.39 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.50 g, 2.2 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 3 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5.0 mL) and water (2.0 mL) at 40° C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(3-hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.53 g, 76%) as a yellow crystalline solid; mp 215-216° C., lit.5 219-222° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 6.59 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6=8.5 Hz, 1H, H5′), 7.10-7.13 (m, 2H, H2′, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.47 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.99 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([N+:33]([O-:35])=[O:34])[CH:25]=3)(=[O:30])=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and 4-chloro-3-nitro-benzenesulphonic acid chloride analogously to Example 2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([N:14]([CH3:15])[C:12]2[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]3[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:18][CH2:17]1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2)C1CC1

Procedure:
The title compound was prepared from [2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-(cyclopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M70) (215 mg, 0.42 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (87 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[F:13][C:14]([F:30])([F:29])[CH:15]([NH2:28])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:28][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:17]=1)[C:14]([F:13])([F:30])[F:29])=[O:8]
Reactant: NC(c1cccc(N2CCOCC2)c1)C(F)(F)F
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1F)NC(c1cccc(N2CCOCC2)c1)C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 2-fluorocinnamic acid (33 mg), 2,2,2-trifluoro-1-(3-morpholin-4-yl-phenyl)-ethylamine, Preparation 23 (52 mg), DMAP (24 mg), EDC.HCl (80 mg), and Et3N (80 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 65 mg of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH:8]=C)[CH2:2][CH2:3][CH3:4].[O:15]=[O+][O-]>CO>[CH2:1]([O:5][CH:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH:8]=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=[O+][O-]
Reactant: C=CCC(OCCCC)OCCCC
Solvent: CO
Product: CCCCOC(CC=O)OCCCC
Temperature: 35 °C

Procedure:
300 g of 4,4-di-n-butoxybutene are dissolved in 1 liter of methanol and are reacted with ozone, and subsequently hydrogenated, analogously to the procedure indicated in Example 8. The hydrogenation is carried out in such a way that the content of peroxides in the hydrogenation solution does not exceed 0.02 mole/liter, and a pH value between 4 and 5 and a temperature of 35° C. are maintained. The consumption of hydrogen is 32.4 standard liters, corresponding to 96% of theory.