Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[C:16](=[O:17])[NH:15][N:14]=[C:13]2[N:4]1[C:5]1[CH:6]=[C:7]3[N:20]([C:21]4([CH3:25])[CH2:24][NH:23][CH2:22]4)[CH:19]=[CH:18][C:8]3=[CH:9][C:10]=1[O:11][CH2:12]2.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([N:23]1[CH2:22][C:21]([N:20]2[C:7]3[C:8](=[CH:9][C:10]4[O:11][CH2:12][C:13]5[N:4]([C:5]=4[CH:6]=3)[C@H:3]([CH3:2])[C:16](=[O:17])[NH:15][N:14]=5)[CH:18]=[CH:19]2)([CH3:25])[CH2:24]1)(=[O:28])[CH3:27]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc4ccn(C5(C)CNC5)c4cc3N21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CC(C)(n2ccc3cc4c(cc32)N2C(=NNC(=O)[C@H]2C)CO4)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a mixture of (R)-1-methyl-10-(3-methyl-azetidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one hydrochloric acid (Example #148, 0.4 g, 1.2 mmol) in DCM (15 mL) was added acetyl chloride (0.42 g, 5.35 mmol) and TEA (0.37 g, 3.69 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (Table 3, Method 29) to give (R)-10-(1-acetyl-3-methyl-azetidin-3-yl)-1-methyl-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one (0.146 g, 11%) as a pale yellow solid. 1H NMR (400 MHz, methanol-d4): δ 7.27 (s, 1H), 7.21 (s, 1H), 6.87 (d, J=10.8 Hz, 1H), 6.45 (s, 1H), 5.04 (m, 1H), 4.90 (m, 1H), 4.61 (m, 4H), 4.34 (m, 1H), 2.04 (m, 3H), 1.79 (m, 3H), 1.44 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.836 min.; MS m/z: 368 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([S:28]([CH3:31])(=[O:30])=[O:29])[C:5]1[C:6]([CH:25]2[CH2:27][CH2:26]2)=[CH:7][C:8]2[C:12]([CH:13]=1)=[N:11][N:10]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[C:9]=2[C:21]([NH:23][CH3:24])=[O:22].[NH:32]1[C:36]([CH2:37][C:38](O)=[O:39])=[N:35][N:34]=[N:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([N:10]2[C:9]([C:21]([NH:23][CH3:24])=[O:22])=[C:8]3[C:12]([CH:13]=[C:5]([N:4]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:3][CH2:2][NH:1][C:38](=[O:39])[CH2:37][C:36]4[N:32]=[N:33][NH:34][N:35]=4)[C:6]([CH:25]4[CH2:26][CH2:27]4)=[CH:7]3)=[N:11]2)=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCN)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCNC(=O)Cc3nn[nH]n3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.2 %

Procedure:
To a mixture of Compound (7) (34 mg, 67 μmol) and tetrazole acetic acid (10 mg, 81 μmol) in DMF (3 mL) at 0° C. was added HATU (31 mg, 81 μmol) and DIPEA (18 μL, 0.1 mmol). The mixture was stirred at RT for 40 min. Ethyl acetate (5 mL) was added and the mixture was washed with 1M hydrochloric acid and saturated sodium bicarbonate. The combined aqueous phase was neutralised to pH 7 (by addition of 6M hydrochloric acid) and lyophilised. The crude material was then purified by reverse phase flash column chromatography eluting with ACN/water (5-100%) to give Compound (8) (17 mg, 41%). ESI-MS m/z calculated for [M+H]+: 616.11/618.11; found: 615.96/617.96. 1H NMR (400 MHz, d4-MeOH) δ 9.42 (s, 1H), 9.27 (d, J=8.7 Hz, 2H), 9.10 (d, J=8.7 Hz, 2H), 8.87 (s, 1H), 5.55-5.37 (m, 2H), 5.37-5.14 (m, 2H), 5.01 (t, J=6.5 Hz, 2H), 4.70 (s, 3H), 4.52 (s, 3H), 3.95-3.73 (m, 1H), 2.69-2.41 (m, 3H), 2.27-2.10 (m, 1H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH3:13]O>>[Cl-:1].[C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH3+:2])=[CH:12][CH:11]=1)([O:10][CH3:13])=[O:9]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: Cl
Reactant: CO
Product: COC(=O)c1ccc(C[NH3+])cc1
Product: [Cl-]
Yield: 62 %

Procedure:
Gaseous hydrochloric acid was hubled for 5 minutes through a suspension of 4-(aminomethyl)benzoic acid (20 mmol) in 100 mL of methanol, upon which it dissolved. After heating at reflux for 10 minutes a precipitate was formed which was filtered off and washed with diethyl ether to yield 2.5 g (12.4 mmols, 62%) of 4-carbomethoxy-benzylammonium chloride. A solution of 1.5 g of this compound in 10 mL ethanolamine was heated at 37° C. overnight. After removal of the solvent by vacuum destillation, the residue was dissolved in 300 mL water and treated with 50 g of Dowex H+ (SO3H). The resin was washed several times with water and 50% aq. methanol. Treatment of the resin with 5% aq. ammonia and yielded 1.0 g (5.15 mmol, 69%) of amine 7 as a yellow solid, m.p. 140°-143° C. A sample (approx. 100 mg) was further purified by preparative reverse-phase HPLC to give the pure trifluoroacetate salt as a colorless solid after lyophilyzation, the latter was used as cofactor.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[CH2:31]([O:33][C:34](=[O:68])[C@@H:35]([O:65][CH2:66][CH3:67])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44]/[CH:45]=[C:46](/[C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][C:57](/[C:60](/[CH3:64])=[CH:61]/[CH2:62]O)=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)\[CH3:47])=[CH:39][CH:38]=1)[CH3:32]>C1COCC1.O.C(OCC)(=O)C>[CH2:21]([O:20][C:18](=[O:19])[C@@H:17]([O:16][CH2:14][CH3:15])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:62]/[CH:61]=[C:60](/[C:57]2[CH:56]=[CH:55][C:54]([C:51]3[CH:52]=[CH:53][C:48](/[C:46](/[CH3:47])=[CH:45]/[CH2:44][O:43][C:40]4[CH:39]=[CH:38][C:37]([CH2:36][C@H:35]([O:65][CH2:66][CH3:67])[C:34]([O:33][CH2:31][CH3:32])=[O:68])=[CH:42][CH:41]=4)=[CH:49][CH:50]=3)=[CH:59][CH:58]=2)\[CH3:64])=[CH:28][CH:29]=1)[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/CO)cc3)cc2)cc1)OCC
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/COc4ccc(C[C@H](OCC)C(=O)OCC)cc4)cc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (0.50 g, 1.89 mmol) was added at 0–5° C. to a stirred solution of tributylphosphine (0.37 mL, 1.89 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.32 g, 1.32 mmol) and (E)(E)(S) 2-ethoxy-3-(4-{3-[4′-{3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionic acid ethyl ester (0.65 g, 1.26 mmol) in dry THF (15 ml). The mixture was warmed to room temperature, and stirred for 18 h. The resulting mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 580 mg (63%) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][C@@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:60]([C@H:9]1[CH2:10][CH2:11][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13])[CH2:8]1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a 0° C. solution of (+)-(1R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (745 mg, 3.44 mmol) (from Example 29b supra) and triphenyl phosphine (1.17 g, 4.47 mmol) (Aldrich) in anhydrous tetrahydrofuran (60 mL) was added dropwise diethyl azodicarboxylate (710 μL, 780 mg, 4.47 mmol) (Aldrich). After 2 to 3 minutes followed a dropwise addition of diphenylphosphoryl azide (950 μL, 1.23 g, 4.47 mmol) (Aldrich). The mixture was allowed to warm up slowly to room temperature stirred overnight and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered, concentrated and the resulting residue was chromatographed on a silica gel column with a 0–20% diethyl ether in hexanes gradient to give (+)-(1S,3S)-(3-azido-cyclopentyloxy)-tert-butyl-dimethyl-silane as a colorless liquid. (Yield 589 mg, 70%).
Reaction SMILES: [Si](O[C@H](CO[Si](C(C)(C)C)(C)C)C[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20]Br)=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:22]#[N:23])(C(C)(C)C)(C)C.[NH:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]2[C:41]3[CH:48]=[C:47]([CH2:49][C:50]([F:53])([F:52])[F:51])[S:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:52][C:50]([F:51])([F:53])[CH2:49][C:47]1[S:46][C:42]2[N:43]=[CH:44][N:45]=[C:40]([NH:39][CH:36]3[CH2:35][CH2:34][N:33]([CH2:20][C:16]4[CH:15]=[C:14]5[C:19](=[CH:18][CH:17]=4)[NH:11][C:12]([C:22]#[N:23])=[CH:13]5)[CH2:38][CH2:37]3)[C:41]=2[CH:48]=1
Reactant: FC(F)(F)Cc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Cn1c(C#N)cc2cc(CBr)ccc21)O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2[nH]1
Yield: 33.8 %

Procedure:
58 mg of (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-(bromomethyl)-1H-indole-2-carbonitrile (0.1 mmol) and 31 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.12 mmol) were dissolved in 0.2 mL of DCM. 26 mg of DIPEA (0.2 mmol) was added to that solution and reaction mixture was stirred for 18 hs. Then reaction mixture was directly loaded on silica gel column and the product was eluted with DCM-MeOH 30:1. After evaporation of solvent TBDMS-protected intermediate was dissolved in 0.2 mL of MeOH and 0.02 mL of 12M HCl was added. The homogenous reaction mixture was stirred overnight and then all volatiles were removed in vacuo. The residue was quenched ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and concentrated. The residue was purified on silica gel column using DCM-MeOH 20:1 to afford 15.9 mg of 5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 188). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. Monohydrochloride salt exists as a mixture of rotomers in approximate ratio 10:1, NMR is described for the major one: 1H NMR (600 MHz, MeOD-d4): 8.63 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.77 (d, 1H, J=8.6 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.37 (s, 1H), 4.57 (m, 1H), 4.56 (m, 1H), 4.50 (s, 2H) 4.37 (m, 1H), 4.04 (m, 1H), 3.99 (q, 2H, J=10.3 Hz), 3.65 (m, 2H), 3.60 (d, 2H, J=5.5 Hz), 3.29 (m, 2H), 2.37 (m, 2H), 2.12 (m, 2H). 13C NMR (150 MHz, MeOD-d4): δC 157.45, 150.99, 139.90, 132.27, 129.16127.89, 127.37, 127.00, 125.54, 123.11, 122.50, 118.58, 114.32, 114.25, 113.35, 113.31, 72.35, 64.85, 61.99, 52.44, 49.82, 48.12, 35.32 (q, J=33 Hz), 29.64. ESI MS [MH+]: 545.1941.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][C:37]([NH:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[F:29])=[O:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1ccccc1F
Product: O=C(Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1F

Procedure:
The title compound was prepared from 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-fluorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 513.9.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH:10]=1)([O-])=O.[CH2:27]([C:29]([CH3:31])=O)[CH3:28]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:28][CH:27]([NH:3][C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH:10]=1)[CH2:29][CH3:31]
Reactant: CCC(C)=O
Reactant: O=[N+]([O-])c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(C)Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Reaction time: 2 h

Procedure:
0.9 g (24 mmol) of sodium borohydride is added to a suspension, cooled to 0° C., of 2.8 g (12 mmol) of nickel dichloride hexahydrate in a solution of 2 g (6 mmol) of 4-nitro-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example 7, and 10 ml of methyl ethyl ketone in 50 ml of ethanol. This temperature is maintained for 30 minutes and allowed to rise to room temperature, stirring is continued for 2 hours, the mixture is evaporated under vacuum, the residue is taken up with ethyl acetate and 1.22 g of 4-(2-butyl))amino-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained in liquid form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CCCC)CCCC)CCC.[C:39](OCC)(=[O:41])C>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>[Cl:1][C:2]1[CH:7]=[C:6]([C:39](=[O:41])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: CCOC(C)=O
Reactant: Nc1ccccc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: C[C@@](O)(C(=O)Nc1ccc(C(=O)Nc2ccccc2)cc1Cl)C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (0.35 g), aniline (0.117 ml), tributylamine (0.232 ml) and dichlorobis-(triphenylphosphine)palladium(II) (0.009 g) was heated at 100° C. under an atmosphere of carbon monoxide for 4 hours. Ethyl acetate (10 ml) was added and the mixture was washed with water and brine then was dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 5-50% ethyl acetate/hexane followed by passing through a Varian Isolute SCX column to give the title compound (0.17 g) as a solid. NMR: 1.6 (s, 3H), 7.1 (t, 1H), 7.35 (t, 2H), 7.75 (d, 2H), 7.92 (s, 1H), 7.98 (dd, 1H), 8.12 (s, 1H), 8.2 (d, 1H), 9.8 (s, 1H), 10.26 (brs, 1H); MS (ESP−): 386.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]([O:14][C:15](=[O:17])[CH3:16])([C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]>O.O1CCOCC1>[CH:13]([C:8]1[C:7]([C:5]([O:14][C:15](=[O:17])[CH3:16])([CH3:4])[CH3:6])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:2]
Reactant: O=[Se]=O
Reactant: CC(=O)OC(C)(C)c1cccnc1C
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OC(C)(C)c1cccnc1C=O
Temperature: 100 °C
Reaction time: 60 h
Yield: 46.2 %

Procedure:
Selenium dioxide (1.44 g, 13.0 mmol) was added to a solution of acetic acid 1-methyl-1-(2-methyl-pyridin-3-yl)-ethyl ester (1.25 g, 6.48 mmol) dissolved in a mixture of water (2.5 mL) and 1,4-dioxane (25 mL). The resulting mixture was stirred at 100° C. for 60 hours. The solvent was removed under reduced pressure and the brown oil was quenched with saturated NaHCO3 (30 mL) and extracted with CH2Cl2 (5×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a brown oil. Purification via column chromatography on silica gel (hexanes:EtOAc, 1:1, v/v) afforded acetic acid 1-(2-formyl-pyridin-3-yl)-1-methyl-ethyl ester as a yellow oil (0.62 g, 46%). 1H NMR (CDCl3) δ 1.91 (s, 6H), 2.03 (s, 3H), 7.48 (dd, 1H, J=9.0, 6.0 Hz), 7.83 (dd, 1H, J=9.0, 3.0 Hz), 8.69 (dd, 1H, J=6.0, 3.0 Hz), 10.49 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][C:6](=[O:9])[CH:5]1[CH2:4][CH2:3][CH2:2]2.C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20]([CH2:22][CH2:23][CH2:24][CH:25]=O)=[O:21].C(O)(=O)C>C(OCC)C.O>[CH3:18][O:19][C:20]([CH2:22][CH2:23][CH2:24]/[CH:25]=[C:7]1/[C:6](=[O:9])[CH:5]2[CH:1]([CH2:8]/1)[CH2:2][CH2:3][CH2:4]2)=[O:21]
Reactant: O=C1CCC2CCCC12
Reactant: COC(=O)CCCC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of (E)-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]bicyclo[3,3,0]-octan-6-one (0.22 g; prepared as described in Reference Example 33 and predominantly in the 2β-configuration) in dry diethyl ether (3 ml) at -78° C. in an atmosphere of argon was treated with a solution of lithium diisopropylamide in diethyl ether (0.5 ml; 1.38M). The solution was stirred for 10 minutes at -78° C. and then treated with 4-methoxycarbonylbutanal (112 mg) at -78° C. After stirring for 10 minutes at -78° C. the reaction mixture was treated with a solution of glacial acetic acid (200 mg) in diethyl ether (400 mg) and the resulting white suspension was allowed to warm to room temperature. The mixture was then diluted with diethyl ether (20 ml) and poured into water (10 ml). The organic phase was separated and washed with aqueous sodium bicarbonate solution (5 ml; 10% w/v) and then with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The resulting oil (0.4 g) was dissolved in benzene (0.2 ml) at 20° C. and treated with methanesulphonyl chloride (83 mg). The stirred mixture was then treated dropwise with triethylamine (0.095 ml) and stirred for a further period of 40 minutes in an argon atmosphere. The mixture was then treated with 1,8-diazabicyclo[ 5,4,0]undec-7-ene (0.51 g) and it was stirred for a further period of 2 hours. The mixture was then treated with diethyl ether (20 ml). glacial acetic acid (2 ml) and water (20 ml). The organic phase was separated and the aqueous layer was extracted with diethyl ether (2×10 ml). The combined organic solutions were washed with saturated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulphate. Concentration in vacuo, followed by chromatography on a silica gel column, using a mixture of ethyl acetate and hexane (1:9 v/v) as eluant, gave 6-[(E)-(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (54 g), predominantly in the 6β-configuration, otherwise known as (±)-methyl (5E,13E)-(9S), [mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][CH2:21][C:22]([F:26])([F:25])[CH2:23][OH:24])=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][C:22]([F:26])([F:25])[CH2:23][OH:24])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCC(F)(F)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(F)(F)CO)c12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-{3-amino-2-[(2,2-difluoro-3-hydroxypropyl)amino]phenyl}-3-(2,4-dichlorophenyl)thiourea (65.0 mg, 0.154 mmol) in tetrahydrofuran (1.5 mL) were added triethylamine (23.4 μL, 0.169 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (29.6 mg, 0.154 mmol). The mixture was stirred at 50° C. for 3 hrs. After cooling, the mixture was diluted with water, extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (53.0 mg, 0.137 mmol, 89%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:21]1[O:23][CH2:22]1>>[OH:23][CH2:21][CH2:22][N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:1]
Reactant: C1CO1
Reactant: CCCCCCCCCCCCCCCCCCNC
Product: CCCCCCCCCCCCCCCCCCN(C)CCO
Temperature: 160 °C
Yield: 86.6 %

Procedure:
An autoclave provided with a stirrer, a thermometer, a pressure gauge and a pressure dropping funnel was charged with 250 g of N-methyloctadecylamine and heated to 160° C. Then 45 g of ethylene oxide was occasionally added dropwise thereto under a pressure of 0 to 6 kg/cm2G. Three hours were required for completing the addition. Next, the resulting mixture was aged, i.e., maintained, at 160° C. for 2 hours and then cooled. The reaction mixture was taken out and distilled to thereby give 250 g of N-(2-hydroxyethyl)-N-methyloctadecylamine. This product had a boiling point of 185° to 190° C./0.2 mmHg.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:28]1([CH2:33][C:34](Cl)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:33][C:34]([N:18]([CH:16]2[CH:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)CC1CCCC1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 88, the title compound 2-cyclopentyl-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using cyclopentylacetyl chloride instead of 4-fluorobenzoyl chloride and was obtained as a light yellow oil. MS m/e: 520.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C@:17]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30](O)=[O:31])[C:18]3=[O:36])[CH2:16]2)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C@:17]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30]([NH:7][C:5]4[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=4)=[O:31])[C:18]3=[O:36])[CH2:16]2)=[CH:11][CH:10]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Product: Cc1cc(NC(=O)c2cccc(CN3C(=O)[C@]4(C[C@@H]4c4ccc(Cl)cc4)c4ccccc43)c2)[nH]n1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 3-methyl-1 H-pyrazol-5-amine, (3-bromomethyl)-benzoate (commercially available), racemic (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C28H23ClN4O2: 482, observed (M+H)+: 483.21H NMR (400 MHz, MeOD-d4) δppm 2.23 (d, J=8.59 Hz, 2 H) 2.55 (s, 3 H) 3.26-3.32 (m, 1 H) 5.08-5.23 (m, 2 H) 5.85 (d, J=1.01 Hz, 1 H) 6.08 (d, J=7.07 Hz, 1 H) 6.73 (t, J=7.58 Hz, 1 H) 6.94 (d, J=7.83 Hz, 1 H) 7.07-7.14 (m, 1 H) 7.19 (d, J=8.08 Hz, 2 H) 7.30 (d, J=8.59 Hz, 2 H) 7.48 (t, J=7.71 Hz, 1 H) 7.58 (d, J=8.34 Hz, 1 H) 7.80 (d, J=7.83 Hz, 1 H) 7.85 (s, 1 H).