Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl.[N:42]1([CH2:48][C:49](O)=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:49](=[O:50])[CH2:48][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:19][CH2:18]2
Reactant: O=C(O)CN1CCCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)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
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCCCC3)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 was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-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 described for the parallel synthesis of C-17 amides above, using piperidin-1-ylacetic acid hydrochloride as the reacting carboxylic acid. LCMS: m/e 655.7 (M+H)+, 4.68 min (method 3).
Reaction SMILES: COC1C=CC(C[S:8][C:9]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[SH:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1SCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(F)(F)F)ccc1S

Procedure:
A solution of methyl 2-(p-methoxybenzylthio)-5-trifluoromethylbenzoate (1.0 g, 2.8 mmol) and anisole (335 μl) in trifluoroacetic acid (10 ml) was stirred at reflux temperature for 20 minutes under a nitrogen atmosphere. The mixture was evaporated under diminished pressure and co-evaporated several times with toluene. The mercaptan was used without further purification in the subsequent step below. NMR (CDCl3, 60 MHz): δ3.88 (s, CO2CH3) p.p.m.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.N1C(C)=CC=CC=1C.[CH:34]([S:37](Cl)(=[O:39])=[O:38])([CH3:36])[CH3:35]>C(Cl)Cl>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:37]([CH:34]([CH3:36])[CH3:35])(=[O:39])=[O:38])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (216 mg, 0.61 mmol) and 2,6-lutidine (180 μl, 1.50 mmol) in DCM (3 ml) was treated with isopropanesulphonylchloride (100 μl, 0.90 mmol) and stirred at room temperature for 18 hours. Reaction was complete but it was left for 12 days before purification commenced. The reaction mixture was diluted with DCM and washed with 1M HCl (2×20 ml), sat. NaHCO3 solution and brine. The organic extract was dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of pentane:EtOAc (90:10) gradually changing to (50:50) to afford the title compound as a colourless oil (157 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH:13]([CH3:15])[CH3:14])[C:11](=[O:16])[O:10]C2=O)=[CH:4][CH:3]=1.O(C1N=C(CO)C=CC=1)C1C=CC=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:12]([C:11]([OH:16])=[O:10])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2C(=O)OC(=O)C2C(C)C)cc1
Agent: OCc1cccc(Oc2ccccc2)n1
Product: Cc1ccc(N[C@H](C(=O)O)C(C)C)cc1

Procedure:
Following the above procedure, 3-(4-methylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with (6-phenoxy-2-pyridyl)methanol to give the (6-phenoxy-2-pyridyl)methyl ester of N-(4-methylphenyl)valine.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:9]2[C@@H:11]([CH:12]([CH3:14])[CH3:13])[C@H:10]2[C:15]([O:17][CH3:18])=[O:16])=[O:8])=[CH:3][CH:2]=1.C(OCC)(=[O:22])C.CCCCC>>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([N:9]2[C@@H:11]([CH:12]([CH3:14])[CH3:13])[C@H:10]2[C:15]([O:17][CH3:18])=[O:16])(=[O:22])=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@@H]1[C@H](C(C)C)N1S(=O)c1ccc(C)cc1
Solvent: CCCCC
Product: COC(=O)[C@@H]1[C@H](C(C)C)N1S(=O)(=O)c1ccc(C)cc1
Yield: 95 %

Procedure:
Following the procedure of Example 11A, but replacing the (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-phenylaziridine with (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-isopropylaziridine (prepared according to Example 4), and performing the flash chromatography with ethyl acetate:n-pentane (2:8) as the eluent afforded the titled compound (0.565 g, 95%): mp 52°-4° C.; [α]D20 -34.3° (c 1.2, CHCl3); IR (KBr): 2963.9, 1755.8, 1597.5, 1209.6 1102.1, 1091.4 cm-1 ; 1H NMR (CDCl3) δ0.84 (d, J=6.6 Hz 3H), 0.89 (d, J=6.8 Hz, 3H), 1.57-1.68 (m 1H), 2.45 (s, 3H), 2.68 (dd, J=7.6 Hz, 9.9 Hz, 1H), 3.45 (d, J=7.44 Hz, 1H),3.74 (s, 3H), 7.35 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H); 13C NMR (CDCl3) δ145.0, 134.0, 129.7, 128.3, 52.6, 50.8, 41.1, 26.7, 21.6, 20.5, 18.9. Anal. Calcd for C14H19 NO4S: C, 56.55; H, 6.44. Found: C, 56.36; H, 6.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1)[CH:6]=O.[Br-].[O:17]1CCO[CH:18]1[CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:22]/[CH:18]=[O:17])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: COc1cc(C=O)ccc1-n1cccn1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: COc1cc(/C=C/C=O)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A mixture of 3-methoxy-4-(1H-pyrazol-1-yl)benzaldehyde (1.52 g, 7.52 mmol, prepared as described in Reference Example 5), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (4.85 g, 11.30 mmol), and TDA-1 (2.40 mL, 7.50 mmol) in dichloromethane (35 mL) and sat. aq. K2CO3 (35 mL) was heated to reflux for 18 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (20 mL) and 10% HCl (20 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 2:1 hexane/ethyl acetate) provided 1.47 g (86%) of the title compound as a yellow solid. MS 229 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:12])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C(=O)NCc2ccccc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 0.98 mmol) and 1,1'-carbonyldiimidazole (206 mg, 1.27 mmol) in 5 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and benzylamine (0.64 mL, 5.88 mmol) is added and stirring is continued at room temperature overnight. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:2) provides 5-chloro-3-(1-methylethoxy)-N-(phenylmethyl)-2-benzofurancarboxamide in 79% yield; mp=80°-82° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:21])[NH:19][NH2:20])[CH3:16]>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:20][NH:19][C:18]([O:17][CH2:15][CH3:16])=[O:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1ccncc1
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Product: CCOC(=O)NN=C(c1ccccc1)c1ccncc1
Temperature: 100 °C
Yield: 42.8 %

Procedure:
A mixture of 9.16 gm (0.05 mole) of phenyl 4-pyridyl ketone, 5.21 gm (0.05 mole) of ethylcarbazate and 75 ml of glacial acetic acid is heated at 100° C. for 8 hr. The acetic acid is removed in vacuo. The residue is slurried with ethyl ether and collected to yield 5.76 gm (39%) of the title compound having a melting point of 188.7° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:10]([C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1)#[CH:11]>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][C:4]([N:1]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:3]=[N:2]2)=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=Nc1ccncc1
Reactant: C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccncc3)nn2)CC1
Yield: 13.5 %

Procedure:
4-Azidopyridine (140 mg) prepared in the above 1) and 207 mg of tert-butyl 4-ethynyl-1,2,3,6-tetrahydropyridine-1-carboxylate were dissolved in 3 ml of toluene and the solution was heated to reflux for 20 hours. The reaction solution was returned to room temperature and the solvent was evaporated in vacuo. The resulting residue was separated and produced by a silica gel chromatography (chloroform/methanol=100/1) to give 44 mg of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[OH-].[Li+].Cl.C(OCC)(=O)C>C1COCC1.CO.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:13]2[C:12]([CH2:11][O:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:26])[N:7]=3)=[C:16]([CH2:17][OH:18])[O:15][N:14]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (250 mg, 0.69 mmol) in THF (1.17 mL), methanol (391 μL) and water (1.17 mL) was added lithium hydroxide (33.8 mg, 1.4 mmol). The reaction mixture was stirred for 2 h at room temperature. Addition of aqueous hydrochloride solution (1 N, 25 mL) and extraction with ethyl acetate yielded the title compound (220 mg, 92%) as a light brown solid. MS: m/e=346.0 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[Cl:50][C:51]1[CH:60]=[CH:59][C:54]2[N:55]=[C:56]([SH:58])[NH:57][C:53]=2[CH:52]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:50][C:51]1[CH:60]=[CH:59][C:54]2[NH:55][C:56]([S:58][C:2]3[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([Cl:26])[CH:17]=4)([CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH2:6][C:7]=3[OH:8])=[N:57][C:53]=2[CH:52]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-benzimidazole-2-thiol was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 1.34 (d, J=6.1 Hz, 6H), 1.41-1.82 (m, 10H), 2.07-2.14 (m, 1H), 2.55-2.88 (m, 4H), 3.4 (brs, 1H), 4.44-4.48 (m, 1H), 6.81-6.91 (m, 2H), 7.13-7.39 (m, 4H), 12.0 (brs, 1H); ESIMS (MH+) (C28H30Cl2N2O4S): 562.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH:13]C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 18a (3.26 g, 11.37 mmol) in 10 mL of DCM, was added TFA (5 mL, 64.9 mmol). The mixture was stirred at room temperature for 2 h and the solvent were evaporated. The residue was dissolved in DCM and a saturated solution of NaHCO3 and 1N NaOH were added until pH was 8. The layers were separated and the aqueous layer was extracted with 3:1 DCM:IPA (3×40 mL). The organic extracts were combined, dried, filtered and evaporated to afford 1.89 g (89%) of 18b.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:24]3[C:19](=[C:20]([O:25][CH3:26])[N:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[CH:17]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH:1]1([CH2:4][N:5]([CH3:31])[C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:24]3[C:19](=[C:20]([O:25][CH3:26])[N:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[CH:17]=2)[CH2:3][CH2:2]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CC3)cn(C)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N(C)CC3CC3)cn(C)c12
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of the product from Example 44B (0.116 g, 0.301 mmol) in dimethylformamide (2 mL) under nitrogen was treated with sodium hydride (0.018 g, 0.451 mmol) at ambient temperature, stirred for 30 minutes, treated with iodomethane (0.038 mL, 0.602 mmol), stirred for 30 minutes at ambient temperature and quenched into cold water. The mixture was extracted into ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.12 g, 100%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.C(OC(=O)C)=O.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:28][CH2:27]2)=[CH:21][CH:20]=1>C(Cl)Cl>[N:33]1[CH:34]=[CH:35][CH:36]=[N:37][C:32]=1[N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][NH:17][CH:5]=[O:7])=[CH:20][CH:21]=2)[CH2:27][CH2:28]1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Agent: CC(=O)OC=O
Solvent: O=CO
Solvent: ClCCl
Product: O=CNCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A mixture of acetic anhydride (0.30 ml) and formic acid (0.13 ml) was stirred at 50-60° C. for 1 hr. To the obtained acetic formic anhydride was added a solution of 2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidin (0.42 g) in methylene chloride (10 ml) under ice-cooling and the mixture was stirred at 5-10° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give a yellow oil. (0.46 g). The obtained yellow oil was crystallized from ethyl acetate/diisopropyl ether to give the title compound (0.45 g) as pale-yellow crystals, m.p.=97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:26])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:11]2=3)=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:26])=[CH:9]/[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:11]2=3)=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(Cl)cc2)CCN(C)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The title compound was prepared by following general procedure 6. 2-(4-Chlorophenyl)-1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propan-2-ol (100 mg, 0.261 mmol) was taken into 2.0 mL of 25% H2SO4 in water, and stirred at 90° C. for 2 h. The reaction was monitored by LCMS. The reaction mixture was cooled and basified with aq. KOH solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified using reverse phase chromatography to afford 10 mg of product as the TFA salt along with 6-(2-(4-chlorophenyl)allyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[C:22]([O:21][C:19](=[O:20])[N:17]([CH3:18])[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCNCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-(tert-butoxycarbonyl-methyl-amino)-piperidine-1-carboxylic acid benzyl ester (17.5 mmol) and Pd—C (10%, 500 mg) in MeOH (150 mL) hydrogenated at atm. pressure and r.t. for 15 h. The mixture is filtered and evaporated. The residue is dissolved in CH2Cl2 (100 mL) and 1 M aq. NaOH (50 mL) is added. The mixture is stirred for 6 h at r.t., then the phases are separated and the aq. phase is extracted with CH2Cl2 (3×50 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:19])[C:13]([C:15]([O:17]C)=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20].Cl.C(O)(=O)C>O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20]
Reactant: COC(=O)c1cn2c3c(c(F)ccc3c1=O)CCN2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Yield: 81.7 %

Procedure:
To 40 mg (0.14 mmol) of the compound (190) obtained in Example 63, 0.3 ml of concentrated hydrochloric acid and 1.2 ml of acetic acid were added, and the solution was heated at reflux for 3 hours. After air-cooling, 5 ml of water was added to the solution, and deposited crystals were filtered off and washed with water, ethanol and ether in this order to obtain 30 mg of the subject compound (191) in a 79% yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:11]1([NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:29]3[CH2:30][CH2:31][CH:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:27][CH2:28]3)[N:3]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:5]=2)[CH2:13][CH2:12]1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NC2CC2)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, the 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with the 4-(4-fluoro-phenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at 90° C. to yield 4-cyclopropylamino-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=397.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Cl:13])[C:5]=1[CH:6]=[O:7].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C)C=O>[Cl:3][C:4]1[CH:11]=[C:10]([O:12][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:9]=[C:8]([Cl:13])[C:5]=1[CH:6]=[O:7]
Reactant: COCCOCCl
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCOc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
82 mg (3.4 mmol) sodium hydride was added to an ice cooled solution of 500 mg (2.6 mmol) A1 and 342 mg (2.7 mmol) methoxyethoxymethylchloride in 5 ml dry dimethylformamide and the mixture was stirred at 60° C. for 8 hours. The solvent was distilled off and the residue was partitionated between aqueous ammonia and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness yielding 370 mg (51%) A23, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Hg](C#N)C#N.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@@H:22]1Br)(=[O:19])[CH3:18]>>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:22]1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: FC(F)(F)c1ccccc1S
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2C(F)(F)F)SC[C@H]1OC(C)=O
Yield: 34 %

Procedure:
If the procedure described in Preparation I is followed starting from 1.8 g (10.10-3 mol) of 2-trifluoromethylbenzenethiol, 2.55 g (10.10-3 mol) of mercuric cyanide (Hg(CN)2) and 3.95 g (11.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.53 g (yield: 34%) of the expected product are obtained.