Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[CH:18]([NH2:20])=[S:19]>C1COCC1.C(OCC)(=O)C>[S:19]1[CH:2]=[C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[N:20]=[CH:18]1
Reactant: NC=S
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cscn2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
The title compound from Step B above (500 mg, 1.63 mmol) was combined with thioformamide (100 mg, 1.63 mmol) in 5 mL of THF, warmed to 60° C., and stirred overnight. The mixture was cooled to RT and diluted with ethyl acetate. The solution was then washed with water followed by brine. The organics were dried over magnesium sulfate, filtered and concentrated under vacuum. Purification via preparative TLC plates (3×1000 μM) eluting with 60% ethyl acetate/hexane afforded the title compound (282 mg, 63%) as a clear oil. ESI-MS calculated for C13H20N2O2S: Exact Mass: 268.12. Found: 169.12 (M-Boc)+ and 291.14 (MNa)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[Cl:13][CH2:14][Si:15](Cl)([CH3:17])[CH3:16]>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[C:10]([Si:15]([CH2:14][Cl:13])([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2]
Reactant: CCNC(=O)c1ccccc1Cl
Reactant: C[Si](C)(Cl)CCl
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CCl

Procedure:
The title compound was prepared from the compound of Example f and 2.0 eq (chloromethyl)dimethylsilyl chloride according to General Method C. Recrystallization from ethyl acetate gave 3.0 g of the desired compound as a white solid, a 52% yield. m.p. 88°-89° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]1=[O:18].[Br:19]N1C(=O)CCC1=O>C(Cl)Cl>[Br:19][C:10]1[CH:11]=[CH:12][C:6]2[NH:5][CH:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3](=[O:18])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC1Nc2ccccc2CN(C)C1=O
Solvent: ClCCl
Product: COC(=O)CC1Nc2ccc(Br)cc2CN(C)C1=O
Temperature: 28 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (100 g, 0.4 mole) and n-Bu4 N Br (13 g, 0.04 mole) were added to CH2Cl2 (1.0 liter) and refluxed for 0.5 hr. The reaction mixture was cooled to 28° C. and N-Bromosuccinimide added in small portions (72.8 g, 0.41 mole). The reaction was stirred at ambient temperature for 1.0 hr then washed with 5% NaHCO3 solution (400 ml) then water (2×400 ml) CH2Cl2 (800 ml) was replaced with hexane (800 ml) via ‘put and take’ distillation, the resulting slurry was cooled, filtered and washed with hexane. The product was dried in vacuo to yield the title compound (123 g, 93%). HPLC analysis showed 0.7% residual starting material and 0.7% 7,9-dibromide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:12][C:3]=12.[NH2:20][CH2:21][C:22]1[C:23]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:24][CH:25]=[CH:26][CH:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[C:8]([C:7]1[C:2]([NH:20][CH2:21][C:22]2[C:23]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:3]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][C:4]2=[N:5][CH:6]=1)#[N:9]
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Reactant: N#Cc1cnc2[nH]c(-c3ccc(F)cc3)cc2c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1CNc1c(C#N)cnc2[nH]c(-c3ccc(F)cc3)cc12)S(C)(=O)=O
Temperature: 170 °C

Procedure:
4-Chloro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (30 mg, 0.11 mmol), N-(3-aminomethylpyridin-2-yl)-N-methylmethanesulfonamide (159 mg, 0.552 mmol) and N-ethyldiisopropylamine (0.282 ml, 1.656 mmol) are suspended in 0.4 ml of 1-methyl-2-pyrrolidone and heated in a microwave at 170° C. for 40 min. The reaction is still not complete even after a further 40 min, so that a further equivalent of N-(3-aminomethylpyridin-2-yl)-N-methylmethanesulfonamide (31.8 mg, 0.110 mmol) is added, and the batch is heated at 170° C. for a further 60 min. For work-up, the batch is partitioned between water and ethyl acetate, the organic phase is dried (Na2SO4) and evaporated, giving a brown oil, which is purified by chromatography; yield: 17 mg (34%); LC-MS: 451 [M+H]+; HPLC: 3.07 (RT/min).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:48][N:49]([CH3:55])[CH2:50][CH2:51][CH2:52][NH:53][CH3:54]>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([N:53]([CH3:54])[CH2:52][CH2:51][CH2:50][N:49]([CH3:55])[CH3:48])=[N:7][CH:6]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Reactant: CNCCCN(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N(C)CCCN(C)C)nc3)cn2)cc1
Yield: 72.2 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.307 mmol) obtained in Step A in Example 1-D-48 and N,N,N′-trimethyl-1,3-propanediamine (67 μl, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Step B in Example 1-D-48, amination was carried out, to obtain a crude product of N-[5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-N,N′,N′-trimethyl-propan-1,3-diamine as a pale yellow solid (162 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-116) as a colorless powder (67 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=1[F:34])(=[O:27])=[O:26]
Reactant: CC(C)CN
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Product: CC(C)CNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.28 mmol) and isobutylamine (0.15 g, 2.01 mmol), the title compound was obtained as a yellow solid (0.078 g, 45.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 8.01 (d, J=5.1 Hz, 1H), 7.62-7.71 (m, 1H), 7.49-7.53 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.29-7.39 (m, 2H), 7.21 (t, J=9.1 Hz, 2H), 5.65 (d, 1H), 3.03 (br. s., 2H), 1.84 (dt, J=13.4, 6.7 Hz, 1H), 1.40 (s, 9H), 0.88 (d, J=6.6 Hz, 6H). MS (ESI) 592.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([OH:16])[CH:5]=1.[CH2:18]([O:25][CH2:26][CH2:27][CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:28][CH2:27][CH2:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=1
Reactant: OCCCOCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCCOCc2ccccc2)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzoic acid methyl ester (D37) (300 mg, 1.28 mmol, 1 equiv), 3-benzyloxypropan-1-ol (0.28 ml, 1.79 mmol, 1.4 equiv) and triphenyl phosphine (470 mg, 1.79 mmol, 1.4 equiv) in THF (10 ml) at room temperature was treated dropwise with DEAD (0.282 ml, 1.79 mmol, 1.4 equiv). The mixture was stirred for 16 h at room temperature then concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/iso-hexane: 1/4 to 1/1) gave 3-(3-benzyloxy-propoxy)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D38).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ccccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ccccc2c1Cl

Procedure:
Prepared according to Procedure E using 2,4-dichloro-3-methylquinoline (1.038 g, 4.9 mmol), 2-(tributylstannyl)pyridine (2.0 g, 5.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol) in toluene (10.00 mL) to afford product as an off-white solid upon purification by precipitation from EtOAc and chromatography on silica gel, eluting with EtOAc gradient in hexane. Mass Spectrum (ESI) m/e=255.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][OH:13].CC(C)([O-])C.[K+]>C1COCC1>[CH3:16][O:15][C:11](=[O:14])[CH2:12][O:13][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc([N+](=O)[O-])cn1
Yield: 17.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol) and methyl glycolate (0.67 mL, 8.2 mmol) in THF (10 mL) was added potassium tert-butoxide (0.92 g, 8.2 mmol) in one portion. After 1 h the reaction was poured onto ice, the solids isolated by filtration and washed with water. Purification on silica gel by column chromatography using 20% ethyl acetate in hexanes gave 0.23 g (18%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.02 (m, 1H), 7.15 (m, 1H), 5.06 (s, 2H), 3.65 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cccnc1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccnc3)cccc2c1N
Yield: 76.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (200 mg, 0.647 mmol) and pyridin-3-ylboronic acid (160 mg, 1.301 mmol) were reacted to afford the title compound (153 mg, 74% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.89 (m, 1H), 8.68 (m, 1H), 8.54 (br, 1H), 8.13 (m, 1H), 7.93 (m, 1H), 7.85-7.73 (m, 2H), 7.44 (m, 1H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=308 (M+H) HPLC 1.46 min.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.95 g, 5.34 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.213 g, 5.34 mmol) dissolved in water (2.000 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.327 mL, 5.34 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to yield a slightly yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using two injections with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.09 g, 61%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.80-2.17 (m, 4H), 2.72-2.87 (m, 2H), 2.91-3.02 (m, 1H), 3.12-3.24 (m, 1H), 3.52 (s, 3H), 3.95-4.05 (m, 1H), 4.29-4.40 (m, 1H), 5.72 (s, 1H), 6.94-7.12 (m, 3H), 7.12-7.20 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]Cl)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(c1ccccc1)N1CCC(CCCl)CC1
Product: O=C(c1ccccc1)N1CCC(CCN2CCCCC2)CC1

Procedure:
A mixture of 1-benzoyl-4-(2-chloroethyl)piperidine (5.86 g), piperidine (11.52 ml) and IMS (100 ml) was boiled under reflux for 10 hours. The mixture was evaporated to near dryness and then dried by azeotropic distillation with toluene. The residue was dissolved in dichloromethane, washed with 2M sodium hydroxide solution and then brine. The separated organic layer was extracted with 2M hydrochloric acid and the combined acidic layers were basified with 2M sodium hydroxide solution and then extracted with dichloromethane to give 1-benzoyl-4-(2-piperidinoethyl)piperidine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:25]=1)[C:7](=[O:24])[CH:8]=[C:9]([CH:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12])[N:10]=2.[Br:26]Br.O>C(O)(=O)C>[Br:26][C:8]1[C:7](=[O:24])[N:6]2[CH:25]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: BrBr
Reactant: CC(NC(=O)OCc1ccccc1)c1cc(=O)n2cc(F)ccc2n1
Solvent: CC(=O)O
Solvent: O
Product: CC(NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
E1 (385 mg, 1.13 mmol) was dissolved in 14 mL of acetic acid. Bromine (58 μL, 1.13 mmol) was added dropwise. The reaction was stirred for 30 min at room temperature. Water (40 mL) was added into the reaction, and the reaction was stirred for another 30 min generating a white precipitate that was filtered, washed with water and dried to yield E2 (312 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CCN(C(C)C)C(C)C>C(#N)C>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([N:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: CNc1ccc(F)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N(C)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
4-Fluoro-N-methylaniline (0.33 g, 2.67 mmol) is added to a solution of ethyl 2-bromo-2-phenylacetate (0.36 mL, 2.06 mmol) in acetonitrile (6.86 mL) and DIPEA (0.47 ml, 2.67 mmol). The dark solution is stirred at 100° C. under microwave irradiation for 1 hour. Then solvent is evaporated and the crude is purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain intermediate I118 as a yellow solid (0.59 g, 100% yield).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][C:19]2[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:23]=2[CH3:24])[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:2]>C(O)(=O)C.O>[CH2:1]([C:3]1([CH2:18][C:19]2[N:20]=[CH:21][NH:22][C:23]=2[CH3:24])[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:2]
Reactant: CCC1(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CCc2c(C)c3ccccc3n2C1=O
Solvent: CC(=O)O
Solvent: O
Product: CCC1(Cc2nc[nH]c2C)CCc2c(C)c3ccccc3n2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 7-ethyl-8,9-dihydro-10-methyl-7-[(5 -methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one (0.45 g) in acetic acid (10 ml) and water (2.5 ml) was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was diluted with ether (10 ml) and an aqueous solution of sodium hydrogencarbonate (10 ml). The resultant mixture was stirred for 30 minutes at ambient temperature. The insoluble material was collected, washed with water and ether, and dried to give crystalline 7-ethyl-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]-pyrido[1,2-a]indol-6(7H)-one (0.20 g).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:12]=3[N:11]=[C:10]([CH3:28])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:12]=3[N:11]=[C:10]([CH3:28])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)nccc3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)nccc3c21
Yield: 59.2 %

Procedure:
An activated manganese dioxide (108 mg, 1.25 mmol) was added to a solution of 1-(1-ethylpropyl)-6-mesityl-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c][1,7]naphthyridine (93 mg, 0.25 mmol) in toluene (9.0 mL) and methylene chloride (3.0 mL) and the mixture was heated under reflux for three days. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (55 mg) as pale brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:15][CH2:14][N:13]([CH3:16])[C:12]2=[O:17])[CH:7]=[C:6]([O:18]CC2C=CC=CC=2)[CH:5]=1>C1COCC1.CO.[Pd]>[OH:18][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH:11]2[CH2:15][CH2:14][N:13]([CH3:16])[C:12]2=[O:17])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:26]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCN(C)C2=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(O)cc(OC2CCN(C)C2=O)c1
Reaction time: 16 h
Yield: 71.8 %

Procedure:
Methyl-3-(benzyloxy)-5-[(1-methyl-2-oxopyrrolidin-3-yl)oxy]benzoate (6.1 g) (Intermediate 6) was dissolved in THF: Methanol mixture (1:1), and 10% Pd/C (0.6 g) was added to this mixture. The reaction mixture was stirred under hydrogen atmosphere for 16 h. After 16 h, TLC showed absence of starting material and formation of polar spot when checked in 10% methanol: chloroform, the reaction mixture was filtered through celite on Buckner funnel. The filtrate was concentrated under vacuum to get the solid product (3.27 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 1.89-1.92 (m, 1 H), 2.51-2.54 (m, 1 H), 2.77 (s, 3 H), 3.34-3.37 (m, 2 H), 3.80 (s, 3 H), 4.96 (t, J=7.2 Hz, 1 H), 6.66 (t, J=2 Hz, 1 H), 6.97 (t, J=1.6 Hz, 1 H), 7.01 (t, J=1.2 Hz, 1 H), 9.88 (s, 1H); ESI MS m/z (relative intensities): 266.2 (M+H)+ (100%); UPLC Purity: 99.00%, Ret. time: 2.67 min.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH3:12])[CH2:6]1)(=[O:4])=[O:3].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C@H:8]1[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C@H:7]1[CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1CN(S(C)(=O)=O)CCC1=O
Reactant: NCc1ccccc1
Product: C[C@@H]1CN(S(C)(=O)=O)CC[C@@H]1NCc1ccccc1

Procedure:
Racemic cis benzyl-(1-methanesulfonyl-3-methyl-piperidin-4-yl)-amine was prepared in the same manner from racemic 1-methanesulfonyl-3-methyl-piperidin-4-one. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[O:29][CH3:30])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH3:30][O:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]([CH2:17]/1)[CH2:19][C:20](=[O:51])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CO/N=C1\CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Product: CO/N=C1\CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 55 %

Procedure:
The title compound II-br was prepared in 55% yield from 3,3:17,17-bis(ethylendioxy)-7(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 3.72 (s, 3H), 2.89 (m, 1H), 2.63-0.93 (m, 19H), 1.12 (s, 3H), 0.82 (s, 3H).