Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:44][CH2:45][O:46][CH3:47]>CC#N>[CH3:47][O:46][CH2:45][CH2:44][O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: COCCBr
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCOc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A mixture of estrone (10 g; 37 mmol), Nal (1.1 g, 7.4 mmol), Cs2CO3 (18.08 g; 55.5 mmol) and Br(CH2)2OCH3 (15 mL; 156 mmol) in CH3CN (200 mL) was refluxed for 1 h. The mixture was filtered over silica gel and washed successively with CH2Cl2 and EtOAc to give the ether (12.1 g; 99.4%); 1H NMR (300 MHz, CDCl3) δ 7.23 (d, 1H, J=8.6 Hz), 6.75 (dd, 1H, J=2.6, 8.6 Hz), 6.72 (s, 1H), 4.1 (t, 2H, J=4.4 Hz), 3.74(t, 2H, J=3.7 Hz), 3.44 (s, 3H), 2.87 (dd, 2H, J=4.25, 8.5 Hz), 2.48 (dd, 1H, J=8.4, 18.7 Hz), 0.91 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Br[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>C(#N)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>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCCCc1ccc(C#Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 85 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
To a solution of 1-butyl-4-ethynylbenzene (Aldrich, 25.0 g, 0.157 mol) and methyl 4-bromobenzoate (Aldrich, 30.9 g, 0.143 mol) in dry acetonitrile (300 mL) under nitrogen was added cuprous iodide (1.36 g, 7.18 mmol), TEA (43.6 g, 0.431 mol) followed by Pd(PPh3)2Cl2 (5.0 g, 7.18 mmol) and the reaction mixture was stirred at 85° C. for 20 hrs. The solvent was removed under reduced pressure. The residue was taken up with Et2O (300 ml) and washed with water and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (PetEther) gave 23.0 g (55%) of the.title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][N:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]4=[O:32])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=c1ccccn1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCn1ccccc1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.94 mmol), (prepared as described for the starting material in Example 15), 1-(2-chloroethyl)-1,2-dihydro-2-pyridone (175 mg, 1.1 mmol), (J. Am. Chem. Soc. 1951, 73, 3635), and potassium carbonate (260 mg, 1.9 mmol) in DMF (30 ml) was heated at 80° C. for 3 hours, allowed to cool to ambient temperature and stirred for a further 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine mixtures (100/0/0 increasing to 70/30/0.5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(2-oxo-1,2-dihydro-1-pyridyl)ethoxy]quinazoline (50 mg, 12%). m.p. 209-211 ° C. 1H NMR Spectrum: (DMSOd6) 3.94(s, 3H); 4.35(t, 2H); 4.41 (t, 2H); 6.22(dd, 1H); 6.40(d, 1H); 7.14(s, 1H); 7.35(dd, 1H); 7.42(ddd, 1H); 7.5-7.6(m, 2H); 7.70(d, 1H); 7.80(s, 1H); 8.35(s, 1H); 9.53(s, 1H) MS-ESI: 441 [MH]+
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.I.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](SC)=[NH:20].O>CN(C=O)C>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:19]([C:15]3[S:14][CH:18]=[CH:17][CH:16]=3)=[NH:20])=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CNCCO2
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: O
Solvent: CN(C)C=O
Product: N=C(Nc1ccc2c(c1)CNCCO2)c1cccs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylamine (3.67 g, 18 mmol) in DMF (60 ml) was added 2-thiophenecarboximidothioic acid, methyl ester, hydroiodide (5.52 g, 19 mmol). The mixture was heated to 50° C. for 24 h. The mixture was poured into water (50 ml), then basic water (150 ml) and was allowed to stir for 1 h. The solids were collected by filtration. The solid was dissolved in hot ethyl acetate, filtered, and diluted with hexane. The solids were collected by filtration (3.13 g, 64%), MS m/Z 274 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: CN(C)CCCl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using 1-chloro-2-dimethylaminoethane hydrochloride. Title compound: ES-MS: 346.0 [M+H]+; single peak at tR=5.89 min (System 1); Rf=0.34 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:24](=[O:44])[N:25]([CH2:34][C:35]1[C:40]2[N:41]=[CH:42][S:43][C:39]=2[CH:38]=[CH:37][CH:36]=1)[CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:17][CH:18]=1)[C:24]([N:25]([CH2:34][C:35]1[C:40]2[N:41]=[CH:42][S:43][C:39]=2[CH:38]=[CH:37][CH:36]=1)[CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:44]
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reaction time: 2 h

Procedure:
To a solution of [1-[Benzothiazol-4-ylmethyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-carbamic acid benzyl ester (3.64 g, 5.76 mmol) in MeOH (50 mL) was added Pd/C (500 mg). After 2 h of stirring under H2 atmosphere, the solution was filtered on Celite and the solvent was evaporated to afford 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)—N-(2,2-diethoxy-ethyl)-propionamide, which was used next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5].O.O[Li].O>CO>[Cl:28][C:25]1[CH:24]=[CH:23][C:22](/[CH:21]=[CH:20]/[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:29])=[O:2])=[O:9])=[CH:27][CH:26]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.4 %

Procedure:
38 mg 2-({1-[(E)-2-(4-chloro-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester were dissolved in 3 ml of MeOH and 1 ml of water was added. After addition of 5 mg of LiOH.H2O the reaction was stirred at room temperature for 14 h. Filtration of the crude mixture, RP-HPLC and freeze-drying gave 35 mg of 2-({1-[(E)-2-(4-Chloro-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid (96%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][CH2:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[CH3:21][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:23].CO.N>C(O)CCC>[CH3:23][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:2]2[N:7]=[C:6]([N:8]([CH2:15][CH2:16][CH2:17][CH3:18])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:33][CH:34]=1)[CH3:21]
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: CCCCN(c1ccccc1)c1ccnc(Cl)n1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCCCO
Product: CCCCN(c1ccccc1)c1ccnc(Nc2ccc(OCC(O)CN(C)C)cc2)n1
Temperature: 95 °C
Yield: 15.2 %

Procedure:
2-Chloro-4-(N-(n-butyl)anilino)pyrimidine (570 mg, 2.18 mmol) was dissolved in n-butanol (4 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline dihydrochloride (Reference Example D-1; 554 mg, 1.97 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 95° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and then evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%):DCM:aqueous ammonia (1%). The resulting gum was re-evaporated from EtOAc twice to give the title product as a foam (130 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:21])[CH2:3]1.[CH2:23]1[CH2:36]OC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC=C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:24]1>>[CH2:36]1[CH2:23][O:24][C:5]2([CH:4]3[C@:17]([CH3:20])([CH2:18][CH2:19][C@H:2]([OH:1])[CH2:3]3)[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:21])[CH2:10][CH2:9]4)[CH2:6]2)[O:22]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC(=O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CC[C@H]3[C@@H](CC4(OCCO4)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Yield: 70 %

Procedure:
6,6-Ethylendioxyandrostane-3β,17β-diol was prepared in 70% yield from 3β,17β-dihydroxyandrostan-6-one by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-5-androstene (Prepn. 5). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 6,6-ethylendioxyandrostane-3β,17β-diol. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.45 (d, 1H), 4.41 (d, 1H), 3.90-3.57 (m, 4H), 3.41 (m, 1H), 3.29 (m, 1H), 1.87-0.53 (m, 20H), 0.84 (s, 3H), 0.60 (s, 3H).
Reaction SMILES: [CH:1]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]#[CH:15])[CH3:12].C(N(CC)CC)C>C(OCC)C>[CH2:11]([O:13][CH:14]1[C:1]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:9])[CH2:15]1)[CH3:12]
Reactant: O=C(Cl)C1CCCCCC1
Reactant: C#COCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC1CC(=O)C12CCCCCC2
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.1 %

Procedure:
A solution of cycloheptyl carbonyl chloride (10.0 g, 0.062 mol) and ethoxyacetylene (40% w/w solution in hexanes, 6.0 g, 0.083 mol, 12 ml) in diethylether (50 ml) was treated dropwise with triethylamine (20 ml, 0.14 mol) and the reaction stirred for 5 d at room temperature. Filtration and concentration of the filtrate in vacuo followed by chromatography (SiO2, 5:1 EtOAc:hexanes) gave the title compound as a pale yellow oil (10.5 g, 0.054 mol, 87%). δH (CDCl3, 300K) 4.78 (1H, s), 4.20 (2H, q J 7.1 Hz), 1.94-1.87 (2H, m), 1.83-1.77 (2H, m), 1.71-1.66 (2H, m), 1.63-1.52 (6H, m), 1.45 (3H, t J 7.1 Hz); m/z (ES+, 70V) 194.9 (MH+).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[C:8]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])(=[O:10])[CH3:9].CN1CCOCC1.[NH2:24][C:25]1[C:26]([Cl:44])=[C:27]([C:40]([Cl:43])=[CH:41][CH:42]=1)[CH2:28][O:29][C:30]1[C:31]2[N:32]([CH:36]=[C:37]([CH3:39])[N:38]=2)[CH:33]=[CH:34][CH:35]=1>CN1CCCC1=O>[C:8]([N:11]([CH2:13][C:14]([NH:24][C:25]1[C:26]([Cl:44])=[C:27]([C:40]([Cl:43])=[CH:41][CH:42]=1)[CH2:28][O:29][C:30]1[C:31]2[N:32]([CH:36]=[C:37]([CH3:39])[N:38]=2)[CH:33]=[CH:34][CH:35]=1)=[O:16])[CH3:12])(=[O:10])[CH3:9]
Reactant: Cc1cn2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Reactant: CC(=O)N(C)CC(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(=O)N(C)CC(=O)Nc1ccc(Cl)c(COc2cccn3cc(C)nc23)c1Cl
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
Pivaloyl chloride (0.22 ml) was added dropwise to a mixture of acetylsarcosine (264 mg), N-methylmorpholine (0.22 ml) and N-methylpyrrolidone (30 ml) under a dry ice-tetrachloromethane bath cooling. This mixture was stirred for 10 minutes under ice-cooling, and 8-[3-amino-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (500 mg) was added thereto under a dry ice-tetrachloromethane bath cooling. The mixture was stirred for 22 hours at ambient temperature. The mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo, and the residue was purified by flash column chromatography (methylene chloride:methanol=50:1, V/V) to give 8-[3-(acetylsarcosylamino)-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (260 mg).
Reaction SMILES: OC([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])C=C.C(O[CH:35]([O:39]C(C)(C)C)[N:36]([CH3:38])[CH3:37])(C)(C)C.[C:44]1(C)[C:45](C)=CC=C[CH:49]=1>>[CH3:38][N:36]([CH3:37])[C:35](=[O:39])[CH2:45]/[CH:44]=[CH:49]/[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: Cc1ccccc1C
Reactant: C=CC(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C/CC(=O)N(C)C)ccc21
Reaction time: 3.5 h
Yield: 40 %

Procedure:
A mixture of methyl 4-[5-(1-hydroxyallyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.57 g, prepared as described in Example 87, part a), N,N-dimethylformamide di-tert-butylacetal (1.63 g, redistilled) in dry xylene (15 ml), under an atmosphere of nitrogen, was stirred and heated under reflux for 2 hr. A further portion of the acetal (1.63 g) was added, and refluxing continued for a further 3.5 hr. The cooled solution was introduced directly into a column of silica gel and the product purified by flash chromatography, eluting with 7:3 ethyl acetate:hexane, to give methyl E-4-[5-[4-(dimethylamino)-4-oxobut-1-enyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.71 g, 40%) as an off-white solid: mp 122.5°-123.5°; partial NMR (300 MHz, DMSO-d6): 0.81(t, 3H, CH2CH3), 1.75(m, 2H, CH2CH3), 2.83(s, 3H, NCH3), 3.01(s, 3H, NCH3), 3.24(d, 2H, --COCH2CH=), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.05(s, 4H, ArCH2Ar', NCH2CH2), 6.15(d of t, 1H, CH2CH=CH), 6.45(d, 1H, CH2CH=CH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([C:15]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=1)=[O:14].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:26][N:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[S:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=S(c1nc2ccccc2[nH]1)c1ccccc1-c1ccccn1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(S(=O)c2ccccc2-c2ccccn2)nc2ccccc21
Yield: 75.3 %

Procedure:
2-[2-(2-Pyridyl)-phenyl sulphinyl]-1H-benzimidazole (Example 13) (0.7 g) in dry dimethylformamide (50 ml), methyl iodide (0.34 g) and anhydrous potassium carbonate (1.1 g) were stirred at room temperature for 1.75 hours. The mixture was poured onto water, extracted into ethyl acetate, washed, dried and evaporated under reduced pressure to leave the title compound as a cream solid (0.55 g).
Reaction SMILES: CS[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.O[O:13][S:14]([O-:16])=O.[K+].[CH3:18]O>O>[CH3:18][S:14]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1)(=[O:16])=[O:13]
Reactant: CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nc2ccccc2[nH]1
Reaction time: 5 h
Yield: 89 %

Procedure:
According to the procedure of B. M. Trost, et al., Tetrahedron Lett., 22 (14), 1287 (1981), to a cooled (0° C.), stirred solution of 2-(methylthio)benzimidazole (14.5 g, 0.088 mol) in MeOH (350 mL) was added a solution of oxone (2 KHSO5.KHSO4.K2SO4 ; 81.6 g, 0.133 mol) in H2O (350 mL) over 10 minutes. The cooling bath was removed after 10 minutes, stirring was continued at room temperature for 5 hours. The MeOH was removed under reduced pressure and the white solid was collected by filtration to give 15.5 g (89%) of product m.p. 200°-202° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][N:17]12.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1.CCCCCC>[CH2:29]([O:28][C:26]([C:23]1([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:22][N:17]2[C:18]3[C:14]([CH:15]=[C:16]2[CH2:25][CH2:24]1)=[CH:13][CH:21]=[CH:20][CH:19]=3)=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1CCc2cc3ccccc3n2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(C(=O)OCC)CCc2cc3ccccc3n2C1
Reaction time: 0.17 h

Procedure:
A stirred solution of 2.52 ml of diisopropylamine in 20 ml of THF was cooled in a bath at -78° C. under an argon atmosphere and treated with 11.25 ml of a 1.6M solution of n-butyllithium in n-hexane. The mixture was treated with a solution of 2.85 g of ethyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-7-carboxylate in 80 ml of THF. After 10 minutes, 1.46 ml of ethyl bromoacetate were added and the cooling bath was removed. The mixture was stirred and then diluted with diethyl ether. The solution was washed in succession with saturated aqueous ammonium chloride, water and sodium chloride solution and then dried. The solvent was removed by evaporation and the residue was subjected to chromatography on silica gel using ethyl acetate/n-hexane (1:9) for the elution to give 2.55 g of ethyl 7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido-[1,2-a]indole-7-acetate.
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[Cl:21])=O)(C)(C)C.Cl>>[ClH:21].[Cl:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[C:18]2[C:13]=1[C:12](=[O:22])[N:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@H:10]12
Reactant: COc1cc(Cl)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: Cl
Product: COc1cc(Cl)c2c(c1)[C@@H]1CNCCN1C2=O
Reaction time: 0.02 h

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one (16 mg, 0.05 mmol) was added concentrated aqueous hydrochloric acid (1 mL, 12N). After 1 min, the solution was concentrated, diluted with water, and lypholized to give a white solid (13 mg, quant). MS (ESI) 253.2, 255.2 (M−Cl).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: CO
Product: COc1cccc2c(OC)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 285(MH+).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:10](=[O:11])[N:9]([CH:12]3[C:18](=[O:19])[NH:17][C:15](=[O:16])[CH2:14][CH2:13]3)[CH2:8][C:4]2=[C:5]([NH2:7])[CH:6]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>N1C=CC=CC=1>[O:19]=[C:18]1[CH:12]([N:9]2[CH2:8][C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[NH:7][C:20](=[O:23])[CH2:21][CH3:22])[C:10]2=[O:11])[CH2:13][CH2:14][C:15](=[O:16])[NH:17]1
Reactant: CCC(=O)Cl
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Solvent: c1ccncc1
Product: CCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A solution of lenalidomide (0.020 g, 0.077 mmol) in pyridine (0.8 mL) was cooled to 0° C. (ice bath). Propionyl chloride (0.009 mL, 0.100 mmol) was added dropwise and the reaction was allowed to warm to room temperature over 16 h. Volatiles were removed in vacuo and the crude residue was purified by flash chromatography on silica gel (0→5% MeOH in DCM as eluant) to afford desired product 27 (0.012 g, 50%) as an off-white powder. 1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 9.79 (s, 1H), 7.80 (dd, J=6.6, 2.3 Hz, 1H), 7.64-7.29 (m, 2H), 5.14 (dd, J=13.2, 4.9 Hz, 2H), 4.35 (q, J=7.5 Hz, 2H), 3.00-2.79 (m, 1H), 2.60 (m, 1H), 2.35 (m, 1H), 2.05-1.92 (m, 1H), 1.08 (t, J=7.5 Hz, 3H). MS (ESI) m/z calcd for C16H18N3O4 [M+H]+ 316.3, found: 316.8.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](=[O:11])[NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:4]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCN1CCOCC1)c1cc(Cl)ccn1
Reaction time: 20 h
Yield: 95.4 %

Procedure:
To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf 0.50.