Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:14])[CH2:9]1>O1CCCC1>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:9]1
Reactant: CC1CCCC(N)C1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCC(C)C1
Temperature: 20 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
A solution of 7.5 g of diketene in 30 ml of tetrahydrofuran was added to a mixture of 10 g of 3-methylcyclohexylamine and 60 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 4 hours and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 12 g of N-(3-methylcyclohexyl)-acetylacetamide. 12 g of the latter product and 0.3 g of p-toluene sulfonic acid were added to a mixture of 10.6 g of methyl orthoformate and 20 ml of methanol and the mixture was stirred at 20° C. for 1 hour and stood still for 16 hours at 20° C. 0.6 g of quinoline were added thereto and the mixture was evaporated to dryness under reduced pressure. The residue was added to 50 ml of toluene and the mixture was heated at 145° C. for 3 hours while distilling a toluene-methanol azeotrope and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with an 8-2 methylene chloride-acetone mixture gave 9.2 g of N-(3'-methylcyclohexyl)-3-methoxy-crotonamide whose RMN spectra showed it to be the E isomer.
Reaction SMILES: [Si](OC[C@@H](N)C(C)=C)(C(C)(C)C)(C)[CH3:2].BrCC(N(OC)C)=O.[Si:23]([O:30][CH2:31][C@@H:32]([N:35]([CH2:43][C:44]([N:46]([O:48][CH3:49])[CH3:47])=[O:45])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[CH2:34])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>>[Si:23]([O:30][CH2:31][C@@H:32]([N:35]([CH2:43][C:44]([N:46]([O:48][CH3:49])[CH3:47])=[O:45])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[C:33]([CH3:2])=[CH2:34])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25]
Reactant: C=C(C)[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: CON(C)C(=O)CBr
Product: C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Yield: 39 %

Procedure:
The title compound was prepared from (S)-1-(tert-butyldimethylsilyloxy)-3-methylbut-3-en-2-amine (Intermediate 187, 5.57 g, 25.86 mmol) and 2-bromo-N-methoxy-N-methylacetamide (Intermediate 4, 4.28 g, 23.53 mmol) following the procedure described for Intermediate 5. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product as a colorless oil (4.24 g, 39%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[CH:32]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].CC(O)=O.[BH3-]C#N.[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[CH2:32][NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccsc3C=O)n(CC(=O)OC(C)(C)C)c2c1
Reactant: CN(C)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccsc3CNCCN(C)C)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-(2-formyl-3-thienyl)-1H-indole-6-carboxylate in THF (0.05 M) was treated with N,N-dimethylethane-1,2-diamine (10 eq) and the pH was adjusted to 6 with AcOH; after stirring for 1 h at RT solvent was removed and the residue dissolved in MeOH (0.05M), then NaCNBH3 (1.5 eq) was added and the mixture was stirred during the weekend. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated affording methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-1H-indole-6-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]=[N:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=1[OH:24])([O-])=O.C(N)CCC.[H][H]>[Pt].C1(C)C(C)=CC=CC=1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]2=[N:1][N:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[OH:24])[N:11]=[C:5]2[CH:6]=1
Reactant: Cc1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCCCN
Solvent: Cc1ccccc1C
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
60 g of 2-nitro-5-chloro-2'-hydroxy-3'-tert-butyl-5'-methylazobenzene (purity 86%), 40 g of xylene, 60 g of n-butylamine and 1 g of 1% Pt on activated carbon are put into a 300 ml hydrogenation reactor at room temperature under argon. Argon is then replaced by hydrogen. After the injection of 10 bar hydrogen, the hydrogenation is carried out at 35°-37° C. with intensive stirring. The heat released is removed by cooling. The end of the hydrogenation reaction is easily detectable by the hydrogen absorption ceasing after 2 mol equivalents of hydrogen, relative to the azobenzene starting product. The total hydrogenation time is about 1.5 hours.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].N1CCCC1.[CH3:13][C:14]1[C:15]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=O)=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1>C(O)C>[CH3:13][C:14]1[C:15]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=[C:5]2[NH:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[C:22]=2[CH:23]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Solvent: CCO
Solvent: C1CCNC1
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
A mixture of 2,4-imidazolidinedione (101 mg, 1.0 mmol), pyrrolidine (0.04 mL, 0.5 mmol) and 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde (336 mg, 1.0 mmol) in ethanol (15 mL) was heated under reflux for 24 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with saturated aqueous NH4Cl (60 mL), saturated NH4Cl (70 mL), saturated aqueous NaCl (60 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a yellow solid that was purified by column chromatography, using a Biotage 40S cartridge, eluting with ethyl acetate/hexane (3:7). The title compound was isolated as a yellow solid (270 mg, 65%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:13]=2)O1.[F:28][C:29]1[CH:30]=[C:31]([NH:55]C(C2C(=O)N(C3C=CC(F)=CC=3)N=CC=2)=O)[CH:32]=[CH:33][C:34]=1[O:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]2[N:42]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[N:43]=[C:44](I)[C:37]=12.C(=O)([O-])[O-].[K+].[K+]>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>[NH2:55][C:31]1[CH:32]=[CH:33][C:34]([O:35][C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[N:42]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)[N:43]=[C:44]([C:9]4[CH:10]=[N:11][N:12]([CH:14]5[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]5)[CH:13]=4)[C:37]=23)=[C:29]([F:28])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Cn2nc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 36.1 %

Procedure:
A 100 mL round-bottomed flask was charged with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.289 g, 0.765 mmol), 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.250 g, 0.510 mmol from Example 63, Step A), potassium carbonate (0.106 g, 0.765 mmol), Pd(PPh3)4 (0.0295 g, 0.0255 mmol), degassed DMF (2 mL) and water (0.5 mL). The reaction mixture was heated at 100° C. using a CEM microwave for 2 hours. The reaction mixture was cooled to ambient temperature and extracted with EtOAc/water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by preparative TLC (2.0 mm eluting with EtOAc). Isolated 0.113 g (32%) of the desired product. LRMS M+1 (614.1) observed.
Reaction SMILES: [CH:1]1([O:4][CH:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[C:15]([N+:25]([O-])=O)[C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:3][CH2:2]1>C(O)(=O)C.[Zn]>[NH2:25][C:15]1[C:16](=[O:24])[CH2:17][CH2:18][C@@:19]2([CH3:20])[C:14]=1[CH2:13][CH2:12][C@@H:11]1[C@@H:21]2[CH2:22][CH2:23][C@@:6]2([CH3:7])[C@H:8]1[CH2:9][CH2:10][CH:5]2[O:4][CH:1]1[CH2:2][CH2:3]1
Reactant: C[C@]12CCC(=O)C([N+](=O)[O-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(OC3CC3)CC[C@@H]12
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)C(N)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(OC3CC3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A solution of 17-cyclopropyloxy-4-nitroandrost-4-en-3-one (1.0 g, 2.71 mM) in acetic acid (10 mL) is treated with zinc dust (1.0 g). The combination is vigorously stirred for 1.5 hours at room temperature. The zinc salts are removed by filtration and washed with ethyl acetate. The combined filtrate and wash are combined and concentrated to a yellow solid which is then redissolved in ethyl acetate and extracted three times with 1M hydrochloric acid (150 ml). The combined acid extracts are neutralized with sodium hydroxide (pH 14) and further extracted with ether. The combined organic layers are then dried over sodium sulfate and concentrated to give 4-amino-17-cyclopropyloxyandrost-4-en-3-one (0.59 g), m.p. 100-102° C. (aqueous methanol).
Reaction SMILES: [Li][CH3:2].[Li+].[Br-].[I:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2=[O:16].[NH4+].[Cl-]>O.C1COCC1>[I:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([CH3:2])[OH:16]
Reactant: O=C1CCOc2ccc(I)cc21
Reactant: [Li]C
Agent: [Br-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CCOc2ccc(I)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
CeCl3 (4.9 g, 19.8 mmol) was dried in vacuo at 140° C. for 3 h and then slurried with dry THF (100 ml) for 1 h. The white suspension was chilled to −78° C. followed by the addition of MeLi.LiBr (14.2 ml, 21.4 mmol) over 15 minutes. The mixture was stirred for 30 min followed by the addition of a THF (20 ml) solution of 6-iodo-2,3-dihydro-4H-chromen-4-one dropwise via syringe. After 30 min TLC (15% EtOAc/hexanes) indicated complete reaction. The mixture was treated with NH4Cl (aq.) 30 ml and diluted with water 150 ml. The mixture was extracted with EtOAc and the organic layer dried over Na2SO4. The Na2SO4 was removed by filtration and the filtrate concentrated in vacuo to yield 6-iodo-4-methylchroman-4-ol as an off white solid 4.7 g (95%). HRMS (ESI+) calcd for C10H11IO2 m/z 289.9806 (M+H)+. Found 289.9803.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2([O:15][CH3:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([OH:8])[CH:7]=1.I[CH2:18][C:19]#[N:20]>>[C:19]([CH2:18][O:8][C:6]1[CH:5]=[C:4]([C:9]2([O:15][CH3:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=[C:2]([OH:1])[CH:7]=1)#[N:20]
Reactant: COC1(c2cc(O)cc(O)c2)CCOCC1
Reactant: N#CCI
Product: COC1(c2cc(O)cc(OCC#N)c2)CCOCC1
Yield: 27 %

Procedure:
4-(3,5-Dihydroxyphenyl)-4-methoxytetrahydropyran was reacted with one equivalent of iodoacetonitrile using the procedure described in Example 1 to give 4-(3-cyanomethoxy-5-hydroxyphenyl)-4methoxytetrahydropyran (27%) as an oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: CC(C)(CO)CCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCCCBr)COC1CCCCO1
Yield: 82.6 %

Procedure:
According to the procedure for the preparation of 207d, (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818) 206c (521.0 g, 2.49 mol) was reacted with 3,4-dihydro-2H-pyran (278.0 g, 3.30 mol) and p-toluenesulfonic acid hydrate (3.13 g, 16 mmol) in CH2Cl2 (2.2 L) to yield 207c (603.0 g, 83%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1H, J=3.3), 3.84 (m, 1H), 3.50 (m, 1H), 3.47 (d, 1 H , J=9.0), 3.42 (t, 2H, J=6.7), 2.99 (d, 1H, J=9.0), 1.88 (m, 2H), 1.75-1.33 (m, 10H), 0.91 (s, 3H), 0.90 (s, 3H). 13C NMR (CDCl3): δ 99.37, 76.58, 62.17, 38.56, 34.43, 34.19, 33.90, 30.88, 25.79, 24.80, 24.71, 22.89, 19.67. HRMS (LSIMS, nba): Calcd for C13H25BrO2 (MH+): 293.1116, found: 293.1128.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH:38]=O)[CH3:37].O>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>[CH3:35][N:36]([CH2:38][C:2]1[CH:10]=[C:9]([C:2]2[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]3[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=3[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:37]
Reactant: CC[C@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC[C@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3cccc(CN(C)C)c3)cc21

Procedure:
(S)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.23 mmol), N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine, HCl (100 mg, 0.34 mmol) and Palladium Tetrakis (26 mg, 0.023 mmol) in DMF/water (3 ml:1 ml) were stirred for 10 min under nitrogen. Cesium carbonate (220 mg, 0.68 mmol) was added and the insoluble mixture was irradiated (microwave) at 150° C. for 15 min. The contents were evaporated, dissolved in DCM/MeOH (1:1), and pre-absorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 80:20:2 in DCM). The isolated product was first treated with EtOAc along with some hexanes. The product was then dissolved in MeOH and purified by reverse-phase HPLC (30×100 Varian Polaris C18 column, eluent: 10-80% gradient of MeCN in water with 0.1% TFA). The product fractions were combined, most of the solvent was evaporated, and a sat. solution of NaHCO3 was added. Solids that crashed out were filtered, air-dried for 15 min, and dried in vaccum-oven overnight. The solid product was collected as 87 mg (75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (br. s., 1H), 8.23 (t, J=4.67 Hz, 1H), 7.77 (d, J=1.01 Hz, 1H), 7.60-7.64 (m, 2H), 7.40 (t, J=7.58 Hz, 1H), 7.30 (s, 1H), 7.20-7.26 (m, 2H), 5.87 (s, 1H), 4.59-4.68 (m, 1H), 4.36 (s, 1H), 4.35 (s, 1H), 3.46 (s, 2H), 2.24 (s, 3H), 2.18 (s, 9H), 2.11 (s, 3H), 1.76-1.88 (m, 2H), 1.41 (d, J=6.57 Hz, 3H), 0.74 (t, J=7.33 Hz, 3H); LCMS: 499.4 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[N:5][C:4]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:3]1[C:20]#[N:21].[CH2:22](N(CC)CC)[CH3:23].BrCC>CN(C=O)C.ClCCl>[CH2:22]([N:17]1[CH2:16][CH2:15][N:14]([C:4]2[N:5]=[C:6]([CH2:8][C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)[NH:7][C:2](=[O:1])[C:3]=2[C:20]#[N:21])[CH2:19][CH2:18]1)[CH3:23]
Reactant: N#Cc1c(N2CCNCC2)nc(Cc2ccsc2)[nH]c1=O
Reactant: CCN(CC)CC
Solvent: CCBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.17 mmol) of 6-oxo-4-(piperazin-1-yl)-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are dissolved together with 34 mg (0.33 mmol) of triethylamine in DMF and, after addition of 19.9 mg (0.18 mmol) of bromoethane, stirred at RT overnight. The mixture is then diluted with dichloromethane and washed with water. The organic phase is separated off and dried over sodium sulphate, and the residue is flash-chromatographed on silica gel (mobile phase: dichloromethane/methanol 100:1, 80:1, 60:1, 40:1). 38 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C(O)(=O)C(C(C(O)=O)O)O.COC1C=CC(C=O)=CC=1.O>CO>[NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: COC(=O)C(N)CCSC
Agent: COc1ccc(C=O)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](N)CCSC
Reaction time: 44 h
Yield: 111.6 %

Procedure:
Similarly to Example 45 but using methyl DL-methioninate (10.033 g., 61.5 mmole) and (+)-tartaric acid (9.506 g., 63.4 mmole, 1.03 equiv.) in dried methanol (50 ml., i.e. 20% ester concentration) and adding anisaldehyde (7.5 ml., 8.43 g., 61.9 mmole, 1 equiv.) and stirring for 44 hours to give methyl L-methioninate (+)-hemitartrate (11.208 g., 58%), [α]D21 + 28.8° (c 3.038, H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)\[CH:10](C(OC2C(C(C)C)CCC(C)C2)C([O-])=O)[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[OH-:35].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)\[CH:10]([OH:35])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC1CCC(C(C)C)C(OC(C(=O)[O-])C(/C(=C\c2ccc(Cl)cc2)n2cncn2)C(C)(C)C)C1
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Yield: 69.6 %

Procedure:
Similarly, 1.2 g of (+)-[(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-yl]-(-)-menthoxyacetate was treated with 20 cc of a 95% aqueous ethanol solution containing 0.2 g of potassium hydroxide and the resulting crude crystals were recrystallized from a carbon tetrachloride-n-hexane mixture to obtain 0.5 g of (+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol: [α]D24 +14.0 (c=1.0, CHCl3); m.p. 169°-170° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([SnH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8].CC(N=NC(C#N)(C)C)(C#N)C>>[CH2:14]([Sn:9]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH3:13])/[CH:3]=[CH:2]/[CH2:1][OH:4])[CH2:15][CH2:16][CH3:17]
Reactant: C#CCO
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/CO)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To neat propargyl alcohol (5 ml) were added tributyltin hydride (29.2 ml) followed by AIBN (716 mg). The mixture was heated for 2.75 h at 80° C., cooled to RT and directly purified by CC (EA/Hept 5/95) to afford the desired compound (12.9 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:15][CH:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:13]([OH:22])[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[BH3-]C#N.[Na+].CC([O-])=O.[Na+].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1>CO>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:19]2[CH2:20][CH2:21][N:16]([CH:14]3[CH:13]([OH:22])[CH2:12][N:11]([C:9]([C:6]4[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=4)=[O:10])[CH2:15]3)[CH2:17][CH2:18]2)=[CH:35][CH:34]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2)C1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
(4-Chloro-phenyl)-(3-hydroxy-4-piperazin-1-yl-pyrrolidin-1-yl)-methanone hydrochloride (100 mg, 0.290 mmol), NaCNBH3 (20 mg, 0.319 mmol), NaOAc (23.8 mg, 0.29 mmol), 4-chloro-benzaldehyde (42.8 mg, 0.30 mmol) were added to methanol (3 mL). The reaction mixture was stirred in room temperature for over night. The mixture was concentrated. K2CO3 and Ethyl acetate were added to the residue. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude was purified by column chromatography to give 70 mg of desired product as an oil (56% yield).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)(=O)C.[NH4+].[OH-]>CO>[Br:24][C:20]1[CH:19]=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-acetoxy-4-(3-bromo-phenylamino)-7-methoxy-quinazoline (1.59 g, 4.11 mmol) (from Example 17, Step A, supra) in MeOH (30 mL) was added an aqueous solution of NH4OH (29%, 0.83 mL, 12.3 mmol). The reaction mixture was stirred at room temperature for 18 hours, then heated at 100° C. for 1.5 hours. The mixture was then cooled to room-temperature and filtered. The precipitate was collected and dried in vacuo to give the desired 4-(3-bromo-phenylamino)-7-methoxy-quinazolin-6-ol as a gray solid. (Yield 1.25 g, 88%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[CH:25]=[CH:24][C:13]([C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:15])=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(O)C>[CH2:3]([C:10]1[CH:25]=[CH:24][C:13]([C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:15])=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCc1ccc(C(=O)CCCCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1
Yield: 77 %

Procedure:
The title compound is then prepared from the methyl ester as follows. 2N Sodium hydroxide (108 ml) is added to a solution of methyl 5-(4-n-heptylbenzoyl)pentanoate (22.8 g, 0.07 mole) in ethanol (216 ml) and the mixture heated under reflux for about 2 hours. The reaction mixture is cooled and extracted with ether (2×350 ml). The ether phase is discarded and the aqueous phase acidified (pH 2) with concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water, and recrystallized from ethanol to give 5-(4-n-heptylbenzoyl) pentanoic acid (16.4 g) as colorless crystals, m.p. 80°-81° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([O:28]CCC)=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[CH3:11][N:12]([C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from phenylacetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 377.