Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][O:15][C:14]1=[O:24])=[O:12])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][C:35]1[CH:51]=[CH:50][C:38]([CH:39]=[N:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C.C[Si](Cl)(C)C.S([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH:10]([CH:39]([C:38]1[CH:50]=[CH:51][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)[NH:40][C:41]1[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=1)[C:11]([N:13]1[CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][O:15][C:14]1=[O:24])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(C(Nc2ccc([N+](=O)[O-])cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To 5.4 g (12.0 mmol) of product 1 and 6.2 g (24 mmol) of product 2 in 135 ml of methylenchloride 8 ml of diisopropylethylamin is added at 10° C. and 4.8 ml of trimethylsilylchloride is added dropwise. After 1 h 14 ml of a 1 molar solution of titantetrachloride in methylenchloride is added dropwise at —10° C. It is stirred for 3 h at −10° C. and further 12 h at −30° C. stored without stirring. Afterwards 8 ml of acetic acid and 140 ml of a 7% aqueous solution of tartratic acid is added and it is stirred for further 2 h at room temperature. After addition of 50 ml of a 20% aqueous solution of sodiumhydrogensulfit it is stirred for another 1 h and extracted with methylenchloride. The organic phase is dried by magnesium sulfate, evaporated and purified by chromatography on silica gel/Ethylacetate/heptane=1/3−>1/1. 6.3 g (74%) of product 3 is obtained in form of a light yellow solid compound: C40H47N3O7Si (709.92) MS (ESI+) 710 (M+H+).
Reaction SMILES: C([N-]C1CCCCC1)(C)C.[Li+].[CH3:12][C:13]([CH3:32])=[CH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].[Br:33]Br.Cl>C1COCC1.CCOCC.CN(P(N(C)C)(N(C)C)=O)C>[Br:33][CH:14]([C:13]([CH3:32])=[CH2:12])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: CC(C)=CC(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: BrBr
Agent: CC(C)[N-]C1CCCCC1
Agent: Cl
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
A 100 ml flask is flushed with nitrogen and to it is added 25 ml of a 1 M THF solution of lithium N-isopropylcyclohexylamide (0.025 mole) followed by HMPT (5 ml). The flask is cooled to -78° and 7.1 g (0.025 mole) of m-phenoxybenzyl 3-methyl-2-butenoate in THF (25 ml) is added dropwise over 5 minutes. After the addition the mixture is stirred at -20° for 1 hour. This cold solution is then added dropwise to 1.1 equivalent of bromine in THF at -78°. After a further 1 hour at -78°, 5 ml of concentrated hydrochloric acid is added and the mixture allowed to come to RT and poured into ether plus cold aqueous hydrochloric acid. The ether layer is washed with water and brine and dried over calcium sulfate. Removal of the solvent gives m-phenoxybenzyl 2-bromo-3-methyl-3-butenoate, which is reacted with p-methylaniline by the process of Example 5 to give m-phenoxybenzyl ester of 2-(p-methylphenylamino)-3-methyl-3-butenoate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1c[nH]c2cc(C(=O)N[C@@H](COCC3CCNCC3)c3ccccc3)ccc12
Product: Cc1c[nH]c2cc(C(=O)N[C@@H](COCC3CCN(C(C)C)CC3)c3ccccc3)ccc12

Procedure:
Using alkylation method A, 3-methyl-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (400 mg, 1.0 mmol) and acetone (0.75 mL, 10 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 197 mg (44%) of the title compound.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CO>[CH:22]1([N:25]=[C:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:5]([CH2:4][CH2:3][C@:2]23[CH3:1])[C@:15]2([CH3:21])[C:14]([CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16]2)=[CH:13][CH2:12]4)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NC3CC3)CC[C@@H]12
Temperature: 25 °C

Procedure:
To a solution of 21 g of dehydroepiandrosterone in a mixture of 175 ml of cyclopropylamine and 150 ml of methanol was added 5 g of molecular sieves The reaction mixture was refluxed for 48 hours, cooled to room temperature, and filtered through magnesium sulfate. The magnesium sulfate was washed with ethyl acetate and the solvent was removed from the combined filtrates under reduced pressure to give 17-(cyclopropylimino)androst-5-en-3β-ol melting at about 187° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N:9]2[CH2:14][CH2:13][O:12][C@H:11]([C@@H:15]([OH:19])[C:16]([OH:18])=O)[C:10]2=[O:20])[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][O:30][C:31](=[O:33])[N:32]=2)=[CH:24][CH:23]=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N:9]2[CH2:14][CH2:13][O:12][C@H:11]([C@@H:15]([OH:19])[C:16]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:26][CH:27]=3)=[O:18])[C:10]2=[O:20])[CH:3]=1
Reactant: Cc1ccc(F)cc1N1CCO[C@H]([C@@H](O)C(=O)O)C1=O
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1N1CCO[C@H]([C@@H](O)C(=O)Nc2ccc(-c3noc(=O)[nH]3)cc2)C1=O

Procedure:
According to the Step 1-3 in synthetic method for EXAMPLE 1, a cyclic carbonate analogue (0.11 g) derived from compound 63-6 and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one with DMF were used instead of 1-2 and 6-amino-1-bis(tert-butoxycarbonyl)aminoisoquinoline to obtain compound 64-1 (43.2 mg) as a pale pink amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:7][C:8]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:12]=2.C1C(=O)N([I:38])C(=O)C1>CC(C)=O>[I:38][C:17]1[C:16]2[C:11](=[CH:12][C:13]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:8]1[CH:7]=[C:6]([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[N:5]=[N:4][C:3]=1[O:2][CH3:1]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CN3CCCCC3)cc2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
1.05 g 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-piperidin-1-ylmethyl-1H-indole are suspended in 30 mL acetone and 690 mg NIS is added. After stirring for 30 minutes at rt, the solvent is removed in vacuo. HPLC purification affords 560 mg (43%) 3-iodo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-piperidin-1-ylmethyl-1H-indole and 287 mg (27%) starting material.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4](O)=[CH:3][CH:2]=1.ClC1C([O:17][C:18](=[O:21])[NH:19]C)=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH2:26](N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:26][C:4]1[C:3]([O:21][C:18](=[O:17])[NH2:19])=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[O:8]
Reactant: CCN(CC)CC
Reactant: CNC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1
Product: Cc1c(C=O)cccc1OC(N)=O

Procedure:
3.1 g (0.0254 moles) of salicylic aldehyde are dissolved in 30 ml of anhydrous toluene and 8.1 g (0.025 moles) of N-methyl-carbamic acid-pentachlorophenyl-ester are added under stirring at room temperature, whereafter 2.6 g (0.0257 moles) of triethylamine are added to the mixture under stirring. During the addition of the triethylamine an elevation of the temperature of about 2°-5° C. may be observed. The reaction mixture is stirred at 25°-30° C. for 2 hours, after about 1 hour the reaction mixture becomes clear. The unreacted active ester is filtered, the toluene is removed from the filtrate and the residual oily substance is recrystallized from a three-fold amount of diisopropylether. 2-methyl-carbamoyloxy-benzaldehyde is obtained. Mp.: 128°-132° C.
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Br:19])=[CH:11][C:10]=1[NH:20][C:21]([C:23]([O:25]CC)=O)=[O:22])(C(OCC)=O)=O>Cl.C(O)(=O)C>[Br:19][C:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:9]2[N:8]=[C:23]([OH:25])[C:21]([OH:22])=[N:20][C:10]=2[CH:11]=1
Reactant: CCOC(=O)C(=O)Nc1cc(Br)c2ccccc2c1NC(=O)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: Oc1nc2cc(Br)c3ccccc3c2nc1O
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A mixture of 2,0 g (4,6 mmol) 1,2-diethoxalylamino-4-bromonaphthalene in 50 ml 2N hydrochloric acid and 25 ml acetic acid was refluxed for 1,5 h. After cooling to 25° C., the precipitate was filtered off. The crude product was recrystallized (dimethylformamide-water) to give 1,2 g (90%) of pure 6-bromo-2,3-dihydroxybenzo(f)quinoxaline.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([N:16]=[C:17]=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Cl:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:17]([NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:18])[CH:7]=1
Reactant: O=c1[nH]cc(Cl)c(=O)[nH]1
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)n1cc(Cl)c(=O)[nH]c1=O
Yield: 31 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 1, starting from 5-chlorouracil (0.10 g, 0.68 mmol); 1.2 equivalents of hexyl isocyanate were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (petroleum ether:EtOAc from 70:30 to 50:50) to afford the title compound (0.06 g, 31%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (t, J=6.8 Hz, 3H), 1.21-1.35 (m, 6H), 1.46-1.54 (m, 2H), 3.24-3.29 (m, 2H), 8.41 (s, 1H), 9.07 (t, J=5.3 Hz, 1H), 12.24 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 13.85, 21.97, 25.81, 28.57, 30.82, 40.55, 109.55, 135.56, 149.21, 150.61, 158.78. MS (ESI) m/z: 272 [M-H]−.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C[O-].[Na+]>CO>[C:1]([N:4]1[C:8]2=[CH:9][C:10]3[C:11]([C:20]4[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=4)=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc3[nH]ccc3cc21
Reactant: CN1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCc2cc3[nH]cc(C4=CCN(C)CC4)c3cc21
Yield: 50.8 %

Procedure:
To a stirred suspension of 1-acetyl-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (J. Med. Chem. 1995, 38, 2524) (1.60 g, 8 mmole) and 1-methylpiperidin-4-one (1.81 g, 16 mmole) in dry methanol (70 ml) was added sodium methoxide (2.59 g, 48 mmole). The mixture was heated at reflux under argon for 24 hours, then cooled and concentrated by evaporation to approx. 25% volume; then treated with water (5 ml), stirred and the solid precipatate collected by filtration. The solid was suspended in ethanol (20 ml), heated to boiling, cooled and filtered to leave the title compound as a pale cream powder (1.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])[CH2:22]P(OCC)(OCC)=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:52][N:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[CH:58]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:58]/[C@H:54]4[CH2:55][CH2:56][CH2:57][N:53]4[CH3:52])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCC[C@@H]1C=O
Reactant: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (300 mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1.2 mL, 1.18 mmol) was added dropwise. After the mixture was stirred for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (133 mg, 1.18 mmol) was added, and the mixture was stirred for another 1 hour, then warm up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 9 (130 mg, yield 47.3%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>CCO>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:36][C:34](=[O:35])[NH:33]2)[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH3:19]
Reactant: COc1cccc(C(=O)Cc2ccccc2)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccc(OC)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 27.1 %

Procedure:
A mixture of 1-(3-methoxyphenyl)-2-phenylethanone (100 mg, 0.44 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (72 mg, 0.34 mmol), urea (80 mg, 1.33 mmol), and concentrated HCl solution (0.04 mL, 0.44 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC to give Compound 15 (42.57 mg, yield 21%). 1H NMR (DMSO-d6 400 MHz): δ 10.29 (s, 1H), 8.72 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.18-7.12 (m, 2H), 7.08-7.02 (m, 3H), 6.86-6.81 (m, 3H), 6.77-6.74 (m, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.05 (q, J=6.8 Hz, 2H), 3.63 (s, 3H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 462.1 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:18]([O:29][CH3:30])[C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[C:5]([C:14]([O:16]C)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].O1CCCC1.[OH-].[Na+].O>CO>[C:1]([C:3]1[C:4]([CH:18]([O:29][CH3:30])[C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1C(OC)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(c1ccc2ccccc2c1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To methyl 4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (10.56 g, 25 mmol) in a round bottom flask equipped with a stirbar was added tetrahydrofuran (278 mL) and 1.000 M of sodium hydroxide in water (208 mL, 208 mmol). Methanol (139 mL) was added to the mixture, and the resulting yellow mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of 1N HCl aqueous solution to adjust the pH to 2 and EtOAc was added. The mixture was transferred to a separatory funnel, separated layers, extracted aqueous 2×w/EtOAc, combined organics, washed w/brine, dried over Na2SO4, filtered, added celite, rotavapped, dried on high vacuum for 45 min. The crude material was purified using a dry load on 330 g silica gel ISCO column (gradient elution: 0-20% MeOH/DCM) to obtain the product as an impure beige solid (9.8 g). Took 2 g, redissolved in DCM, added Celite, rotovapped, dried on high vac 45 min. Repurified this portion of product on 120 g ISCO silica gel column (gradient elution: 0-12% MeOH/DCM) to obtain 2.0 g beige foam product (racemate). LC/MS (FA) ES− 407; 1H NMR (400 MHz, DMSO) δ 13.57 (s, 1H), 7.96 (s, 1H), 7.89-7.86 (m, 3H), 7.53-7.46 (m, 3H), 6.68 (s, 1H), 3.73-3.67 (m, 4H), 3.50-3.45 (m, 4H), 3.43 (s, 3H). Enantiomeric separation of the enantiomers was performed by chiral HPLC on CHIRALPAK IC 4.6×250 mm with 85/5/10/0.1% HEX/IPA/ETOH/DEA 10 uL Injection at 1.0 mL/min for 50 min.
Reaction SMILES: ClC1C=CC=C(C)C=1[N:9]1[CH2:14][CH:13]=[CH:12][N:11]2[CH2:15][CH2:16][N:17]=[C:10]12.CC(C)([O-])C.[K+].N1CCN2C=CCNC=12>CS(C)=O>[N:17]1[CH2:16][CH2:15][N:11]2[CH2:12][CH:13]=[CH:14][NH:9][C:10]=12
Reactant: Cc1cccc(Cl)c1N1CC=CN2CCN=C21
Agent: C1=CN2CCN=C2NC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C1=CNC2=NCCN2C1

Procedure:
Six hundred twenty milligrams of 8-(2-chloro-6-methylphenyl)-2,3,7,8-tetrahydro-imidazo[1,2-a]pyrimidine were dissolved in 5 ml of dimethylsulfoxide, and 280 mg of potassium tert.butoxide were added to this solution, under stirring. The mixture was then heated to 50° to 60° C. for 48 hours. Subsequent to this time, some of the 2,3,7,8-tetrahydro-imidazo[1,2-a]pyrimidine added isomerized to form 2,3,5,8-tetrahydro-imidazo[1,2-a]pyrimidine. After the solvent was evaporated and the mixture of isomers was dissolved in dilute 1 N hydrochloric acid, as described in Examples 1 and 2, the isomers were separated by fractional extraction at increasing pH values (monitored by thin layer chromatography).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:20])([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]#[N:14])(=O)[CH3:2].C(Cl)(Cl)(Cl)Cl.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:20][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:21]=[C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][C:4]=1[CH2:1][CH3:2])[C:13]#[N:14]
Reactant: CCCCCC(C)(C#N)CCCCCOc1cc(OCc2ccccc2)ccc1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC(C)(C#N)CCCCCOc1cc(OCc2ccccc2)ccc1CC
Reaction time: 24 h
Yield: 90 %

Procedure:
7-(2-Acetyl-5-benzyloxyphenoxy)-2-methyl-2-n-pentylheptanenitrile was dissolved in carbon tetrachloride containing 6 equivalents of triethylsilane. After addition of 60 equivalents of trifluoroacetic acid, the solution was stirred 24 hours and then evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether to provided the title product as an oil in 90% yield, NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]1)=[O:11].O.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)C1CCN(C(=O)Cc2cc(C)ccc2C)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C)c(CC(=O)N2CCC(C(=O)O)CC2)c1
Temperature: 0 °C

Procedure:
Methyl 1-[(2,5-dimethylphenyl)acetyl]-4-piperidinecarboxylate (i.e. the product of Example 9, Step A) (4.95 g, 17.1 mmol) was dissolved in 20 mL of tetrahydrofuran, and 15 mL of water was added. With vigorous stirring the reaction mixture was cooled to 0° C., and 35 mL of a 1 N aqueous sodium hydroxide solution was added dropwise. The reaction mixture was stirred at room temperature for 1 h, diluted with 20 mL of brine, washed with diethyl ether (3×20 mL), and the aqueous phase was acidified with 1 N aqueous hydrochloric acid to pH 3-4. The precipitate was collected and dried to give 4.08 g of the title compound.
Reaction SMILES: [OH-].[Na+].[C:3](=O)=O.[CH2:6]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9].S(Cl)(Cl)=O>CO>[CH2:6]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([O:17][CH3:3])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(OCCC(C)C)cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
In a three-neck reaction flask with a reflux condensor attached to 2 gas wash bottles, the second one filled with NaOH(aq) for absorption of developing CO2 and SO2, 3.7 g (14.6 mmol) 3-iso-pentyloxy-5-nitrobenzoic acid (10) were dissolved in methanol and cooled to 0° C., then 1.6 mL (21.9 mmol) thionyl chloride were added dropwise under stirring. The mixture was refluxed for 4 h, then stirred overnight at r.t.. It was concentrated, then repeatedly taken up in methanol and concentrated again, and put under vacuum. Finally, 2.97 g (76%) of a red-brown liquid, which was found to be sufficiently pure by NMR, were obtained. 1H NMR (CDCl3) δ 8.44 (dd, J1=1.4 Hz, J2=2.2 Hz, 1H), 7.88 (t, J1=2.2 Hz, J2=2.2 Hz, 1H), 7.87 (dd, J1=1.4 Hz, J2=2.2 Hz, 1H), 4.41 (t, J=6.8 Hz, 2H, PhOCH2CH2CH(CH3)2), 3.94 (s, 3H, OCH3), 1.88-1.65 (m, 3H), 0.99 (d, J=6.6 Hz, 6H, CH(CH3)2).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[NH:34][C:11]2=[C:12]([N:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25]3)[N:13]=[C:14]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH:15]=[C:10]2[C:9]=1[CH3:35].C1OCCOCCOCCOCCOCCOC1.[Cl:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58]Cl>O1CCCC1>[ClH:54].[Cl:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][N:34]1[C:11]2=[C:12]([N:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25]3)[N:13]=[C:14]([CH2:16][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH:15]=[C:10]2[C:9]([CH3:35])=[C:8]1[CH3:7]
Reactant: ClCc1cccc(Cl)c1
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(CN3CCN(C)CC3)cc2c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(CN3CCN(C)CC3)cc12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
Potassium tert-butoxide (15 mg, 0.12 mmol) was added to a solution of 2-[2,3-dimethyl-5-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline (30 mg, 0.074 mmol) prepared in Step 1 of Example 874 and 18-crown-6 (3.1 mg, 0.012 mmol) in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred for 1 hour at room temperature and then 3-chlorobenzyl chloride (15.2 μl, 0.12 mmol) was added thereto. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 21.0 mg of the titled compound as a white solid.