Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([CH3:16])[C:10]=2[CH:9]=[CH:8][C:7]1=[O:21].[CH2:22]([NH2:24])[CH3:23]>C1COCC1>[CH2:22]([NH:24][C:13]1[N:14]=[C:15]([CH3:16])[C:10]2[CH:9]=[CH:8][C:7](=[O:21])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=2[N:12]=1)[CH3:23]
Reactant: CCN
Reactant: COCCCn1c(=O)ccc2c(C)nc(S(C)(=O)=O)nc21
Solvent: C1CCOC1
Product: CCNc1nc(C)c2ccc(=O)n(CCCOC)c2n1
Yield: 50 %

Procedure:
8-(3-methoxypropyl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one, and a solution of 2M ethylamine in THF (20 mL) was stirred for 2 h. THF was removed under reduced pressure and the crude product was purified by flash column chromatography to give 2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.18 g, 50% yield over 2 steps).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([CH2:16][N:17]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]=[CH:18]3)[CH2:13]2)[CH2:8][N:7]1C(OC)=O)=[O:5])[CH3:2].I[Si](C)(C)C.ClCCl>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([CH2:16][N:17]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]=[CH:18]3)[CH2:13]2)[CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn(C[C@H]2CC[C@H]3CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]3C2)c1C(=O)OCC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1ncn(C[C@H]2CC[C@H]3CN[C@H](C(=O)OCC)C[C@H]3C2)c1C(=O)OCC
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A solution of [3S,4aR,6S,8aR]-ethyl-6-((4,5-bis-ethoxycarbonyl-1H-imidazol-1-yl)methyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (10.55 g, 0.02138 mol), iodotrimethylsilane (21.39 g, 0.1069 mol), and dichloromethane (428 mL) was stirred for 16 hours at ambient temperature until complete as determined by tic (ethyl acetate/hexane, 2:1). The reaction mixture was concentrated to approximately 200 mL, ethanol (100 mL) was added and the resulting solution concentrated to a yellow foam. The residue was dissolved in methanol (190 mL) and stirred for 30 minutes with Amberlyst 15 resin (50 g). The resin was filtered and washed with methanol (100 mL). The product was eluted from the Amberlyst resin with 2N ammonia in methanol (2×100 mL). The filtrate was concentrated to an oil. The residue was purified by Biotage Flash 40M (dichloromethane/methanol, 19:1) to give 4.72 g of the free base of the final title compound, [3S,4aR,6S,8aR]-ethyl-6-((4,5-bis-ethoxycarbonyl-1H-imidazol-1-yl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[C:15]([CH2:18][S:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)([CH2:16][OH:17])[O:14][C:13](=[O:29])[C:12]=1[OH:30].Cl.[CH3:32][N:33]([CH2:35][C:36](Cl)=[O:37])[CH3:34].C(N(CC)CC)C>CN(C=O)C.Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[C:15]([CH2:16][O:17][C:36](=[O:37])[CH2:35][N:33]([CH3:34])[CH3:32])([CH2:18][S:19][C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[O:14][C:13](=[O:29])[C:12]=1[OH:30]
Reactant: O=C1OC(CO)(CSc2nc3ccccc3[nH]2)C(Sc2nc3ccccc3[nH]2)=C1O
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)OCC1(CSc2nc3ccccc3[nH]2)OC(=O)C(O)=C1Sc1nc2ccccc2[nH]1

Procedure:
A solution of 4-(1H-benzoimidazol-2-ylsulfanyl)-5-(1H-benzoimidazol-2-ylsulfanylmethyl)-3-hydroxy-5-hydroxymethyl-5H-furan-2-one (220 mg, 0.50 mmol), dimethylaminoacetyl chloride hydrochloride (174 mg, 1.10 mmol) and triethylamine (0.280 mL, 2.00 mmol) in DMF (15 mL) was stirred for 22 h. The reaction mixture was then passed through a plug of SiO2, which was then washed with hexane to remove excess DMF, and subsequently with a 1:1 mixture of EtOAc and MeOH to collect dimethylamino-acetic acid 3-(1H-benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-ylmethyl ester. Upon evaporation of solvent, the residue was subjected to column chromatography (SiO2: CH2Cl2:MeOH:Acetic Acid, 87:10:3 v/v/v) which yielded an off-white solid which was dissolved in 0.5 M HCl and lyophilized (73 mg, 26%, GLI-1007817b). 1H NMR (D2O, 300.16 MHz) δ: 7.20-7.38 (m, 8H), 4.67 (q, J=12.0 Hz, 2H), 3.9104.18 (m, 4H), 2.86-2.96 (m, 6H).). 13C NMR (D2O, 75.04 MHz) δ: 167.4, 165.4, 155.7, 147.2, 145.3, 131.5, 130.9, 126.2, 126.1, 113.1, 112.7, 102.0, 85.2, 65.8, 56.6, 43.7, 36.4. MS (ESI-Pos) m/z: 526.2 (M+H+).
Reaction SMILES: [C:1]([N:5]1[CH2:34][CH2:33][CH2:32][CH2:31][C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]([O:22]C)=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:35])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[C:1]([N:5]1[CH2:34][CH2:33][CH2:32][CH2:31][C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]([OH:22])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc2c(cc1OC)CCn1c3c(c(-c4cccs4)c1-2)CCCCN(C(C)(C)C)C3=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1C(=O)O)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 80 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
To a solution of 480 mg 26a in 10 mL methanol was added a solution of 164 mg potassium hydroxide in 10 mL water. The mixture was stirred at 80° C. for 5 h and then at 50° C. for 16 h. The reaction mixture was poured into a 2M solution of citric acid in water and was extracted with 2×50 mL dichloromethane. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give 460 mg of compound 26b.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24]C(=O)OC(C)(C)C)=[O:16])[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)Nc1cccc(O)c1
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)CCCCCC(=O)Nc1cccc(O)c1

Procedure:
The solution of tert-Butyl (2-(7-((3-hydroxyphenyl)amino)-7-oxoheptanamido)phenyl)carbamate in EtOAc was stirred at 0° C. and bubbled with HCl gas for 20 min. The pH value of the solution was adjusted to 6 by saturated aqueous solution of Na2CO3. The aqueous phase was extracted with EtOAc (100 mL). The organic layers were combined and dried over Na2SO4 and then concentrated to give the crude product. The crude product was purified by flash chromatography SiO2 (EtOAc) to give desired compound CC No. 2 (0.25 g, yield 25.7%).
Reaction SMILES: [OH-].[Li+].[C:3]1([CH3:22])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11]>CO.O>[C:3]1([CH3:22])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1OC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Lithium hydroxide (54 mg, 2.24 mmol) was added to a solution of methyl 4-(1-(o-tolyloxy)ethyl)benzoate (151 mg, 0.56 mmol) in methanol (100 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was removed in vacuo. 3 mol/L aqueous hydrogen chloride was added to make pH 2˜3, and the product was extracted with dichloromethane (100 mL*3) The combined organic phase was washed with Sodium Chloride (20 mL*3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 4-(1-(o-tolyloxy)ethyl)benzoic acid (127 mg, 88%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]1=[O:18].C(N(CC)CC)C>ClCCl>[S:2]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]1=[O:18])([CH3:1])(=[O:4])=[O:3]
Reactant: O=c1sc2ccccc2n1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1c(=O)sc2ccccc21

Procedure:
Methanesulfonyl chloride (1.625 ml, 2.4 g, 21 mmol) in dichloromethane (10 ml) was added dropwise with stirring to 3-(2-hydroxyethyl)benzothiazolin-2-one (3.9 g, 20 mmol) (J. J. D'Amico and F. G. Bollinger; J. Heterocyclic Chemistry 1988, 25, 1601).and triethylamine (3.478 ml, 2.525 g, 25 mmol) in dichloromethane (80 ml) and stirred for one hour at room temperature. The reaction mixture was then washed with water and dried (MgSO4), filtered and the solvent evaporated in-vacuo to give the title product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[N:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)C>[N:17]1([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=3)[N:4]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: FC(F)(F)c1ccc2nc(CCl)ccc2c1
Solvent: CCO
Product: FC(F)(F)c1ccc2nc(CN3CCOCC3)ccc2c1
Yield: 96.7 %

Procedure:
2-(Morpholin-4-ylmethyl)-6-trifluoro-methylquinoline may be prepared by carrying out the procedure as in Example 29, but starting with 3 g of 2-chloromethyl-6-trifluoromethylquinoline and 3.18 g of morpholine in 30 ml of ethanol. The crude product obtained is chromatographed on a silica gel column, eluting with a mixture of dichloromethane and methanol (97.5-2.5 by volume). 3.5 g of 2-(morpholin-4-yl-methyl)-6-trifluoromethylquinoline are thus obtained in the form of an orange-coloured oil [1H NMR spectrum in CDCl3, T=300K, δ in ppm (300 MHz): 2.55 (4H, m, 2 NCH2), 3.75 (4H, m, 2 OCH2), 3.85 (2H, s, NCH2), 7.75 (1H, d, J=8 Hz, arom. CH), 7.85 (1H, dd, J=8 and 2 Hz, arom. CH), between 8.10 and 8.25 (3H, m, 3arom. CH)].
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-chlorobenzoyl)indole (Example 30) and methoxyacetyl chloride. m.p.: 154-155° C. 1H-NMR (CDCl3) δ: 10.22 (1H, br s), 8.41 (1H, br s), 8.21 (1H, d, J=9.2 Hz), 7.77 (1H, dd, J=1.5, 2.2 Hz), 7.68 (1H, ddd, J=1.1, 1.5, 7.7 Hz), 7.59 (1H, ddd, J=1.1, 1.8, 7.7 Hz), 7.49 (1H, dd, J=7.7, 8.1 Hz), 7.34 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.8, 8.8 Hz), 4.05 (2H, s), 3.53 (3H, s)
Reaction SMILES: [Br:1]Br.[C:3]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=[O:5])[CH3:4].O>CO>[Br:1][CH2:4][C:3]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)C1Cc2ccccc2C1
Solvent: CO
Solvent: O
Product: O=C(CBr)C1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
10 g of pure bromine are rapidly added at 0° C. to a solution of 10 g of 2-acetylindane in 150 ml of anhydrous methanol. After one hour at ambient temperature, 100 ml of water are added and the whole is stirred for 12 hours. After extracting twice with 200 ml of diethyl ether each time, and washing the organic phase with a sodium hydrogen carbonate solution and then with water, the expected product is dried over magnesium sulphate and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: Cc1ccc(CO)cc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: Cc1ccc(COC(=O)CCC(=O)CN)cc1
Reaction time: 48 h

Procedure:
From 4-methylbenzyl alcohol (5.0 g; 41 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 2 days. The yield was 0.84 g (52%).
Reaction SMILES: NC1C=CC(C([NH:8][CH:9]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]([NH:19][CH:20]([CH:25]=[O:26])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[O:11])=O)=CC=1Cl.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([Cl:46])[C:44]=1[OH:45])[C:39]([OH:41])=O>>[Cl:46][C:43]1[CH:42]=[C:38]([CH:37]=[C:36]([Cl:35])[C:44]=1[OH:45])[C:39]([NH:8][CH:9]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([NH:19][CH:20]([CH:25]=[O:26])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[O:11])=[O:41]
Reactant: CS(=O)(=O)CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC(C=O)CC(=O)O
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Product: CS(=O)(=O)CC(NC(=O)c1cc(Cl)c(O)c(Cl)c1)C(=O)N1CCCC1C(=O)NC(C=O)CC(=O)O

Procedure:
Compound 20s was prepared according to the procedure used for the preparation of 20i, using 3,5-dichloro-4-hydroxybenzoic acid in place of 1-isoquinolinecarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([CH:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:43][O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]([CH:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:48][CH2:47][CH2:46][C:45]([O:44][CH3:43])=[O:49])=[O:24])=[CH:26][CH:27]=2)[CH2:16][CH2:17][CH3:18])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])=[CH:9][CH:10]=1
Reactant: CCCC(c1ccc(C(=O)O)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: COC(=O)CCN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the product from Step A (6.2 g, 15.3 mmol), EDC (4.4 g, 23.0 mmol), and HOBt (3.1 g, 23.0 mmol) in anhydrous DCM (200 mL) was stirred for 30 min at RT, then β-alanine methyl ester (2.1 g, 15.3 mmol) and DIEA (8.0 mL, 45.9 mmol) were added. After being stirred for 12 hours at RT, the mixture was diluted with DCM then washed with 100 mL of 0.5 M HCl (aq) then 100 mL of saturated NaCl (aq). The organic layer was dried over Na2SO4, filtered, then concentrated. The major diastereomer of the title compound was obtained by trituration with hexane.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:14])[C:12]=1[CH3:13].CN([CH:18]=[O:19])C.[NH4+].[Cl-]>CCCCCC>[Br:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:18]=[O:19])[CH:8]=[N:9][CH:10]=1
Reactant: Cc1c(Br)cncc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: Cc1c(Br)cncc1C=O
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
Under argon, an n-butyllithium solution in hexane (1.55N, 4.6 ml) is added dropwise to a 3,5-dibromo-4-methylpyridine solution (intermediate 10.1, 1.76 g, 7 mmol) kept at −100° C. After stirring for 5 min, DMF (0.84 ml, 1.54 equiv.) is added dropwise. The stirring is maintained for 20 min at −100° C. and then for 1 h at −78° C. An aqueous NH4Cl solution is added and the reaction mixture is extracted with a diethyl ether/water mixture. The yellow solid obtained is purified on silica gel (100 g), eluting with AcOEt/petroleum ether (1/4).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[CH3:10][C:11]([O:15]C1CCCCO1)([CH3:14])[CH:12]=O.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:10][C:11]([CH3:14])([OH:15])[CH3:12])=[CH:4][N:3]=1
Reactant: CC(C)(C=O)OC1CCCCO1
Reactant: Nc1cnc(Cl)nc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(O)CNc1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
To a mixture of 2,4-dichloropyrimidin-5-amine (542 mg, 3.31 mmol) and 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanal (740 mg, 4.30 mmol) in dichloromethane (10 ml) at 0° C. was added dropwise a solution of titanium tetrachloride (0.401 ml, 3.64 mmol) in dichloromethane (4 ml). After the reaction mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (656 mg, 9.92 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 16 hours. After the reaction mixture was diluted with dichloromethane, the reaction mixture was poured carefully into NaHCO3 aqueous solution. EtOAc was added and then the insoluble materials were filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, dried and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 2:3) to afford 1-(2,4-dichloropyrimidin-5-ylamino)-2-methylpropan-2-ol (315 mg, 1.34 mmol, 40% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (s, 6 H) 3.16 (d, J=6.32 Hz, 2 H) 4.64 (s, 1 H) 5.60-5.68 (m, 1 H) 8.31 (s, 1 H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(O)CC(C)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(4-chlorophenyl)piperazine (100.2 mg; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 and worked up; yield: 83 mg (47%), crystals;
Reaction SMILES: CC1CC(=O)CC(C)(C)C=1.[CH3:11][C:12]1[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[CH2:16][C:14](=[O:15])[CH:13]=1.CC1CC(C)(C)CC(=O)C=1>>[CH3:11][C:12]1[CH:18]([OH:19])[C:17]([CH3:21])([CH3:20])[CH2:16][C:14](=[O:15])[CH:13]=1
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Agent: CC1=CC(C)(C)CC(=O)C1
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: CC1=CC(=O)CC(C)(C)C1O

Procedure:
It is well known that beta-isophorone can be oxidized by air using noble metal catalysts (FR-A 2 335 486). In addition to 4-ketoisophorone and alpha-isophorone, the desired 4-hydroxyisophorone is obtained in this reaction as a byproduct also. 4-Hydroxyisophorone can also be obtained directly from alpha-isophorone in small yields using a biochemical method with Aspergillus niger (JP-OS 81 35 990; Y. Mikami et al., Agric. Biol. Chem. 1981, 45, 791-3). A. Heymes and P. Teisseire obtained 4-hydroxyisophorone in 34% yield by oxidation with monoperphthalic acid (Recherches 1971, 18, 104-8), while N. S. Zarghami and D. E. Heinz (Phytochemistry 1971, 10, 2755-61) disclosed no yield information for the reaction with peracetic acid. J. N. Marx and F. Sondheimer report a yield of 87% from the treatment of beta-isophorone with m-chloroperbenzoic acid, but the recalculation of the results they reported shows only a yield of 56%, which is also in agreement with other information in the literature (Tetrahedron, Suppl. No. 8, Pt. 1, 1-7, 1966; see also O. Isler et al., Helv. Chim. Acta 39, 2041, 1956).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH:18]12[O:24][CH:23]1[CH2:22][CH2:21][CH2:20][CH2:19]2>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH:22]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:23]3[OH:24])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C1CCC2OC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2C2CCCCC2O)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 gm, 5 mmol) was taken in DMF (10 ml). NaH (300 mg, 12.5 mmol) was added to it and the reaction mixture stirred at RT for 15 min. 7-oxabicyclo[4.1.0]heptane (0.9 ml, 9.0 mmol) was taken in DMF (3 ml) and added drop wise to the reaction mixture. After complete addition, reaction mixture was heated at 60-65° C. overnight. The reaction was monitored by LCMS. After completion of the reaction, reaction mixture was cooled to RT and quenched with water, extracted with ethyl acetate (3×25 ml), dried over sodium sulfate and concentrated under vacuum to obtain the crude product. This crude was purified by silica gel column chromatography (Eluent: 20% Methanol in DCM) to get 900 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)cyclohexanol as yellow semi solid. 1H NMR (CDCl3) FREE BASE 7.37-7.30 (m, 2H), 7.20 (s, 1H), 4.37-4.22 (bs, 1H), 3.67-3.64 (s, 1H), 3.61-3.57 (m, 2H), 3.0-2.80 (m, 3H), 2.60-2.40 (m, 7H), 1.98-1.82 (m, 4H), 1.50-1.38 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH:12]=O)[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([Mg]Br)[CH3:17].C(OCC)(=O)C>C(OCC)C.CCCCCC>[CH:12]1([N:7]2[CH2:6][C:5]([CH3:15])([CH3:14])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[CH2:8]2)[CH2:17][CH2:16]1
Reactant: CC1(C)CN(C=O)Cc2ccc(O)cc21
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CN(C2CC2)Cc2ccc(O)cc21
Temperature: 55 °C
Yield: 63 %

Procedure:
A stirred, cooled (0° C.)solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 20, 2.3 g, 11.21 mmol) in anhydrous tetrahydrofuiran (40 mL) under argon was treated with titanium tetra-iso-propoxide (8.28 mL, 28 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (18.7 mL) and the reaction mixture was then heated at 55° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a yellow oily solid. Flash column chromatography over silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent afforded the title compound as a pale yellow solid (1.55 g, 63%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([NH:19]C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]#[C:17][CH3:18])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[ClH:27].C(OCC)(=O)C>>[ClH:27].[C:1]([O:4][CH2:5][C@@H:6]([NH2:19])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]#[C:17][CH3:18])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC#CCOc1ccc(C[C@@H](COC(C)=O)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C[C@H](N)COC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propyl acetate was dissolved in a solution (3.0 mL) of 1 M hydrogen chloride/ethyl acetate, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound.