Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)ncnc1N1CCCCC1
Solvent: ClC(Cl)Cl
Product: Cc1c(CCl)ncnc1N1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Thionyl chloride (4.5 ml) in chloroform (30 ml) was added dropwise to a stirred solution of 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine (4.24 g) in chloroform (30 ml) cooled in an ice-salt bath. The mixture was allowed to warm to room temperature and stirred for a further 22 hours. The solution was stripped to a residual glass which was triturated with diethyl ether to give 4-chloromethyl-5-methyl-6-piperidino-pyrimidine hydrochloride, 5.24 g, m.p. 182°-184°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].Br.Br[CH2:10][C:11](=[O:21])[CH2:12][C@H:13]1[C@H:18]([O:19][CH3:20])[CH2:17][CH2:16][CH2:15][NH:14]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[Br:33])[N:29]=[CH:28][NH:27][C:26]2=[O:34]>>[Br:33][C:32]1[CH:31]=[C:30]2[C:25]([C:26](=[O:34])[N:27]([CH2:10][C:11]([CH2:12][CH:13]3[CH:18]([O:19][CH3:20])[CH2:17][CH2:16][CH2:15][N:14]3[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3])=[O:21])[CH:28]=[N:29]2)=[CH:24][C:23]=1[Cl:22]
Reactant: C=CCOC(=O)Cl
Reactant: CO[C@@H]1CCCN[C@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2cc(Br)c(Cl)cc12
Agent: Br
Product: C=CCOC(=O)N1CCCC(OC)C1CC(=O)Cn1cnc2cc(Br)c(Cl)cc2c1=O

Procedure:
The said known procedure comprises reacting trans 1-(3-methoxy-2-piperidyl)-2-propanone hydrobromide with hydrobromic acid as in U.S. Pat. No. 2,775,597 to form the trans 3-bromo-1-(3-methoxy-2-piperidyl)-2-propanone hydrobromide, reacting the latter with allyl chloroformate as indicated in J. Org. Chem., Vol. 20 (1955), p. 118-142 to block the nitrogen atom of the piperidine with allyloxycarbonyl by forming 1-allyloxycarbonyl-2-(ω-bromoacetonyl)-3-methoxypiperidine, condensing the latter with 6-chloro-7-bromo-3,4-dihydro-4-quinazolinone as described in French Pat. No. 1,550,956 to obtain 7-bromo-6-chloro-3-[3-(1-allyloxycarbonyl-3-methoxy-2-piperidyl)-acetonyl]-4(3H)-quinazolinone, subjecting the latter to hydrobromic acid as taught in French Pat. No. 1,550,956 to obtain 7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidyl)-acetonyl]-4(3H)-quinazolinone hydrobromide and treating the latter with a base to form the corresponding free base which if desired may be salified with a non-toxic, pharmaceutically acceptable acid to form the desired acid addition salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C(OC(OCC)C[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:35]([NH:34][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH3:16])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(CNCc1ccccc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A except using 2(S)-t-butoxycarbonylaminohexanoic acid (1.98 g, 8.57 mmol), EDC.HCl (1.96 g, 10.28 mmol), N-benzyl 2-aminoacetaldehyde diethyl acetal (1.91 g, 8.57 mmol), HOBT (1.15 g, 8.57 mmol) in DMF. The title compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.[N:18]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1)#[N:18]
Reactant: N#CBr
Reactant: Cc1ccc2onc(C3CCN(C)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2onc(C3CCN(C#N)CC3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
A suspension of 0.5 g of 3-(1-methyl-4-piperidyl)-5-methyl-1,2-benzisoxazole, 0.37 g of cyanogen bromide and 1.5 g of potassium carbonate in 50 ml of chloroform was heated under reflux for 48 hrs and stirred at room temperature for 48 hrs. The reaction was filtered, the solvent was removed and the residue was triturated with hexane to give a solid. The solid was recrystallized from hexane (three times) to give 0.178 g (37%) of product, mp, 125°-126°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:6]=2[C:22]=1[Br:23].[C:24](Cl)(Cl)=[O:25]>ClCCCl.C1(C)C=CC=CC=1.ClC(Cl)C>[Br:23][C:22]1[C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:8][C@@H:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[CH:3][C:2]=1[N:1]=[C:24]=[O:25]
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N)c2Br)N(C)C1=O
Reactant: O=C(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(N=C=O)c2Br)N(C)C1=O

Procedure:
50 g (0.127 mol) of (S)-7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one are dissolved in 700 ml of 1,2-dichloroethane while warming and the still hot solution is added dropwise while stirring and cooling to a mixture of 90 ml (0.173 mol) of a 20 percent solution of phosgene in toluene and 500 ml of dichloroethane in such a manner that the temperature does not exceed 10°. The mixture is subsequently heated to boiling under reflux while stirring for 1 hour, 500 ml of 1,2-dichloroethane are distilled off, the solution is cooled to 10°, made basic with triethylamine and evaporated, there being obtained (S)-[6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate as a foam which can be stored for several days in a refrigerator with the exclusion of moisture.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[C@H:12]([C:13]([CH2:15]Br)=[CH2:14])[CH2:11][N:10]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCN(C)C1=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@@:8]12[CH2:14][C:13](=[CH2:15])[C@@H:12]1[CH2:11][N:10]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(CBr)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Product: C=C1C[C@@]2(C(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
(3S,4R)-1-Benzyloxycarbonyl-4-[1-(bromomethyl)vinyl]pyrrolidine-3-carboxylic acid tert-butyl ester (22.8 g, 53.7 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (19.5 mL, 161 mmol) were dissolved in a mixed solution of tetrahydrofuran (220 mL) and toluene (220 mL). Lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran) (80.6 mL, 80.6 mmol) was added dropwise at −78° C., and then the mixture was stirred at room temperature for five minutes. The reaction solution was extracted with a saturated ammonium chloride solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=24:1→2:1) to give 8.34 g of the title compound as a colorless syrup.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.O1CCOCC1.[OH-].[Na+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O.C(OCC)(=O)C>[C:18]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
In a 1-L round-bottom flask with a stir bar and equipped with an additional funnel was charged isonipecotic acid (13 g, 0.1 mol) followed by 1,4-dioxane (50 mL). The resulting stirred white suspension was added 5N NaOH aqueous solution (30 mL, 0.15 mol) at room temperature and the overall almost homogeneous solution was cooled in an ice-water bath. CbzCl (19 mL, 0.13 mol) was dropped from an additional funnel slowly in 15 min and the overall heterogeneous mixture was stirred at room temperature for 3.5 h. The resulting mixture was diluted with water (20 mL) and ethyl acetate (100 mL) and the separated aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give the N-Cbz isonipecotic acid 3 as a colorless oil which was carried through to the next step without further purification. MS (ES+): 264 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[C:13]([CH2:17][CH2:18][OH:19])=[N:12][C:11]=2[CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:25]([N:27]=C=O)=[O:26]>O1CCCC1.O>[C:25]([O:19][CH2:18][CH2:17][C:13]1[N:14]([CH2:15][CH3:16])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:20]([CH3:21])[CH3:22])[N:12]=1)(=[O:26])[NH2:27]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCn1c(CCO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(CCOC(N)=O)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
In 15 ml of dry tetrahydrofuran was dissolved 1.5 g (4.2 mmol) of the alcohol compound (123a), and the mixture was cooled to -30° C., followed by addition of 1.2 g (6.4 mmol) of trichloroacetylisocyanate. After 5 minutes, the mixture was warmed to 0° C., and stirred for 10 minutes. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water, and ethyl acetate was distilled off. To the residue was added 15 ml of methanol, 0.26 g of triethylamine and 0.72 ml of water, and the mixture was heated at 50° C. for 0.5 hours. The mixture was diluted with ice-water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% methanol:ethyl acetate), and recrystallized from ethyl acetate-n-hexane to give 1.5 g of Compound I-137 as crystals (yield 89%). mp 161-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:7]([CH:8]=O)=[C:6]([N+]([O-])=O)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2].[CH3:21]N(C)C=O.C[CH:27]([SH:31])[C:28]([O-:30])=[O:29]>C(N(CC)CC)C>[CH3:21][O:30][C:28]([C:27]1[S:31][C:6]2[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([O:3][CH2:1][CH3:2])[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:7]=2[CH:8]=1)=[O:29]
Reactant: CCOc1cc(C=O)c([N+](=O)[O-])c([N+](=O)[O-])c1OCC
Reactant: CC(S)C(=O)[O-]
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc2cc(C(=O)OC)sc2c([N+](=O)[O-])c1OCC
Reaction time: 8 h

Procedure:
4,5-Diethoxy-2,3-dinitro-benzaldehyde (1.53 g) was dissolved into N,N-dimethylformamide (6 ml) and then methylthioglycolate (1.36 ml) was added. Triethylamine (2.6 ml) was added in cold to the reaction solution. The mixture was stirred overnight. The solid was filtered and washed with N,N-dimethylformamide.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:34]3[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]3)=[C:28]([O:35][CH3:36])[C:27]=2[CH3:37])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].[CH2:38]([O:41][NH2:42])[CH:39]=[CH2:40].C(N(CC)CC)C>O1CCOCC1.O>[CH3:36][O:35][C:28]1[C:27]([CH3:37])=[C:26]([C:24]([C:21]2[CH:22]=[CH:23][C:14]([NH:13][C:5](=[O:11])[NH:42][O:41][CH2:38][CH:39]=[CH2:40])=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:25])[N:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[CH:33]2
Reactant: C=CCON
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=CCONC(=O)Nc1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1C(=O)OC
Reaction time: 2.5 h
Yield: 160 %

Procedure:
0.251 g (0.83 mmol) of triphosgene diluted in 3 ml of dioxane is added, under an inert atmosphere at ambient temperature, to 0.4 g (1.18 mmol) of methyl 2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoate in 10 ml of dioxane. After stirring for 2.5 hours, 0.267 g (2.36 mmol) of O-prop-2-en-1-ylhydroxylamine and 0.82 ml (5.91 mmol) of triethylamine are added. The reaction medium is stirred for one hour and then hydrolysed with water. The aqueous phase is extracted with dichloromethane. The organic phase obtained is washed with a 1N aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium chloride, and then dried over sodium sulphate, filtered, and concentrated under reduced pressure. 0.581 g of a yellow solid is obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C([O-])(O)=O.[Na+].O>CN(C=O)C>[O:14]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(N)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(NCC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.0 g, 7.74 mmol), 2-bromoacetophenone (3.08 g, 15.5 mmol), and NaHCO3 (1.30 g, 15.5 mmol) in DMF (20 mL) was stirred at ambient temperature for 18 h. H2O (20 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, adjusted to pH 10 by addition of saturated aqueous Na2CO3 and extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11](O)([CH3:13])[CH3:12].S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[C:6]([C:11]([CH3:13])([CH3:12])[CH3:10])[CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cc1cc(O)ccc1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cc(O)c(C(C)(C)C)cc1Br
Temperature: 25 °C
Yield: 51 %

Procedure:
A solution of 4-bromo-3-methylphenol (Aldrich, 5.1 g, 27.3 mmol) in anhydrous dichloromethane (50 mL) was treated with 2-methyl-2-propanol (15 mL) and concentrated sulfuric acid (3 mL) and stirred at ambient temperature for 3 months. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography using 3–5% ethyl acetate in hexane as the eluent afforded the title compound as a deep yellow oil (3.42 g, 51%). It was used as such for the next step.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:6]=1[O:7][CH2:8][CH:9]([OH:33])[CH2:10][O:11][C:12]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:4].[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C)C=O>[CH2:3]([C:5]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:6]=1[O:7][CH2:8][CH:9]([O:33][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:10][O:11][C:12]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(CC)c(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(CC)c(OCC(COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a suspension of 1.87 g of prewashed 50% sodium hydride in 50 ml of dimethylformamide was added a solution of 17.26 g of 1-(2-ethyl-5-tetradecylphenoxy)-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol in 50 ml of dimethylformamide. This mixture was stirred for 15 minutes, then 5.79 g of benzyl bromide was added. This mixture was stirred 3 hours, quenched slowly with water and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvent removed, giving 19.1 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(O)(=O)C.CN.[C:19]([BH3-])#[N:20].[Na+]>CO.O1CCCC1>[CH3:19][NH:20][CH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNCc1c[nH]c2cc(C)ccc12
Reaction time: 1 h

Procedure:
To a suspension of 6-methyl-1H-indole-3-carbaldehyde (0.96 g, Lit. 5) in methanol (15 ml) was added at 22° C. acetic acid (1.7 ml) and a solution of methylamine in tetrahydrofurane (2 M, 12.0 ml). After stirring for 1 h, sodium cyanoborohydride (0.76 g) was added in 5 portions and stirring was continued for 2 h. The mixture was evaporated and the residue partitioned between aqueous hydrochloric acid (1 N) and dichloromethane. The pH of the aqueous layer was adjusted to 14 using sodium hydroxide followed by extraction with dichloromethane. The organic layer was dried and evaporated to give crude methyl-(6-methyl-1H-indol-3-ylmethyl)-amine.
Reaction SMILES: [C:1]([S:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH2:23][N:24]1C(=O)C2C(=CC=CC=2)C1=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[C:1]([S:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH2:23][NH2:24])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
2-[2-(Tritylsulfanyl)benzyl]-1H-isoindole-1,3(2H)-dione (4.7 g, 9.19 mmol) was suspended in EtOH (150 mL) and treated with hydrazine monohydrate 65% (4.66 mL, 62 mmol). The mixture was heated under reflux for 1.5 h, cooled to RT and the precipitate was filtered. The filtrate was concentrated, triturated with EtOAc and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (3.0 g, 86%) as a colourless oil. 1H NMR (300 MHz, CDCl3): δ 7.34-7.28 (6H, m), 7.26-7.18 (9H, m), 7.15 (2H, m), 7.10 (1H, m), 6.93-6.85 (1H, m), 3.40 (2H, s).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O-:32].[Na+].O>O1CCCC1>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cn1
Yield: 85 %

Procedure:
To 250 mg of 6-fluoro-4-(4-phenoxy-phenylamino)-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 266 mg (85%) of 6-(2-dimethylamino-ethoxy)-4-(4-phenoxy-phenylamino)-[1,7]naphthyridine-3-carbonitrile as a yellow solid: melting point 159-161° C.; mass spectrum (m/e): M+H 426.0.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH3:9][O:10][C:11]1([O:23][CH3:24])[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1.IC(C)C>C1COCC1.CCOCC>[CH:3]([C:13]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15][C:11]([O:23][CH3:24])([O:10][CH3:9])[CH2:12]1)([CH3:4])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)I
Solvent: CCOCC
Product: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a cooled (−78° C.) solution of LDA (1.5 M in cyclohexane, 41 mL, 61 mmol) in THF (150 mL) was added dropwise over 10 min tert-butyl 3,3-dimethoxycyclopentanecarboxylate (9.37 g, 40.7 mmol) in 25 mL of THF. The resulting mixture was stirred at −78° C. for 30 min, then was treated dropwise with 2-iodopropane (16.3 mL, 163 mmol). After stirring for an additional 10 min, the reaction mixture was permitted to warm to room temperature. After stirring overnight, the reaction mixture was diluted with ether and washed with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. After storing the crude product under vacuum overnight, it was purified by MPLC (silica, 20% ethyl acetate/hexane) to give 8.32 g of tert-butyl 1-isopropyl-3,3-dimethoxycyclopentanecarboxylate (75%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=O.[BH4-].[Na+].[C:21](C1NC=CN=1)(C1NC=CN=1)=[O:22]>CCO.O>[CH:1]1([N:7]2[CH2:11][C:10]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:9]=3[O:8][C:21]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1ccc(C=O)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)OC(=O)N(C1CCCCC1)C2
Reaction time: 1.5 h

Procedure:
40 g of cyclohexylamine are added to a solution of 26 g of 2-hydroxy-4-methoxy-benzaldehyde in 800 ml of absolute EtOH at RT. The mixture obtained is stirred for 1.5 hours, cooled to 0°, and 20 g of NaBH4 are added in portions. The mixture obtained is stirred for 3 hours at RT, poured into H2O and the mixture obtained is extracted with CH2Cl2. Two phases are formed and are separated. The organic layer obtained is dried, 42 g of carbonyl-diimidazole are added and the mixture obtained is stirred for 16 hours at RT. Additional 21.5 g of carbonyl-diimidazole are added, the mixture obtained is stirred for 3 hours, washed with 1N HCl, a saturated, aqueous solution of NaHCO3 and brine, dried and concentrated in vacuo. 3-Cyclohexyl-7-methoxy-3,4-dihydrobenzo[e][1,3]-oxazin-2-one is obtained. m.p.: 76-77°.