Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][CH:43]=[CH:42][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@@H:18]2[O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]3[O:39][C:38](=[O:40])[NH:37][C:36]=3[CH:41]=2)=[CH:13][CH:12]=1.[H-].[Na+].Cl[CH2:49][CH2:50][CH2:51][O:52][CH3:53].[I-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:45]=[CH:44][CH:43]=[CH:42][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]3[O:39][C:38](=[O:40])[N:37]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:36]=3[CH:41]=2)=[CH:13][CH:12]=1
Reactant: COCCCCl
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3oc(=O)[nH]c3c2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCn1c(=O)oc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
The solution of 0.206 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-(3R,4R)-3-(2-oxo-2,3-dihydrobenzoxazol-5-ylmethoxy)piperidine-1-carboxylate in 2 ml of N,N-dimethylformamide is cooled to 0° C. with stirring and admixed with 12 mg of sodium hydride dispersion (60%). The mixture is stirred at 0° C. for 30 minutes and subsequently admixed with 0.048 ml of 1-chloro-3-methoxypropane and 5 mg of sodium iodide. The reaction mature is stirred at 80° C. for 14 hours, cooled and poured onto water (40 ml). The mixture is extracted with ethyl acetate (2×40 ml). The organic phases are washed successively with water (2×40 ml) and brine (1×40 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue as a slightly yellowish oil by means of flash chromatography (SiO2 60F). Rf=0.25 (2:1 toluene-EtOAc); Rt=6.03.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[C:9](=[O:19])[N:10]3C(C4C=CC=CC=4)[O:12][C:3]=1[C:4]=23.B.[Na].[C:28](OCC)(=O)C.O>CO>[OH:12][C:3]1[C:4]2[NH:10][CH:9]([O:19][CH3:28])[CH:8]3[CH2:20][CH2:21][CH2:22][N:7]3[C:6](=[O:23])[C:5]=2[CH:24]=[CH:25][C:2]=1[CH3:1]
Reactant: CCOC(C)=O
Reactant: Cc1ccc2c3c1OC(c1ccccc1)N3C(=O)C1CCCN1C2=O
Agent: B
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Then, 1.43 g of the 6,8,9,10,10a,11-hexahydro-3-methyl-1-phenyl-1H-oxazolo[5,4,3-jk]pyrrolo[2,1-C] [1,4]benzodiazepin-6,11-dione was dissolved in 110 ml of methanol. To the solution, cooled to 0° to 5° C., was slowly added 820 mg of sodium boron hydride with stirring, and the whole mixture was stirred at 0° to 5° C. for 2.5 hours. 800 ml of ethyl acetate and 500 ml of water were added to the reaction mixture, the ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The both ethyl acetate layers were combined, dehydrated and concentrated under reduced pressure. The concentrate was dissolved in 375 ml of 2:1 mixture of methyl alcohol and 0.01 N hydrochloric acid and subjected to hydrolyzation at room temperature for 3 hours with stirring. The liquid reaction mixture was extracted with chloroform, the chloroform layer was washed with water and then it was concentrated under reduced pressure at a temperature not exceeding 40° C. The concentrate was dissolved in 50 ml of methanol and heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure at 40° C. or below. The concentrate was dissolved into 4 ml of hot methanol, cooled to -20° C. and allowed to stand at this temperature for 3 days. Thus, 0.35 g of 2,3,5,10,11,11a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo[2,1-C] [1,4]benzodiazepin-5-one was obtained in a colorless crystalline form. Recrystallization of the resulting product from methanol gave a colorless needle-like crystal having a melting point of 152.5° to 155.5° C.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)[C:4]=2[O:3]1.[F:26][C:27]1[CH:28]=[C:29]([NH:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:33]([C:29]5[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=5)[N:34]=[CH:20][CH:19]=4)=[N:12]3)[C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OC(F)(F)O3)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2cccc3c2OC(F)(F)O3)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-15) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=413.2 (M+H)+
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:29][C:30]([Cl:37])([Cl:36])[CH2:31][O:32][C:33](Cl)=[O:34].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:29][C:30]([Cl:37])([Cl:36])[CH2:31][O:32][C:33]([N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:4][CH2:3]1)=[O:34]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Temperature: 25 °C

Procedure:
To a mixture of 430 mg (1.55 mmol) of 1-methyl-4-(9H-xanthene-9-ylidene)piperidine [Tetrahedron Letters, 29, 5701 (1988)] and 649 μL (4.65 mmol) of triethylamine in 20 mL of dry toluene at 85° C. under an atmosphere of argon was added over 10 min 1.06 mL (7.7 mmol) of 2,2,2-trichloroethyloxycarbonyl chloride. After 30 min the mixture was cooled to room temperature, poured into a solution of 25% aqueous sodium hydroxide, and was extracted with ethyl acetate (3×). The combined organic portions were dried over sodium sulfate, filtered, and concentrated with vacuo to afford the title compound as a crude oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[C:8]([Br:17])[N:7]=1)=O)C.O.[NH2:19][NH2:20].O>CCO>[NH2:12][C:11]1[C:6]([C:4]([NH:19][NH2:20])=[O:3])=[N:7][C:8]([Br:17])=[C:9]([C:13]([F:16])([F:15])[F:14])[N:10]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Temperature: 90 °C

Procedure:
To a solution of 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Int. F1) (1.00 g, 3.18 mmol) in dry EtOH (25 ml) was added hydrazine monohydrate (309 ul, 6.37 mmol) and the mixture was stirred at reflux (ca. 90° C.). After 3 hr 45 min the reaction mixture was cooled in an ice bath and added to water. The resulting yellow ppt was filtered under vacuum and dried in a vacuum oven overnight to give the title compound as a yellow solid 1H NMR (400 MHz, DMSO-d6) 610.10 (1H, s), 8.00 (2H, s), 4.65 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>P(Cl)(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:26][CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:9]2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCN(C(=O)Cc2ccc(OCc3ccccc3)cc2)c2ccc(F)cc2)c1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A solution of N-(4-fluorophenyl)-N-{2-(3-methoxyphenyl)ethyl}-2-{4-(phenylmethoxy)phenyl}acetamide (6.0 g, 12.8 mmol) in phosphorous oxychloride (130 mL) under nitrogen was heated to 80° C. After 20 hours, the reaction was cooled to RT and very slowly poured over ice with vigorous stirring. Ethyl acetate (500 mL) was then added and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (4.61 g, 80% yield): ES−MS (m/z) 452 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@@H:10]3[CH:11]=[CH:12][C:13](=[O:20])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.C([O-])([O-])=O.[K+].[K+].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>CN(C=O)C>[CH:28]1([C:31]([N:19]2[CH2:18][CH2:17][C@@:15]34[C:16]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[CH2:11][CH2:12][C:13](=[O:20])[CH2:14]4)=[O:32])[CH2:30][CH2:29]1
Reactant: COc1cccc2c1[C@]13CCN[C@H](C2)[C@@H]1C=CC(=O)C3
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1[C@]13CCN(C(=O)C4CC4)[C@H](C2)[C@@H]1CCC(=O)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a mixture of 1.5 g (5.18 mmol) 4-methoxymorphinen-6-one.1 H2O, 1.3 g (9.41 mmol) anhydrous K2CO3 and 10 ml dry DMF were added dropwise a solution of 0.29 ml (5.31 mmol) cyclopropanecarboxylic acid chloride in 5 ml dry DMF during 10 min. at room temperature. This mixture was stirred at room temperature for 1 h, then poured on 50 ml ice water and extracted with ether. The organic layer was extracted with 2 N HCl, water and brine, dried and evaporated to give an oil, which was crystallized with ether/n-hexane. To 1.5 g (85%) N-cyclopropylcarbonyl-4-methoxymorphinan-6-one, m.p. 144°-147°, [α]D26 -210.0° (c 1.04, CHCl3), were obtained.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: NCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Product: N#Cc1cccc(NC(=O)NCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 2-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 210-a) as a starting material, and using 3-cyanophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([NH2:27])=[N:19][C:20]([NH2:26])=[N:21]3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([NH2:27])=[N:19][C:20]([NH2:26])=[N:21]3)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc3nc(N)nc(N)c23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
4-(2,4-Diamino-quinazolin-5-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (16.4 g; 44.0 mmol) was suspended in 80 mL of dioxane and 4M HCl in dioxane (176 mL, 176 mmol) was added changing the mixture from homogenous to heterogenous. After 5 hrs of stirring at room temperature, solids were filtered off and rinsed once with ether. Solids were triturated with 1 N NaOH for 30 minutes. Solids were collected by filtration and dried to yield 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine. (9.05 g; 75% yield).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])[CH3:6].C(O[C:18](=O)[CH2:19][C:20]1[S:24][CH:23]=[N:22][C:21]=1[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)C>C(Cl)Cl>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:21]1[N:22]=[CH:23][S:24][C:20]=1[CH2:19][C:18]1[N:7]([CH2:5][CH3:6])[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]=1
Reactant: CCNc1ccncc1N
Reactant: CCOC(=O)Cc1scnc1-c1nccs1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCn1c(Cc2scnc2-c2nccs2)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (2M in toluene)(2.2 mL, 4.4 mmol) is added dropwise under N2 yo a solution of N4-Ethyl-pyridine-3,4-diamine (237 mg, 1.73 mmol) in DCM (5 mL). The mixture is stirred at room temperature for 1 hour. A solution of [2,4′]bithiazolyl-5′-yl-acetic acid ethyl ester (440 mg, 1.73 mmol mmol) in DCM (2 mL) is added. The mixture is reluxed for 3 days. On cooling, the reaction is quenched with water added dropwise and DCM (40 mL) is added. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and solvent removed. The residue is purified by PTLC (10% methanol in DCM) to give 2-[2,4′]bithiazolyl-5′-ylmethyl-1-ethyl-1H-imidazo[4,5-c]pyridine as a solid. 1H NMR (CDCl3) δ 9.05 (s, 1H0), 8.76 (s, 1H), 8.41 (d, 1H), 7.88 (d, 1H), 7.41 (d, 1H), 7.25 (d, 1H), 5.35 (8, 2H), 4.26 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:25])[N:3]=1.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31]O>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH3:33])[CH3:26])=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:25])[N:3]=1
Reactant: CN(C)CCCCO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCCCN(C)C)cc1O

Procedure:
The title compound was prepared using product of example 79 step (i) (80 mg) and 4-(dimethylamino)butan-1-ol using the general coupling method of example 74 step (iii). The product was purified by RPHPLC to give the product, 25 mg.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:44][C:45](=[O:49])[C@H:46]([CH3:48])[NH2:47])C>CCOCC>[CH3:32][Si:29]([CH3:30])([CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:47][C@H:46]([C:45]([OH:49])=[O:44])[CH3:48])=[O:11])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1)C(=O)O

Procedure:
A solution of 4.64 g. of 4-[N-trifluoroacetyl-14-(trimethylsilyl)tetradecylamino]benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization yields the product as a white, crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]([OH:15])[CH2:13][OH:14])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(O[Si](C)(C)C)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1>C(OCC)C.Cl>[CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:13][O:14][C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15]1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)[C@@H](CO)OCc1ccccc1
Reactant: C[Si](C)(C)OC1=CCCCC1
Agent: Cl
Solvent: CCOCC
Product: OC[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96624.1 %

Procedure:
4.34 g (0.02 mol) of (2R,3R)-2-benzyloxybutane-1,3,4-triol were suspended in a mixture of 3.4 g (0.02 mmol) of 1-cyclohexenyloxytrimethylsilane and 40 ml of diethyl ether. Two drops of concentrated hydrochloric acid were added and the mixture was stirred at room temperature for 30 minutes. The mixture was then evaporated to give 5.65 g of β(R)-benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in the form of a colourless viscous oil; MS: m/e 292 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>CCN(CC)CC>[CH3:25][O:24][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCc1cccs1
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCc1cccs1
Reaction time: 4 h

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-[5-(2-thienyl) pentoxy] quinoline (4.00 g, 0.0108 mol) and 4-bromo-1-phthalimidopentane (BPP) (6.40 g, 0.0216 mol) was heated at 110°-115° C. while Et3N (4 ml) was slowly added during 25 min. After 4 h at 115°-120° C., more BPP (6.4 g, 0.0216 mol) and Et3N (2 ml during 10 min) were added and heating was continued for 4 h. A final batch of BPP (1.60 g, 0.0054 mol) and Et3N (1 ml during 5 min) were added and heating was continued for 2 h. On cooling, the mixture was extracted with Et2O (200 ml) leaving behind a gray residue. The extract was washed with H2O (2×75 ml), dried (Na2SO4) and concentrated to a black oil. The oil was dissolved in CHCl3 (12 ml), applied to a silica gel column and eluted with 5% EtOAc in hexane. After recovering the unreacted BPP, the eluting solvent was changed to 10% EtOAc in hexane. Product eluates were combined and concentrated to give 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-[5-(2-thienyl) pentoxy] quinoline as a thick orange-yellow oil, 5.57 g (87%). This material was used without further purification.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:33]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)#[N:34].O>CS(C)=O>[C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:5][CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:37][CH:36]=1)#[N:34]
Reactant: CS(=O)(=O)OCCCC1CCN(CCCOc2ccc(C#N)cc2)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Into a solution of 91.9 g of 3-{1-[3-(4-cyanophenoxy)propyl]-4-piperidinyl}propyl methanesulfonate in 460 mL of dimethylsulfoxide, 66.9 g of potassium carbonate and 28.8 g of 4-cyanophenol were added at room temperature, and the solution was stirred at 60° C. for 2 hours. To the reaction mixture, after being cooled down to room temperature, 640 mL of water was dropped over 20 min, and then the mixture was stirred at room temperature for 35 min, and under water cooling for 30 min. The solid matter was collected by filtration, and washed twice with 180 mL of water and then 360 mL of 2-propanol to obtain 90.0 g of 4-(3-{4-[3-(4-cyanophenoxy)propyl]-1-piperidinyl}propoxy)benzonitrile as a white solid.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(N(CC)CC)C.[Cl-].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>CN(C)C=O.Cl>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:27]([C:26]1[CH:30]=[CH:31][C:23]([C:22]([O:33][CH3:34])=[O:32])=[CH:24][CH:25]=1)=[O:28])#[N:10]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Br
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Reaction time: 3 h

Procedure:
1.50 g (6.2 mmol) of 3-(2-aminoethoxy)benzonitrile hydrobromide and 3 ml of triethylamine were stirred in 15 ml of dimethylformamide under cooling with ice. 1.23 g (6.2 mmol) of monomethyl terephthalate chloride was slowly added thereto, and they were stirred for 3 hours. The temperature was elevated to the room temperature, and the reaction liquid was diluted with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C(C(O)=O)[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([C:2]([Cl:4])=[O:3])[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ncc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.4 %

Procedure:
Oxalyl chloride (0.07 ml, 0.800 mmol) was added to a stirred solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (WO 2008074820; 86 mg, 0.40 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated in vacuo to give a yellow gum (123 mg) which was used in the subsequent reaction (D53) without further purification
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[CH3:16][C:17]([CH3:31])([CH3:30])[CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19][CH:20]=O>[Na].C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:16])([CH3:30])[CH3:31])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CC(C)(C)OC(=O)NC(CC=O)C(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCN1C[C@@H]2COCCN2c2nc(Cl)ncc21)C(C)(C)C

Procedure:
The title compound was prepared in a manner similar to PREPARATION x63 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 115 mg, 0.507 mmol), tert-butyl 4,4-dimethyl-1-oxopentan-3-ylcarbamate (116 mg, 0.507 mmol), titanium(IV) chloride in CH2Cl2 (1M, 0.761 mL, 0.761 mmol) and sodium triacetoxyhydroborate (237 mg, 1.116 mmol) in CH2Cl2 (5 mL) (53 mg, 24%). ESI-MS m/z [M+H]+ calc'd for C21H34ClN5O3, 440.24; found 440.4.