Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:30][C:31]1[CH:58]=[CH:57][C:34]([O:35][C:36]2[N:37]=[CH:38][C:39]([NH:42][C:43](=[O:56])[CH2:44][CH2:45][C@H:46](O)[C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[CH:48]=3)=[N:40][CH:41]=2)=[CH:33][CH:32]=1>C1COCC1>[Cl:30][C:31]1[CH:58]=[CH:57][C:34]([O:35][C:36]2[N:37]=[CH:38][C:39]([N:42]3[C@@H:46]([C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[CH:48]=4)[CH2:45][CH2:44][C:43]3=[O:56])=[N:40][CH:41]=2)=[CH:33][CH:32]=1
Reactant: COc1cccc([C@@H](O)CCC(=O)Nc2cnc(Oc3ccc(Cl)cc3)cn2)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1cccc([C@H]2CCC(=O)N2c2cnc(Oc3ccc(Cl)cc3)cn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
Tri-n-butylphosphine (0.178 mL, 0.72 mmol) is added to a solution of di-tert-butyl azodicarboxylate (167 mg, 0.72 mmol) in dry THF (1.5 mL) at room temperature. The resulting mixture is stirred for 5 min at room temperature, then added dropwise to a solution of (S)—N-[5-(4-chlorophenoxy)pyrazin-2-yl]-4-hydroxy-4-(3-methoxyphenyl) butanamide (194 mg, 0.47 mmol) in THF (1.5 mL) at 0° C. and under argon. The reaction mixture is allowed to warm slowly to ambient temperature and stirred for 1.5 h, then partitioned between saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (10 mL). The aqueous layer is extracted with CH2Cl2 (3×10 mL). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is then purified on silica gel (0-33% ethyl acetate in hexane) to give (R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-methoxyphenyl)pyrrolidin-2-one (130 mg, 70%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 9.11 (d, J=1.2 Hz), 7.99 (d, J=1.6 Hz, 1H), 7.37-7.31 (m, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.07-7.02 (m, 2H), 6.81-6.72 (m, 3H), 5.68 (dd, J=8.2, 3.8 Hz, 1H), 3.77 (s, 3H), 2.89-2.74 (m, 1H), 2.72-2.57 (m, 2H), 2.10-1.99 (m, 1H). HPLC-MS calculated C21H18ClN3O3 (M+H+): 396.11, found: 396.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][O:17]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:24]([CH3:25])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(CCCCc2ccccc2OCC2CO2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1cccc(Cl)c1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 1(b), 840 mg of 2-{2-[4-(3-chlorophenyl)butyl]phenoxy methyl]oxirane [prepared as described in step (a) above] dissolved in 20 ml of tetrahydrofuran were treated with 4 ml of 50% by volume aqueous dimethylamine. The crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 789 mg (yield 82%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH2:10][OH:11])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=1[CH:16]=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:2]1([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[O:1][CH:16]([C:15]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:14]=2[Cl:13])[O:11][CH2:10]1
Reactant: CCCCOC(=O)C(C)(O)CO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C1(C)COC(c2cc([N+](=O)[O-])ccc2Cl)O1
Yield: 101.6 %

Procedure:
19.4 g of n-butyl 2,3-dihydroxyisobutyrate is added to 18.6 g of 2-chloro-5-nitrobenzaldehyde and 0.5 g of p-toluenesulfonic acid in 250 ml of toluene, and the mixture is refluxed for 5 hours using a water separator. The mixture is cooled, the solvent is removed and the remainder is dried in a high vacuum. There is obtained 35 g of 3-(5-methyl-5-n-butyloxycarbonyl-1,3-dioxolan-2-yl)-4-chloronitrobenzene (oil).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[C:5]([C:7]2[S:23][C:10]3[C:11]4[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][C:12]=4[O:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[N:6]=1.[Cl-].[NH4+].C[N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[C:5]([C:7]2[S:23][C:10]3[C:11]4[CH:19]=[CH:18][C:17]([C:20]([NH2:34])=[O:21])=[CH:16][C:12]=4[O:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[N:6]=1
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(-c2ccccc2Cl)s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3nc(N)sc3-c3ccccc3Cl)sc1-2

Procedure:
Following Example 47, 2-(2-amino-5-(2-chlorophenyl)thiazol-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid and ammonium chloride were coupled with HATU and DIPEA in DMF to give 268.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[C:10]1([CH:17]=[CH:16][C:14](O)=[CH:13][CH:12]=1)[OH:11]>O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][C:14]1[CH:16]=[CH:17][C:10]([OH:11])=[CH:12][CH:13]=1)=[O:8]
Reactant: Oc1ccc(O)cc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: O
Product: O=C1CC[C@@H](C(=O)Oc2ccc(O)cc2)N1
Reaction time: 18 h

Procedure:
129 g (1 mol) of (l)-pyroglutamic acid and 110 g (1 mol) of hydroquinone are intimately mixed, the mixture is stirred at 175° under a stream of nitrogen for 18 hours, the temperature is lowered to 50° and the mixture is diluted with water (300 ml) and extracted with ethyl acetate (3×400 ml). A crude product is thus prepared which is purified by being made into a paste twice with ethyl acetate (250 ml) to give the title derivative in the form of crystals melting at 179°/82°. In TLC, the product shows a single spot of Rf(i)=0.33.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:25]=[CH:24][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[C:17]([Cl:23])[CH:16]=[CH:15]3)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:22][C:20]1[C:19]2[N:18]=[C:17]([Cl:23])[CH:16]=[CH:15][C:14]=2[C:13]2[CH:24]=[CH:25][C:10]([CH2:9][OH:8])=[CH:11][C:12]=2[N:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)nc(N)c1nc(Cl)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1nc2cc(CO)ccc2c2ccc(Cl)nc12

Procedure:
A solution of 8-((tert-butyldimethylsilyloxy)methyl)-3-chlorobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq.) and TBAF (1.1 eq.) in THF was stirred at ambient temperature overnight. The reaction was quenched with saturated NaHCO3. The two phases were separated, and the aqueous layer was extracted twice with Et2O. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give (5-amino-3-chlorobenzo[f][1,7]naphthyridin-8-yl)methanol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18](O)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.CCN(S(F)(F)[F:34])CC>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18]([F:34])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)CC(CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate (1.97 g, 5.0 mmol) in dichloromethane was added DAST (4.03 g, 25 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by chromatography to give the title compound. MS (m/z): 396 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]1[C:22]([O:24]CC)=[S:23].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]1[C:22]([OH:24])=[S:23]
Reactant: CCOC(=S)c1c(Cc2ccccc2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: OC(=S)c1c(Cc2ccccc2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 16 h
Yield: 28.2 %

Procedure:
Ethyl N-(3,4-dichlorobenzyl)-3-benzylthioindole-2-carboxylate (0.31 g) was dissolved in THF/methanol (1:1) and sodium hydroxide (2M, 2.0 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo and the residue dissolved in water. The solution was acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered, washed with water and dried in vacuo to give the desired end product (0.082 g, 28%); NMR d (CD3SOCD3) 4.04 (s, 2H), 5.72 (s, 2H), 6.83-7.62 (m, 12H); M/z (−) 442 (M+), 440, 428, 398, 396, 307, 305.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](Cl)=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:11])[C:9]([CH3:10])=[C:34]([C:30]3[O:29][CH:33]=[CH:32][N:31]=3)[N:12]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: O=C(Cl)c1ncco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
In a 25 mL round-bottomed flask, 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (522 mg, 2.01 mmol) was combined with THF (4 mL) to give a yellow solution. Sodium bis(trimethylsilyl)amide (1.0 M in THF) (5.02 mL, 5.02 mmol) was added slowly dropwise, resulting in a dark red solution. A mixture of oxazole-2-carbonyl chloride (344 mg, 2.61 mmol) in THF (8 mL) and 8 drops of DMF were added to the reaction mixture. The resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was quenched by the addition of water and the aqueous layer was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, then concentrated to afford a yellow oil. The crude material was purified by flash chromatography (silica gel, 80 g, 25-65% ethyl acetate in hexanes) to give 7-chloro-3-methyl-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one (160 mg, 23.6%) as a yellowish solid. MS calcd. for C19H13ClN2O2 [(M+H)+] 337, obsd. 337.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:11][C:12]=3[CH:13]=2)[NH:4][C:3]1=[O:22].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][N:2]1[C:14]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:21])=[CH:11][C:12]=3[CH:13]=2)[NH:4][C:3]1=[O:22]
Reactant: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)O)cc3cc21
Reactant: C1CCNCC1
Product: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)N4CCCCC4)cc3cc21

Procedure:
This compound, m.p. 215°-217° C., prepared analogous to Example 15 from 4-[(2,3-dihydro-1-methyl-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoic acid and piperidine.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[SH2:28]>N1C=CC=CC=1>[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH2:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11]
Reactant: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21

Procedure:
Triethylamine (98.4 cc) is added to a solution of 10-[(1RS)-2-hydroxy-1-methylethyl]-2-phenothiazine-carbonitrile (197.7 g) in anhydrous pyridine (750 cc), and hydrogen sulphide is bubbled through for 6 hours 30 minutes at 25° C. while the mixture is kept stirred. The mixture is stirred for 16 hours at 25° C., then purged with a stream of nitrogen for 2 hours and poured into distilled water (3000 cc). The oil which forms is separated after settling has taken place, washed with distilled water (3×1000 cc) and dissolved in ethyl acetate (3000 cc). The solution obtained is washed with distilled water (7×1 liter), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a yellow crystalline mass (225 g). This product is recrystallized in ethanol (1350 cc) to give 10-[(1RS)-2-hydroxy-1 -methylethyl]-2-phenothiazinecarbothioamide (158.4 g) in the form of yellow crystals, m.p. 152° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Br:24])=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cc(CCO)ccc1OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(CCBr)ccc1OCc1ccccc1
Yield: 34.2 %

Procedure:
To a stirred solution of 2-benzyloxy-5-(2-hydroxyethyl)-N,N-dimethylbenzamide (300 mg) in dichloromethane (5 ml) were added carbon tetrabromide (366 mg) and triphenylphosphine (289 mg) at room temperature, and the mixture was stirred for minutes. After concentration of the reaction mixture under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) gave 2-benzyloxy-5-(2-bromoethyl)-N,N-dimethylbenzamide (124 mg). 1H-NMR(CDCl3) δ ppm: 2.86 (3H, s), 3.00-3.15 (2H, m), 3.11 (3H, s), 3.45-3.60 (2H, m), 5.11 (2H, s), 6.90 (1H, d, J=8.3 Hz), 7.05-7.20 (2H, m), 7.25-7.40 (5H, m)
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([Br:23])=[CH:25][C:26]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCc1ccccc1
Yield: 77.7 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (8.35 g, 24.8 mmol), (prepared as described for the starting material in Example 4), and 4-bromo-2 fluoroaniline (5.65 g, 29.7 mmol) in isopropanol (200 ml) was heated at reflux for 4 hours. The resulting precipitated solid was collected by filtration, washed with isopropanol and then ether and dried under vacuum to give 7-benzyloxy4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (9.46 g, 78%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])#[N:14]>O1CCCC1>[N:1]1([S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]#[N:14])(=[O:23])=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1S(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) To a mixture of pyrrolidine (4.92 ml) and triethylamine (6.91 ml) was added a solution of 2-cyanobenzene-1-sulfonyl chloride (10.0 g) in tetrahydrofuran (40 ml) at 0° C. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was suspended in water, and the suspension was filtered. The filtered solid was dissolved in dichloromethane, and the solution was washed with water. The organic layer was dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 2-(pyrrolidin-1-ylsulfonyl)benzonitrile (11.3 g).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[N:14][CH:13]=[CH:12][CH:11]=2)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:2][CH2:3][C:4]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CC(C)CNc1c(NC(=O)CCl)cnc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(CCl)nc2cnc3cccnc3c21
Temperature: 25 °C
Yield: 101.4 %

Procedure:
To a solution of 2-chloro-N-{4-[(2-methylpropyl)amino][1,5]naphthyridin-3-yl}acetamide hydrochloride (from Part C, approximately 70 mmol) in 3:1 ethanol/water (280 mL) was added 6 M aqueous potassium carbonate (17.5 mL). The reaction mixture was stirred at room temperature over the weekend. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (200 mL) and brine (100 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 19.5 g of 2-(chloromethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine, which contained a small amount of dichloromethane and was used without further purification in the next step.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[CH3:13][C:14]([NH:16][CH:17]1[C:27]2[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]=2[C:25]2[C:20](=[CH:21][C:22]([O:37][CH3:38])=[C:23]([O:35][CH3:36])[C:24]=2[O:33][CH3:34])[CH2:19][CH2:18]1)=[O:15]>C1COCC1>[C:9](=[O:10])([O:11][CH3:12])[O:32][C:29]1[CH:30]=[CH:31][C:26]2[C:25]3[C:24]([O:33][CH3:34])=[C:23]([O:35][CH3:36])[C:22]([O:37][CH3:38])=[CH:21][C:20]=3[CH2:19][CH2:18][C@H:17]([NH:16][C:14](=[O:15])[CH3:13])[C:27]=2[CH:28]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc2c(c1)[C@@H](NC(C)=O)CCc1cc(OC)c(OC)c(OC)c1-2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Triethylamine (70 μl; 0.5 mmol) and methyl chloroformate (39 μl; 0.5 mmol) were added to a solution of N-acetyl-colchicinol (0.178 g; 0.5 mmol) in THF (3 ml). The mixture was stirred at ambient temperature for 90 minutes. After removal of the insoluble material by filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (98/2) to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl methyl carbonate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10]Cl.[C:13]1([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([OH:29])[CH:25]=3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C.C(#N)C>[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10][O:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[O:20][CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:28][CH2:27]2
Reactant: CN(C)CCCl
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc2c(c1)CCC(c1ccccc1)O2

Procedure:
Cesium carbonate (230 mg) and an excess of 2-(dimethylamino)ethyl chloride in ethyl acetate were added into a solution of 2-phenylchroman-6-ol (150 mg) in acetonitrile (5 ml). The reaction mixture was refluxed for 30 minutes. After removing the solvents, the residue was taken up in water and extracted with ethyl acetate. The combined organic layers were washed with water and then with saturated NaCl-solution and dried with Na2SO4. The dimethyl[2-(2-phenylchroman-6-yloxy)-ethyl]amine was crystallised from heptane. 1H NMR (400 MHz, d6-DMSO) δ: 7.43-7.30 (m, 5H), 6.75-6.67 (m, 3H), 5.03 (dd, 1H, J 10.0, 2.2 Hz), 3.95 (t, 2H, J 5.9 Hz), 2.94 (ddd, 1H, J −16.7, 10.9, 5.8 Hz), 2.69 (ddd, 1H, J −16.7, 5.2, 3.3 Hz), 2.58 (t, 2H, J 5.9 Hz), 2.13 (m, 1H), 1.96 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11].[Br:12][CH:13](Br)[CH3:14]>O.C(O)C>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH2:14][CH2:13][Br:12]
Reactant: Cc1cccc(C)c1O
Reactant: CC(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1OCCBr

Procedure:
To a solution containing sodium hydroxide (80 g) in water (1 liter) and ethanol (0.5 liter) are added 2,6-dimethyl-phenol (245 g) dissolved in ethanol (0.5 liter), and then dibromoethane (750 g). The mixture is refluxed for 48 hours, under vigorous stirring. It is then extracted with methylene chloride. After washing with dilute aqueous sodium hydroxide and then with water, the solvent is evaporated in vacuo. 2(2,6-Dimethyl-phenoxy)-1-bromo-ethane boils at 148°-150° C./25 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][S:36]([Cl:39])(=[O:38])=[O:37].[ClH:40]>C(Cl)(Cl)Cl>[ClH:39].[ClH:40].[CH3:35][S:36]([NH:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][CH:3]=1)(=[O:38])=[O:37]
Reactant: Nc1cccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)n1
Reaction time: 1 h

Procedure:
To a solution of 1-(6-aminopyridin-2-ylmethyl)-4-benzhydrylpiperazine (3.58 g) and triethylamine (1.01 g) in chloroform (20 ml) was dropwise added methanesulfonylchloride (1.15 g) at 5° to 10° C. under cooling with stirring, which was continued at the same temperature for 1 hour. To the resultant mixture, additional triethylamine (0.51 g) and methanesulfonyl chloride (0.57 g) were added successively. The mixture was stirred for 1.5 hours. The reaction mixture was washed with water, dried and evaporated in vacuo. The resulting oily product was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1). The fractions containing the desired compound were combined and evaporated in vacuo to give a residue. According to a conventional manner, the residue was converted to hydrochloric acid salt, which was recrystallized from a mixture of methanol and diethyl ether to give 1-(6-methanesulfonylaminopyridin-2-ylmethyl)-4-benzhydrylpiperazine dihydrochloride (0.97 g). mp: 201°-202° C.