Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:11]3[N:16]=[C:15]([CH2:17]O)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2].P(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:17][C:15]1[S:14][C:12]2[N:13]=[C:8]([N:7]3[C:6]4[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=4[N:4]=[C:3]3[CH2:1][CH3:2])[N:9]=[C:10]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:11]=2[N:16]=1
Reactant: BrP(Br)Br
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)sc2n1
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a suspension of [5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl]methanol (1.18 g, 2.97 mmol) in DCM (60 mL) was added PBr3 (3.36 mL, 3.36 mmol, 1M solution in DCM) and the resulting mixture allowed to stir at r.t. for 1 h. The reaction mixture was diluted with DCM and the organic phase washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo affording the title compound as a yellow solid (673 mg, 49%). LCMS (method H): RT 3.24 min, [M+H]+ 459.1 and 461.1 (1:1)
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][NH:13][CH2:12]1>C(OCC)(=O)C>[CH:5]([N:13]1[CH2:12][CH2:11][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCNCC2
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=CN1CCc2ccccc2CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (40 ml) was added dropwise to formic acid (80 ml) at room temperature and after the mixture was stirred for 30 minutes, a solution of 2,3,4,5-tetrahydro-1H-3-benzazepine (30 g),in ethyl acetate (80 ml) was added dropwise at room temperature. The mixture was then stirred for 30 minutes, after which it was diluted with ice-water and extracted with ethyl acetate. The extract was washed successively with water, aqueous solution of sodium hydroxide (NaOH/H2O), and saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) and recrystallized from-n-hexane to provide the title compound (29 g) as colorless crystals melting at 65-66° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]C)=O)[N:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:1]1[CH:5]=[C:4]([C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[NH:3][CH:2]=1
Reactant: COC(=O)c1c[nH]cn1
Reactant: C1CCNC1
Product: O=C(c1cnc[nH]1)N1CCCC1

Procedure:
A solution of methyl 4-imidazolecarboxylate (CAS#17325-26-7, 460 mg, 3.6 mmol), and pyrrolidine (7 mL) is heated by microwave irradiation at 110° C. for 3.5 hours in a sealed vessel. The reaction is then concentrated to dryness. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:10) to furnish (3H-imidazol-4-yl)-pyrrolidin-1-yl-methanone; MS: (ESI) m/z 166.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][CH:11]1[S:15](=[O:17])(=[O:16])[O:14][CH2:13][CH2:12]1>CC(=O)CC>[CH2:1]([NH:9][CH2:13][CH2:12][CH:11]([S:15]([OH:17])(=[O:16])=[O:14])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CC1CCOS1(=O)=O
Solvent: CCC(C)=O
Product: CCCCCCCCNCCC(C)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of octylamine (2.00 g, 15.5 mmol) in 2-butanone (17 mL) was added 2,4-butane sultone (2.21 g, 16.2 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. It was suspended in a solution of 25% EtOH/acetone (50 mL). The suspension was stirred for 5 minutes. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. 1H NMR (DMSO, 500 MHz) δ ppm 8.45 (s (broad), 1H), 3.01 (m, 1H), 2.84 (m, 2H), 2.58 (m, 1H), 1.92 (m, 1H), 1.75 (m, 1H), 1.51 (m, 2H), 1.10 (d, 1H, J=6.8 Hz), 0.85 (t, 3H, J=6.8 Hz). 13C (DMSO, 125 MHz) δ ppm 53.05, 47.27, 46.15, 31.83, 29.42, 29.13, 26.51, 26.27, 22.75, 17.19, 14.64. ES-MS 266 (M+1).
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:29]([NH:31][O:32][P:33]([CH3:36])(=[O:35])[OH:34])=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1>>[ClH:1].[ClH:1].[NH2:12][C@H:13]([C:29]([NH:31][O:32][P:33]([CH3:36])(=[O:34])[OH:35])=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]
Reactant: CP(=O)(O)ONC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Product: CP(=O)(O)ONC(=O)[C@@H](N)CCCCN

Procedure:
In a manner analogous to Example 1 b), but with hydrogenation in the presence of 2-N hydrochloric acid, starting from [[N2,N6 -bis(benzyloxycarbonyl)-L-lysyl]amino]-methylphosphonic acid there was obtained (L-lysylamino)-methylphosphonic acid dihydrochloride of melting point 212°-217° C (decomposition); [α]D20 = +22.35° (c = 1% in water).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N+](C)C3C=CC=CC=3)[S:9][C:5]=2[CH:4]=1.Cl.[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)CCN
Reactant: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN=c1sc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.3 %

Procedure:
A solution of 5-chloro-N-methyl-N-phenyl-1,3-benzodithiol-2-iminium iodide (9.97g), 3-aminopropanoic acid, ethyl ester, hydrochloride (3.68g) and anhydrous sodium carbonate (2.54g) in 250 ml of anhydrous dimethylformamide is heated at 120° C under nitrogen for three hours, then left stirring at room temperature for 2 days. The reaction mixture is poured into water (1400 ml) and extracted with three 200 ml portions of dichloromethane. The combined dichloromethane extracts are washed with three 100 ml portions of water, dried over sodium sulfate, and concentrated in vacuo. The resultant oil is chromatographed on silica gel (1000 ml), eluting with dichloromethane/pentane (1:1). The fractions containing product with Rf =0.25 (silica gel, dichloromethane) are concentrated and the resultant solid recrystallized twice from pentane to yield 1.1g of the title compound, melting point 64°-65° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.CN1C(=O)N(C)CCC1.[CH:28]1([C:38]([O:40][CH3:41])=[O:39])[CH2:33][CH2:32][CH2:31][CH:30]([C:34]([O:36][CH3:37])=[O:35])[CH2:29]1.[I:42][CH2:43]I>C1COCC1>[I:42][CH2:43][C:30]1([C:34]([O:36][CH3:37])=[O:35])[CH2:31][CH2:32][CH2:33][CH:28]([C:38]([O:40][CH3:41])=[O:39])[CH2:29]1
Reactant: ICI
Reactant: COC(=O)C1CCCC(C(=O)OC)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C1CCCC(CI)(C(=O)OC)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A cooled (−67° C.) solution of dry diisopropylamine (3.65 mL, 26 mmol) in anhydrous THF (20 mL) under nitrogen was treated via syringe with 2.5N n-butyllithium/hexane (9.6 mL, 24 mmol), warmed to 0° C. for 5 min, then recooled (−67° C.). DMPU (12.1 mL, 100 mmol) was added dropwise via addition funnel so as to keep pot temp <−60° C., then a solution of dimethyl cyclohexane-1,3-dicarboxylate (4.00 g, 20 mmol) in anhydrous THF (10 mL) was likewise added dropwise. After 1 h at −67° C., diiodomethane (7.23 g, 27 mmol) in THF (10 mL) was added dropwise, then the mixture was warmed to room temperature over 1 h stirred 1 h, cooled on an ice bath, and quenched with saturated aqueous ammonium chloride (20 mL). The organic solvents were removed in vacuo and water (30 mL) was added, and the aqueous was extracted with hexane (100 mL, then 2×50 mL). The combined organic extracts were washed with water (75 mL), dried (MgSO4), and concentrated in vacuo, then dissolved in methylene chloride and passed through a pad of alumina in a fritted (30 mL) funnel. The concentrated filtrate was chromatographed on silica gel (˜200 cc, eluted with 1:1 hexane/methylene chloride) to afford 4.65 g (68%) of 1-iodomethyl-1,3-dicarbomethoxycyclohexane as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[K].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>CN(C)C=O>[Cl:16][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(OC)cc2)cc1
Yield: 85 %

Procedure:
A solution of 510 mg of 4,6-dichloro-5-(p-methoxyphenyl)pyrimidine and 680 mg of p-methoxybenzenesulfonamide potassium in 3 ml of dimethylformamide was heated at 130° C. for 1 hour. After working-up the reaction mixture, there were obtained 690 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl]-p-methoxybenzenesulfonamide, melting point 165°-167° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.[CH3:12][S:13][CH2:14][CH2:15][NH2:16]>>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:16][CH2:15][CH2:14][S:13][CH3:12])[C:5]2=[N:4][CH:3]=1
Reactant: CSCCN
Reactant: Clc1nccn2c(Br)cnc12
Product: CSCCNc1nccn2c(Br)cnc12

Procedure:
(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methylsulfanyl-ethyl)-amine was prepared by a process analogous to that described in Example 2 starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine and 2-methylsulfanyl-ethylamine.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.Cl>CN(C)C=O.O>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]4[N:6]=[N:5][NH:4][N:3]=4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(CCCCc2nnn[nH]2)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4nn[nH]n4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
46.3 mg (1.84 mmol) 95% sodium hydride were given at 0° C. to a solution of 200 mg (0.916 mmol) 4-(4-tetrazol-5-yl-butyl)-phenol in 5.0 ml N,N-dimethylformamide and stirred for 15 min. 317 mg (0.916 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was neutralized with HCl, poured into water and the resulting precipitate was purified by HPLC-MS, treated with diethyl ether, filtered and dried to yield 106 mg (22%) of the title compound.
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[CH:13]=1)([CH3:8])[C:3]([F:7])([F:6])[CH2:4][OH:5].C([O-])(=O)C.[Na+].[N:26]#[C:27]Br.CCCCCC>C(O)C.C(OCC)(=O)C>[Br:20][C:16]1[CH:15]=[C:14]([N:12]2[CH:13]=[C:9]([C@:2]([NH2:1])([CH3:8])[C:3]([F:6])([F:7])[CH2:4][O:5][C:27]#[N:26])[CH:10]=[N:11]2)[CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@](N)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)CO
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: C[C@@](N)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)COC#N
Temperature: 40 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
A solution of (R)-3-amino-3-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-butan-1-ol (5.1 g, 14.73 mmol) and sodium acetate (3.62 g, 44.2 mmol) in ethanol (90 ml) was warmed to 40° C. Cyanogen bromide (1.71 g, 16.21 mmol) was added and the mixture allowed to stir at 40° C. for 16 hours. Removal of the solvent at reduced pressure followed by purification of the resultant crude material by column chromatography on silica gel using a 3:2-mixture of hexane and ethyl acetate as the eluent yielded the (R)-1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-3-cyanato-2,2-difluoro-1-methyl-propylamine (3.2 g, 58% yield) as a colorless sticky solid. MS (ISP): m/z=369.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([Cr:8][CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH3:13])([CH3:7])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18]C(C=C(C)C)=C[K]>>[CH3:1][C:2]1[C:6]([Cr:8][CH:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:18])[CH3:13])([CH3:7])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: CC(C)=CC(C)=C[K]
Reactant: CC=CC(C)=C[Cr]C1(C)C(C)=C(C)C(C)=C1C
Product: CC(C)=CC(C)=C[Cr]C1(C)C(C)=C(C)C(C)=C1C

Procedure:
The preparation of this compound was substantially the same as that described in Example 1 for [Cr(C5 (CH3)5)(C6H9)] except that 2, 4-dimethylpentadienyl potassium was used instead of 2-methyl pentadienyl lithium (as reported in H. Yashda, Y, Ohnuma, M. Yamauchi, H. Tani, and A. Nakamura, Bulletin Chem. Soc. Japan, 1979, 52, 2036).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:26]O)=[C:11]([CH2:16][O:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:12]=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)#[N:2].CCN(S(F)(F)[F:36])CC.C(=O)(O)[O-].[Na+]>ClCCl>[F:36][CH2:26][C:10]1[C:9]([O:8][CH2:7][C:6]2[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[C:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ncc(COc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(COc2ccc(C#N)cc2)c(CF)c1OCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a solution of 4-(5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethoxy)-benzonitrile (14) (600 mg, 1.6 mmol) in dry dichloromethane (20 mL) was slowly added DAST (251 mg, 1.6 mmol, in 50 mL dry dichloromethane) at −78° C. under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using ethyl acetate:hexane:methyl alcohol (7:7:1) as an eluant to give 4-[4-fluoromethyl-6-methyl-5-(4-cyano-benzyloxy)-pyridin-3-ylmethoxy]-benzonitrile (18) (314 mg, 52% yield) as a colorless solid.
Reaction SMILES: [H-].[Na+].C1(S)C=CC=CC=1.C[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[N:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH3:41])[CH:37]=3)[N:32]([CH3:42])[C:31]2=[O:43])[CH2:26][CH2:25]1.O>CN(C=O)C>[OH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[N:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH3:41])[CH:37]=3)[N:32]([CH3:42])[C:31]2=[O:43])[CH2:26][CH2:25]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
In 5 ml of DMF was suspended 360 mg (9.0 mmol) of 60% sodium hydride, and a solution of 0.92 ml (9.0 mmol) of thiophenol in 10 ml of DMF was added dropwise to the suspension under ice cooling. After stirring for 10 minutes, a solution of 1.38 g (3.0 mmol) of Compound 50 obtained in Example 41 in 10 ml of DMF was added thereto under ice cooling, followed by stirring at 100° C. for 10 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with chloroform. The aqueous layer was adjusted to pH 5 by addition of 4N hydrochloric acid and extracted with chloroform. The combined organic layer was washed with an aqueous solution of sodium chloride and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1). The compound eluted as a component with low polarity was recrystallized from ether to give 302.8 mg (yield: 23%) of Compound 90 as white crystals. The substance eluted as a component with high polarity was recrystallized from ether/ethanol to give 787.9 mg (yield: 59%) of Compound 89 as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(=O)C([Cl:16])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:16])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)Cc1ccc(F)c(F)c1
Temperature: 25 °C

Procedure:
3,4-Difluorophenylacetic acid (3.61 g, 20.9 mmol) in oxalyl chloride (7.31 ml, 83.8 mmol) was refluxed for 4 hours. The solution was cooled to room temperature, concentrated under reduced pressure to give 3,4-difluorophenylacetyl chloride which was used without purification. To a well stirred solution of 3,4-difluorophenylacetyl chloride (2.21 g, 11.59 mmol) in THF (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.47 mL, 23.18 mmol) at room temperature and the solution was stirred for five minutes. Then methylisocyanoacetate (1.55 mL, 11.59 mmol) was added over a three minute period to the reaction mixture. After stirring for 18 hours at room temperature, the reaction mixture was partitioned between ether (100 mL) and water (50 mL). The organic layer was washed with 1N HCl (10 mL), water (15 mL) and saturated solution of sodium bicarbonate (15 mL), and dried over sodium sulfate. The solution was then filtered and concentrated. The residue was chromatographed (hexanes:EtOAc, 3:2) to yield 100 mg (3.4%) of the product; 1H-NMR (CDCl3) δ3.89 (s, 3H), 6.98 (s, 2H), 7.00-7.09 (m, 3H), 7.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:23].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]12[CH2:34][CH:33]3[CH2:35][CH:29]([CH2:30][CH:31]([CH2:32]3)[CH2:36]1)[CH2:28]2)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.2 %

Procedure:
4-[4-Chloro-3-[[(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)amino]carbonyl]phenyl]-hexahydro-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (0.053 g, Example 74a) was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml from a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to ¾ original volume under reduced pressure. Diethyl ether was gradually added to the solution and the resulting precipitate was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a cream solid (0.017 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>CN(C=O)C>[NH:36]1[C:37]2[C:33](=[CH:32][C:31]([O:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:39][CH:38]=2)[CH:34]=[CH:35]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 16.9 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (360 mg, 1.00 mmol), potassium carbonate (215 mg, 1.56 mmol) and 5-hydroxyindole (147 mg, 1.10 mmol) in DMF (8.0 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue purified by silica column chromatography eluting with methanol (2.5 to 5%) in dichloromethane. The resulting solid was recrystallised from ethyl acetate, filtered and washed with diethyl ether to give 4-(indol-5-yloxy)-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (77 mg, 17%).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:59]2[CH:60]=[C:61]3[CH:67]=[CH:66][N:65]([CH3:68])[C:62]3=[N:63][CH:64]=2)[C:13]([C:15]2[CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:39])[N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][C:25]=3[C:40]([N:42]3[C@H:51]([CH2:52][N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)[CH2:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:43]3)=[O:41])[N:18]3[C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:14])=[CH:8][CH:7]=1>C(O)(=O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([C:59]2[CH:60]=[C:61]3[CH2:67][CH2:66][N:65]([CH3:68])[C:62]3=[N:63][CH:64]=2)[C:13]([C:15]2[CH:16]=[C:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:39])[N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][C:25]=3[C:40]([N:42]3[C@H:51]([CH2:52][N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)[CH2:50][C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH2:43]3)=[O:41])[N:18]3[C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:14])=[CH:10][CH:11]=1
Reactant: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCC(=O)N5CCCCC5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O)cc3)cnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2cc(N(C(=O)c3cc(-c4ccc(OCC(=O)N5CCCCC5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O)cc3)cnc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
0.71 g (11 mmol) of sodium cyanoborohydride is added to a solution, in 20 mL of acetic acid, of the compound obtained in Step F (2.0 g, 2.2 mmol). After stirring for 14 hours at ambient temperature, 0.36 g (5.5 mmol) of sodium cyanoborohydride is again added, and then the reaction mixture is heated at 50° C. for 3 hours before a second addition of 0.1 eq. of sodium cyanoborohydride to complete the reaction in 30 minutes at 50° C. The acetic acid is evaporated off under reduced pressure, and then the residue is taken up in dichloromethane and washed with saturated aqueous NaHCO3 solution, water and brine. The combined aqueous phases are extracted with dichloromethane. The resulting organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography over silica gel (dichloromethane/ethanol/ammonia gradient) to yield the title compound in the form of a meringue.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]=[CH:14]/[CH2:15][CH3:16].C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]=[CH:14]/[CH2:15][CH3:16]
Reactant: CC/C=C\C=C/CCCCCCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC/C=C\C=C/CCCCCCCCCC=O

Procedure:
(11Z,13Z)-11,13-hexadecadien-1-ol (3.19 mmol) and acetic anhydride (6.38 mmol), in 5 ml of dry pyridine, are stirred under nitrogen at room temperature for 20 hours. The reaction mixture is then poured in sodium bicarbonate solution and extracted with pentane (2X). The organic layer is washed with dilute HCl and with brine, dried over magnesium sulfate and the solvent removed in vacuo. The crude product is purified to yield the final product, (11Z,13Z)-11,13-hexadecadien-1-al.