Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([NH2:15])[CH2:13][NH2:14].[OH-:16].[Na+]>>[C:2]([N:14]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:16])[CH2:13][CH2:12][NH2:15])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: [OH-]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCN
Agent: [Na+]
Product: NCCN(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
Benzyl chloroformate (40 mL, 280 mmol) was added dropwise over 45 min to a vigorously stirred solution of ethylenediamine (9.4 mL, 0.5 equiv) in 1M NaOH (310 mL, 1 equiv) at 0° C. A heavy white precipitate formed and the mixture was stirred for 4 h following addition. The resulting solid product was collected by filtration, washed with water and then hexane, and then air-dried overnight (46.17 g, 100%). 1H-NMR (CDCl3) δ 3.32 (s, 4H), 5.10 (s, 4H), 5.23 (br, 2H), 7.35 (s, 10HS MS (ESI) 329.3 (MH)+.
Reaction SMILES: [CH:1]1([CH:4]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[O:5][C:6]2[CH:26]=[CH:25][C:9]([CH2:10][NH:11][C:12]3[C:17]([NH2:18])=[CH:16][C:15]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:27][CH3:28])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:44]([N:49]=[C:50]=S)(=[O:48])[O:45][CH2:46][CH3:47].C1(S(Cl)(=O)=O)C=CC=CC=1>O1CCCC1>[CH2:46]([O:45][C:44](=[O:48])[NH:49][C:50]1[N:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([O:5][CH:4]([CH:1]3[CH2:3][CH2:2]3)[C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[C:7]([O:27][CH3:28])[CH:8]=2)[C:12]2=[N:13][CH:14]=[C:15]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:16]=[C:17]2[N:18]=1)[CH3:47]
Reactant: CCOC(=O)N=C=S
Reactant: COc1ccc(C(Oc2ccc(CNc3ncc(-c4cnn(C)c4)cc3N)cc2OC)C2CC2)cn1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OC(c2ccc(OC)nc2)C2CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a stirred solution of N2-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2,3-diamine (0.55 g, 1.13 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.799 g, 7.90 mmol). The resulting mixture was allowed to stir at room temperature. After 15 min, the mixture was treated with ethyl carbonisothiocyanatidate (0.444 g, 3.39 mmol), and the resulting mixture was allowed to stir at room temperature. After 30 min, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (5 mL) and was treated with triethylamine (0.799 g, 7.90 mmol) and benzenesulfonyl chloride (0.259 g, 1.43 mmol). The resulting mixture was allowed to stir at room temperature. After 16 h, the mixture was concentrated. Chromatographic purification of the residue (neutral alumina, 50% ethyl acetate in petroleum ether elute) afforded 0.45 g (68%) of ethyl(3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([C:19]([CH3:24])([CH3:23])[C:20](O)=[O:21])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(O)CCC.[Cl-].[NH4+]>CN(C=O)C.O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:34])=[O:21])[CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCO
Product: CC(C)(C(N)=O)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[6-(4-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-2-methyl-propionic acid (175 mg, 0.490 mmol) and benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP, 382 mg, 0.735 mmol) and butanol (99.3 mg, 0.735 mmol) in N,N′-dimethylformamide (6 mL) was stirred at room temperature for 10 min. Ammonium chloride (52.4 mg, 0.979 mmol) was added and the mixture was stirred 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase is successively washed with sodium hydrogencarbonate 10% and MCI 0.1M. Drying and evaporation of the solvent left a solid which was recrystallised with ethyl acetate and ether (120 mg, 69%). MS: m/e=357.2-(M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[C:14]([Cl:17])(=O)C>CO>[ClH:17].[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([C:7]([O:9][CH3:14])=[O:8])[NH2:6]
Reactant: CC(=O)Cl
Reactant: N[C@H](Cc1ccccc1Br)C(=O)O
Solvent: CO
Product: COC(=O)[C@H](N)Cc1ccccc1Br
Product: Cl
Reaction time: 36 h
Yield: 100.5 %

Procedure:
Dissolve 2-bromo-D-phenylalanine (22.4 g, 91.8 mmol) in methanol (459 mL). Add acetyl chloride (65.3 mL, 917.7 mmol) at room temperature. Stir for 36 hours. Concentrate under reduced pressure to give the title compound (27.2 g, 92.3 mmol). MS (m/z): 258 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[CH2:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27](Cl)=[O:28])=[CH:20]2)[CH3:16]>C(Cl)Cl>[CH2:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[O:28])=[CH:20]2)[CH3:16]
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc2nnc(C(=O)NCC(=O)OC)cc2c1
Reaction time: 5 h

Procedure:
A mixture of glycine methyl ester hydrochloride (2.5 g.) and triethylamine (2.6 ml.) in dry methylene chloride (10 ml.) was added to a solution of 6-ethylcinnolin-3-yl carbonyl chloride (1.1 g.) in dry methylene chloride (10 ml.). The resulting solution was kept at room temperature for 5 hours, diluted with methylene chloride (80 ml.) and washed successively with N-hydrochloric acid, water, 10% w/v sodium bicarbonate solution, and water and then dried (MgSO4). The solvent was evaporated and the solid residue was crystallized from aqueous ethanol to give 6-ethyl-N-(methoxycarbonylmethyl)-cinnolin-3-yl carboxamide, m.p. 135°-137° C.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[C@H:14]([OH:26])[C@@H:13]1[OH:27])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].C(OC([NH:38][C@H:39]([C:55](O)=[O:56])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[ClH:1].[ClH:1].[NH2:38][C@H:39]([C:55]([NH:2][C@H:3]([C:8]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[C@H:14]([OH:26])[C@@H:13]1[OH:27])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:56])[CH2:40][CH2:41][CH2:42][CH2:43][NH2:44]
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 Gram (2.42 mmol) of 5'-O-isoleucyl-5-fluorouridine hydrochloride was dissolved in dimethylformamide (20 ml), and 1.00 g (2.85 mmol) of Nα,Nε -di-benzyloxycarbonyllysine and 0.67 g (3.69 mmol) of diethylphosphoryl cyanide were then added. To this solution was added under ice-cooling 1.54 g (15.2 mmol) of triethylamine, and the mixture was stirred overnight at room temperature. After addition of ice water the reaction liquid was extracted with chloroform (200 ml). The organic layer was dried (over Na2SO4) and concentrated under reduced pressure, and the residue was subjected to separation/purification by way of silica gel column chromatography (first time: 2.5×11 cm, chloroform containing 4% methanol; second time: 5×14 cm, a linear gradient of ethyl acetate-n-hexane (1:1) containing 0→6% methanol) whereby 0.46 g (26%) of 5'-O-{N-(Nα,Nε -di-benzyloxycarbonyllysyl)isoleucyl}-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS([O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47]C[CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:45][CH2:44][N:43]4[CH2:42][CH2:41][O:40][CH2:47][CH2:48]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCOCC4)c3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-morpholinoethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.65 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.59-7.54 (m, 3H), 7.45-7.40 (m, 2H), 7.04-7.02 (m, 2H), 6.22 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=7.8 Hz), 4.25-4.20 (m, 3H), 3.79-3.76 (m, 4 h), 3.68 (brs, 1H), 3.51-3.48 (m, 1H), 2.87 (t, 2H, J=5.7 Hz), 2.64 (brs, 4 h), 2.14-2.06 (m, 3H), 1.78 (brs, 1H), 1.67-1.62 (m, 4 h), 1.50-1.48 (m, 2H), 1.25 (d, 3H, J=6.3 Hz). LC/MS: 500 [M+H]+, tR=1.13 min. HPLC: 95.85% at 214 nm, 95.41% at 254 nm, tR=5.12 min.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[CH3:38][C@H:39]1[CH2:41][O:40]1>C(O)(C)C.C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH2:29][CH3:30])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:38][C@@H:39]([OH:40])[CH3:41])[CH2:6]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: C[C@H]1CO1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CC#N
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 23.6 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (46 mg, 0.11 mmol) (from isomer 1) and triethylamine (50 μL, 0.4 mmol) in isopropyl alcohol (0.3 mL) was added (S)-(−)-methyloxirane (16 μL, 0.23 mmol). The resulting mixture was stirred at 90° C. for 3 h. After cooling, the mixture was diluted with acetonitrile and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (12 mg, 23%). The product was isolated as a single diastereomer. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.38 (d, 1H), 6.15 (m, 1H), 4.26 (d, 1H), 3.76-3.60 (m, 6H), 2.99 (m, 2H), 2.48 (s, 3H), 2.22 (m, 2H), 1.62 (d, 3H), 1.25 (t, 3H), 0.93 (d, 3H) ppm; LCMS calculated for C22H29ClFN6O2 (M+H)+: m/z=463.2; Found: 463.2.
Reaction SMILES: CN(C=O)C.[CH2:6]([Cl:8])Cl.C(Cl)(=O)C(Cl)=O.[N:15]1[C:20]2[S:21][CH:22]=[CH:23][C:19]=2C(=O)[NH:17][CH:16]=1>O>[Cl:8][C:6]1[C:19]2[CH:23]=[CH:22][S:21][C:20]=2[N:15]=[CH:16][N:17]=1
Reactant: O=c1[nH]cnc2sccc12
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2sccc12
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of DMF (90 μL) and CH2Cl2 (2 mL) at 0° C. under N2, oxalyl chloride (148 mg, 1.2 mmol) is added slowly and stirred for 10 min. 3H-Thieno[2,3-d]pyrimid-4-one (81 mg, 0.52 mmol) is added as a solid to the solution and warmed with a heat gun until the solid dissolves. The reaction is stirred at 25° C. for 12 h under N2. The reaction mixture is poured into water and extracted with CH2Cl2 . The phases are separated and the organic layer is dried (Na2SO4) and stripped under reduced pressure to yield 4-chlorothieno[2,3-d]pyrimidine (87.6 mg, 97%) as a solid. 1H NMR (DMSO) δ 8.96 (1H, s), 8.17 (1H, d, J=6.0 Hz), 7.62 (1H, d, J=6.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:6]=2[CH:21]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH3:13])[C:6]=3[CH:21]=2)=[CH:25][CH:24]=1
Reactant: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(N)ccc21
Reactant: OB(O)c1ccc(Br)cc1
Product: CN1C(=O)OC(C)(c2ccc(Cl)cc2)c2cc(Nc3ccc(Br)cc3)ccc21

Procedure:
Prepared from 6-amino-4-(4-chlorophenyl)-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+(457/459/461); MS (ESI) m/z [M−H]−(455/457/459); Anal. calcd for C22H18BrClN2O2: C, 57.73; H, 3.96; N, 6.12. Found: C, 56.88; H, 3.90; N, 5.70.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1C.[CH2:12](N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C:2]1([CH3:1])[CH3:12])(=[O:21])[CH3:20]
Reactant: CC1Cc2ccccc2N1C
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A solution of dimethyl indoline (65 mg, 0.44 mmol) and triethylamine (0.12 mL, 0.88 mmol) in dry dichloromethane (3 mL) was treated with acetyl chloride (0.05 mL, 0.66 mmol) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 16 h. Then the reaction mixture was quenched with water and the product was extracted into ether. The organic layer was washed with water and brine, dried (sodium sulfate) filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 30% EtOAc in hexanes) to give N-acetyl dimethyl indoline as a light yellow oil (68 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]OS(C)(=O)=O)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:27])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:35]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O.[ClH:48]>CN(C=O)C.CCOCC>[OH2:14].[ClH:48].[ClH:48].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:42][CH2:43]3)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:27])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:42][CH2:43]3)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:27])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:48].[ClH:48]
Reactant: CC(C)Oc1cccc(CC(=O)N2CCOC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)c1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccc(CC(=O)N2CCOC(CCN3CCC(N4CCCCC4)CC3)(c3ccc(F)c(F)c3)C2)c1
Temperature: 70 °C

Procedure:
A mixture of 1.3 g of the compound obtained in step C of EXAMPLE 71 and 1.1 g of 4-(piperid-1-yl)-piperidine in 4 ml of DMF is heated at 70° C. for 4 hours. After cooling to RT, the reaction mixture is poured into iced water and extracted with AcOEt, the organic phase is washed with 1N NaOH solution and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (90/10; v/v) as the eluent. The product obtained is taken up with a saturated solution of hydrochloric acid in ether and the precipitate formed is wrung to give 0.49 g of the expected product. M.p.=270° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.O>CN(C=O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([O:1][C:2]2[CH:3]=[C:4]([CH3:13])[C:5]3[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=3[CH:12]=2)[CH:26]=1
Reactant: Cc1cc(O)cc2c1NC(=O)CO2
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2c1NC(=O)CO2
Temperature: 25 °C

Procedure:
0.10 g (0.56 mmol) 7-hydroxy-5-methyl-2H-benzo[b][1.4]oxazin-3(4H)-one and 0.10 g (0.73 mmol) potassium carbonate were placed in 2.0 mL DMF. After 15 min 86 mg (0.56 mmol) 4,6-dichloropyrimidine were added andtmw stirred at RT over the weekend. The reaction mixture was mixed with water, the substance was extracted with ethyl acetate and evaporated down i.vac.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].C(Cl)Cl>ClCCCl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11])[CH2:2]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC1CN2CCC1CC2
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(OC1CN2CCC1CC2)n1ccnc1

Procedure:
According to Method C, 3-quinuclidol is first reacted with a carbonyldiimidazole (DCI) in an inert solvent (e.g. DCM, 1,2-DCE) at room temperature in order to obtain the corresponding imidazole-1-carboxylic acid 1-azabicyclo[2.2.2]oct-3-yl ester. Then, arylalkylamine (II) is metalated in an inert solvent (e.g. THF) using BuLi and the ester was added at a temperature ranging from 0° C. to room temperature.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:31])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[Cr](O)(O)(=O)=O.N1C=CC=CC=1.C(Cl)Cl>[O-2].[O-2].[O-2].[Cr+6].O>[CH3:1][CH:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:31])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: O=[Cr](=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Yield: 79.6 %

Procedure:
To a mixture of ethyl 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-2-ol-1-carboxylate (217 g) and pyridine (215 ml), chromic acid-pyridine (prepared by adding portionwise chromium trioxide (300 g) to a mixture of pyridine (480 ml) and methylene chloride (3000 ml) while cooling with ice) is added thereto, and the resultant mixture is stirred for 4 hours. The reaction mixture is added to water, and the methylene chloride layer is separated, washed with water, dried and evaporated. The residual material (203 g) is chromatographed on silica gel (1kg) using benzene to give ethyl 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-2-one-1-carboxylate (172 g). IR: 1740, 1225 cm-1 (COO); 1710 cm-1 (C=O).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][NH:20][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Yield: 42.6 %

Procedure:
A mixture of 2,2,2,2′,4′-pentafluoroacetophenone (1.05 g, 5.0 mmol), 3,5-dichlorobenzylamine (0.88 g, 5.0 mmol), N,N-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes as eluent to yield the title compounds as a yellowish solid (0.78 g, 43%). 1H NMR (400 MHz, CDCl3): δ 9.28 (br s, 1H), 7.88 (m, 1H), 7.34 (s, 1H), 7.22 (s, 2H), 6.44 (m, 1H), 6.30 (dd, 1H), 4.43 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:3]1=[O:20].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:3](=[O:20])[C:2]2([CH3:21])[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c1N(COCC[Si](C)(C)C)C(=O)C2(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Reaction time: 2 h

Procedure:
The mixture of 3.10 g of 3,3,7-trimethyl-1-(2-trimethylsilanylethoxymethyl)-1,3-dihydroindol-2-one, 1.86 g of N-bromosuccinimide, 0.050 g of dibenzoyl peroxide and 0.033 g of 2,2′-azobis(2-methylpropionitrile) in 100 ml of carbon tetrachloride is kept at reflux with stirring over 2 hours. The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:10 EtOAc-heptane); Rt=26.45 (II).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20]N=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.Cl[C:26]1C=CN=C2NC=CC=12.C(OC(N1CCNCC21CC2)=O)(C)(C)C>>[CH2:10]1[C:9]2([CH2:12][N:13]([C:16]3[CH:26]=[CH:20][N:19]=[C:18]4[NH:22][CH:23]=[CH:24][C:17]=34)[CH2:14][CH2:15][NH:8]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: Clc1ccnc2[nH]ccc12
Agent: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: c1cc(N2CCNC3(CC3)C2)c2cc[nH]c2n1

Procedure:
Prepared in a sequence similar to the sequence described for intermediates 1 and 2, starting from 4-chloro-1H-pyrrolo[2,3-b]pyridine and 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.