Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.Cl.[CH3:14][OH:15]>>[Br:1][C:2]1[C:11]([N:7]2[CH2:8][CH2:3][CH:14]([OH:15])[CH2:5][CH2:6]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: CO
Reactant: O=c1ccc2c(Br)cccc2[nH]1
Agent: Cl
Product: O=C1CCc2c(ccc(N3CCC(O)CC3)c2Br)N1

Procedure:
The above 5-bromocarbostyril was dissolved in 1 ml of hydrogen chloride-methanol solution, and mixture was refluxed for 1 hr. The reaction mixture was concentrated and purified by a silica gel column chromatography to give 24 mg of 5-bromo-6-(4-hydroxypiperidino)-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19]([O:27][CH:28]([CH2:33][CH2:34][CH3:35])[CH:29](Br)[CH2:30][CH3:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:36][N:37](C)C=O.C(N)CN>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19]([O:27][CH:28]([CH2:33][CH2:34][CH3:35])[CH:29]([C:36]#[N:37])[CH2:30][CH3:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCC(OC(=O)c1ccccc1)C(Br)CC
Reactant: CN(C)C=O
Agent: CCCCCCc1ccc(-c2ccccc2)cc1
Solvent: NCCN
Solvent: O
Product: CCCC(OC(=O)c1ccccc1)C(C#N)CC
Yield: 66 %

Procedure:
2.65 g (5.10-3 moles) of p-hexyl biphenyl-3-bromo-4-heptyl benzoate and 0.6 g (6.7×10-3 moles) of cuprous cyanide are introduced into 10 ml of dimethyl formamide. After the solution has been heated under reflux for 7.5 hours, it is cooled and poured into a mixture of 60 ml of deionized water and 5.5 ml of ethylene diamine. After stirring, the solution is extracted with ether. 2.2 g of crude product are obtained, being purified by chromatography on a column of silica, followed by recrystallization from ethanol. 1.6 g of pure product are obtained, corresponding to a yield of 66%.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1.[Cl:19]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: Oc1nc2c3ccccc3sc2c2ccccc12
Product: Clc1nc2c3ccccc3sc2c2ccccc12

Procedure:
The procedure was similar to step S19C, while the starting material was 23B in stead of 19B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([N:18]([CH3:31])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[C:6]([NH:18][CH3:31])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N(C)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(C(=O)OC)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After dissolving 4-tert-butoxycarbonylamino-3-[methyl-(2-nitro-benzenesulfonyl)-amino]-benzoic acid methyl ester (1.41 g, 2.73 mmol) in dimethylformamide (10 ml), potassium carbonate (1.13 g, 8.16 mmol) and thiophenol (0.307 ml, 2.99 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction mixture, and extraction was performed with ethyl acetate (40 ml×3 times). The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (n-hexane/ethyl acetate=85/15) to obtain 4-tert-butoxycarbonylamino-3-methylamino-benzoic acid methyl ester. The compound was identified by LC-MS. Yield: 794.3 mg (62.7%), [M+1]=281.1.
Reaction SMILES: [NH2-].[Na+].[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1.Cl[CH2:20][CH:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1>C1(C)C(C)=CC=CC=1>[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:20][CH:21]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCC1CN2CCC1CC2
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)N(CC1CN3CCC1CC3)c1ccccc1S2
Temperature: 25 °C

Procedure:
19.8 ml of a 50% suspension of sodium amide in xylene were added to a suspension of 68.3 g of 2-methoxyphenothiazine in 700 ml of anhydrous xylene. The mixture was agitated and heated to reflux. After 41/2 hours, 272 ml of an 8.5% solution of 3-chloromethyl-quinuclidine in xylene were added over a period of an hour and reflux was maintained for 16 hours. After cooling to room temperature, the reaction mixture was worked up as in Example 2. After recrystallisation of the crude product in a mixture of ether and isopropyl oxide, 2-methoxy-10-(3-quinuclidinylmethyl)-phenothiazine, m.p. 135°-136° C, was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)=[O:8].[CH2:24]([O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)[CH3:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=2)=[CH:12][CH:13]=1)=[O:8]
Reactant: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2ccc(Br)s2)cc1F
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2ccc(C(=O)NCc3cc(F)c(NS(C)(=O)=O)c(F)c3)s2)c1
Yield: 62 %

Procedure:
5-Bromo-thiophene-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide (80 mg, 0.19 mmol) was reacted with 3-ethoxy phenyl boronic acid (37.5 mg, 0.23 mmol) to give the title compound (55 mg, 62%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C(C[C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10]C)=[O:9])#N.Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([CH2:20][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:22])=[O:21]
Reactant: COC(=O)c1ccc(CC#N)cc1C(=O)OC
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccc(C(=O)O)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
0.78 g of dimethyl 4-cyanomethylphthalate was dissolved in a mixed liquid comprising 15 ml of concentrated hydrochloric acid and 4 ml of acetic acid, followed by stirring under heating at 120° C. for 2.5 hours. The reaction solution was left to cool to room temperature and then extracted by an addition of ethyl acetate and water. The organic layer was post-treated in accordance with a usual method to obtain 0.53 g of the above identified compound as white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: O=C(CO)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc(I)ccc1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cc(I)ccc2OC1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of 5-iodosalicylaldehyde (16.2 g, 65.3 mmol), ethyl 4,4,4-trifluorocrotonate (22.4 g, 133 mmol) and triethylamine (50 ml, 395 mmol) were combined, stirred at 70° C. for 8 h and then heated at reflux for 48 h. The solution was poured into ethyl acetate (300 mL) and washed with 1N hydrochloric acid (3×200 mL). The aqueous layers were combined and extracted with ethyl acetate (1×100 mL). The combined ethyl acetate extracts were washed with saturated ammonium chloride (2×200 mL), dried over magnesium sulfate and concentrated in vacuo yielding a dark red oil. This oil was purified by flash chromatography using ethyl acetate-hexanes (3:7) yielding a red oil. Crystallization of this oil from hexanes yielded the title compound as light red crystals (8.3 g, 31%): mp 105-106° C. 1H NMR (CDCl3 /300 MHz) 7.63 (s, 1H), 7.58 (dd, 2H, J=8.6, J=2.1 Hz, 7.54 (d, 1H, J=2.1 Hz), 6.77 (d, 1H, J=8.6 Hz), 5.70 (q, 1H, J=6.7 Hz), 4.20-4.38 (m 2H), 1.35 (t, 3H, J=7.2 Hz). ESHRMS 415.9926 (M+NH4+ Calc'd 396.9746)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][CH2:31][CH2:32][CH2:33][OH:34].CCOC(C)=O>CN(C=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:14]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH2:3][NH:30][CH2:31][CH2:32][CH2:33][OH:34])[N:13]=2)=[CH:17][CH:18]=1
Reactant: NCCCO
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)c2nc(CNCCCO)nc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (100 mg, 0.286 mmol), Cs2CO3 (201 mg, 0.617 mmol) and 3-amino-propan-1-ol (44 μL, 0.58 mmol) in DMF (1 mL) was heated at 80° C. After 18 h, EtOAc (12 mL) was added and this was washed with water (2×2 mL) and satd NaCl (2×2 mL). The soln was dried (MgSO4), filtered through a plug of silica with a wash of 100:10:1 chloroform:methanol:concd NH4OH then purified by preparative TLC (SiO2/200:10:1 chloroform:2-propanol:concd NH4OH). A band was removed from this preparative TLC plate and further purified by preparative TLC (SiO2/100:10:1 chloroform:methanol:concd NH4OH) yielding the title compound as a yellow oil. The bis(hydrochloride) salt was formed by adding then evaporating a soln of HCl in i-PrOH, giving an off-white solid. 1H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.78 (m, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 7.09 (m, 2H), 6.90 (m, 1H), 4.91 (t(br), 2H), 3.82 (s, 3H), 3.68 (s, 3H), 3.56 (t, J=6.2 Hz, 2H), 3.24 (m, 2H), 1.91 (m, 2H); LC-MS (ESI+; 353 ([M+H]+)).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.C([Li])CCC.CCCCCC.[CH3:43][C:44]1([CH3:52])[CH2:49][CH:48]([CH:50]=O)[CH2:47][CH2:46][O:45]1>C1COCC1.CCOCC>[CH3:43][C:44]1([CH3:52])[CH2:49][CH:48](/[CH:50]=[CH:9]/[CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:47][CH2:46][O:45]1
Reactant: CC1(C)CC(C=O)CCO1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CC(/C=C/CCOCc2ccccc2)CCO1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a stirred suspension of triphenyl{3-[(phenylmethyl)oxy]propyl}phosphonium bromide (20.74 g, 42.2 mmol) in THF (60 ml) at −15° C. under a nitrogen atmosphere was added n-butyl lithium, 1.6M in hexane (26.4 ml, 42.2 mmol) dropwise over 30 mins. The orange/red solution was stirred at −10° C. for 30 mins. A solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (6 g, 42.2 mmol) in THF (10 ml) was added dropwise at −10° C. over 25 mins. The reaction mixture was then stirred at −10° C. for 15 mins and then gradually allowed to warm up to room temperature while stirring under nitrogen atmosphere for 16 hours. Ether (10 ml) was added and the suspension was filtered on Celite. The Celite was washed with ether (2×40 mL). The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica (2×100 g) using a cyclohexane:ethyl acetate 0->25% gradient over 40 mins on a Flashmaster II. The fractions were analysed by TLC (revealed with a permanganate dip). The desired fractions were combined and concentrated under vacuum to yield the title compound as a colourless oil (7.46 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[C:11]([OH:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:10]([S:7]([NH2:6])(=[O:9])=[O:8])[C:11]([OH:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(CNS(=O)(=O)C(c2ccc(OCc3ccccc3)cc2)C(C)(C)O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C(c1ccc(OCc2ccccc2)cc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.3 %

Procedure:
A solution of 3.65 g of N-[2,4-dimethoxybenzyl]-1-(4-benzyloxyphenyl)-2-hydroxy-2-methylpropane-1-sulfonamide in 20 ml of dichloromethane was admixed with 4.00 ml of trifluoroacetic acid and stirred at room temperature for 20 minutes. The conversion was checked by LCMS. Since it was incomplete, another 2.00 ml of trifluoroacetic acid were added and the mixture was stirred for a further 2 hours. The reaction solution was admixed with 20 ml of water and neutralized with saturated aqueous sodium hydrogencarbonate solution. The precipitate was filtered off with suction through a glass frit, washed with dichloromethane and water and dried in a desiccator over P2O5. This gave the product (1.95 g) with a molecular weight of 335.4 g/mol (C17H21NO4S).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:22]([CH3:23])[C:21](=[O:24])[CH2:20][CH2:19][N:18]([CH:25]3[CH2:29][CH2:28][CH2:27][CH:26]3[CH3:30])[C:17]=2[N:31]=1)[C:6]([OH:8])=O.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:65][CH:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:22]([CH3:23])[C:21](=[O:24])[CH2:20][CH2:19][N:18]([CH:25]3[CH2:29][CH2:28][CH2:27][CH:26]3[CH3:30])[C:17]=2[N:31]=1)[C:6]([NH:65][CH:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1)=[O:8]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1C)CCC(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1C)CCC(=O)N2C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
A mixture of 0.043 g (0.0001 mole) of (rac)-3-methoxy-4-[5-methyl-9-(2-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-57a), 0.042 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.044 mL (0.00025 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.00015 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.048 g of (rac)-3-methoxy-4-[5-methyl-9-(2-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(1-methyl-piperidin-4-yl)-benzamide (I-57) as a white solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1>>[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccncc1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5ccncc5)CC4C3)nn12

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-4-carbaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-(pyridin-4-ylmethyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[C:14](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: Oc1ccc(OC(F)(F)F)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
To a stirred suspension of 3-Bromo-4-trifluoromethoxy-phenol (20.0 g, 82.6 mol) and potassium carbonate (46.3 g, 330.4 mmol) in acetone (600 ml) was added drop-wise iodomethane (46.9 g, 330.4 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature then filtered and the filtrate was evaporated in vacuo to afford the title compound as a colourless oil (19.8 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-phenylpiperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=448.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[S:19])=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]([N:9]2[C:17](=[O:18])[N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[S:19])=[C:4]([F:20])[CH:3]=1
Reactant: O=c1n(-c2cc(O)c(Cl)cc2F)c(=S)n2n1CCCC2
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1n(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(=S)n2n1CCCC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
2-(4-Chloro-2-fluoro-5-hydroxyphenyl)hexahydro-3-thioxo-1H-[1,2,4]triazolo-[1,2-a]pyridazin-1-one (0.5 g) was mixed with 2-chloropyrimidine (1 equiv) and potassium carbonate (2 equiv) in dimethylsulfoxide (20 ml) and the resulting mixture stirred at 100° C. for 1.5 hour and at room temperature overnight. The mixture was processed and the residue column chromatographed (silica gel, methylene chloride:ethyl acetate, 3:1). to give the product (0.34 g, 55%). 1H NMR (CDCl3, TMS): 1.92(4H, m), 3.69(2H, m), 3.99(2H, m), 7.05(1H, m), 7.37(1H, d, J=6.5 Hz), 7.39(1H, d, J=9.0 Hz), 8.53(2H, d, J=4.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].C(N(CC)CC)C>O1CCCC1>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: O=C(Cl)c1ccco1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)c3ccco3)c1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.200 g, 0.59 mmol) in 6 mL of tetrahydrofuran was added 2-furanoic acid chloride (0.064 mL, 0.65 mmol), followed by triethyl amine (0.091 mL, 0.65 mmol). The reaction was stirred at room temperature overnight. The crude mixture was partitioned between water and ethyl acetate. The extracts were concentrated to dryness. The crude was not purified (yield not calculated). ES-MS (m/z) 431 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[CH:15][CH2:16][CH:17]([OH:27])[C:18]2[CH:19]=[C:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])[O:21][CH:22]=2)[CH:13]=[O:14])=[CH:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:2]1=2>C1C=CC=CC=1>[S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]([OH:14])[O:27][CH:17]([C:18]3[CH:19]=[C:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])[O:21][CH:22]=3)[CH2:16][CH:15]=2)=[CH:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:2]1=2
Reactant: C[Si](C)(C)c1cc(C(O)CC=C(C=O)CCCCCCc2cc3ccccc3s2)co1
Solvent: c1ccccc1
Product: C[Si](C)(C)c1cc(C2CC=C(CCCCCCc3cc4ccccc4s3)C(O)O2)co1

Procedure:
2-[6-(Benzo[b]thien-2-yl)-hexyl]-5-hydroxy-5-(2-trimethylsilyl-4-furyl)-2-pentenal (0.142 g., 0.31 mmol) was dissolved in 30 ml anhydrous benzene, placed in a quartz tube, and subjected to four freeze, pump, thaw cycles. The tube was flushed with argon and irradiated at 254 nm for 2.5 hours. The solution was concentrated to give an orange gum. This material was purified by flash chromatography (silica, 5 to 30% ethyl acetate/hexane. First eluted was the desired hydroxy acetal as a yellow gum. Second eluted was starting aldehyde as a clear gum.