Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 79 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 79%). 1H NMR (300 MHz, CDCl3): δ 2.42-2.49 (m, 3H), 3.12-3.19 (m, 4H), 3.79 (s, 3H), 4.11-4.13 (m, 4H), 6.97-7.12 (m, 5H), 7.26-7.33 (m, 1H), 7.48-7.63 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2].CN(C)C=O.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>[Cu]I.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:33]=[N:34][NH:35][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1ncccn1)C[C@H](C)N2C(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2ncccn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 5.85 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-2-pyrimidinyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 114) (45 mg, 0.147 mmol) and copper (I) iodide (2.80 mg, 0.015 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and methanol (0.200 mL) and the resulting mixture was treated with trimethylsilyl azide (0.078 mL, 0.588 mmol). The flask was flushed with nitrogen then the mixture was stirred at 100° C. for 1 h under microwave irradiation then cooled to room temperature. Most of the methanol was removed in vacuo and the remaining organic phase was purified by MDAP (modifier: ammonium bicarbonate) to give (2S,4R)-1-acetyl-2-methyl-N-2-pyrimidinyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinamine (3 mg, 8.59 μmol, 5.85% yield) as a colourless film.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)c1ccc(C(=O)CCC(=O)O)cc1
Yield: 68 %

Procedure:
tert-Butylbenzene 10e (99%, 4.3 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 120 h according to the general procedure. Extractive purification of the crude product afforded white crystals of 11e in 68% yield. 1H-NMR: 7.93 (d, 2H Ar--H); 7.48 (d, 2H, Ar--H); 3.30 (t, 2H, CH2CH2COOH); 2.81 (t, 2H, CH2CH2COOH); 1.34 (s, 9H, CH3).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37]1([CH3:49])[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45](Cl)(=[O:47])=[O:46].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:49][C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45]([N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:14][CH:13]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)(=[O:46])=[O:47]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: c1ccc(OC2CCCCO2)c(CNc2ccc(OCCN3CCCC3)cc2)c1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccccc2OC2CCCCO2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.5 %

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[2-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.060 g, 0.19 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.43 mmol) and 2-mesitylene sulfonyl chloride (0.066 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 24 hr. PS-isocyanate resin (0.050 g), PS-trisamine resin (0.050 g), and 1.5 mL methylene chloride were added and the mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated. The residue was purified by preparative TLC (1.0 mm silica gel layer, eluting with 10% methanol/methylene chloride) to afford the title compound of Step A (0.039 g). MS 579.3 (M+1)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]1[C:11]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][S:18][C:12]=2[N:13]=[C:14]([CH2:16][Cl:17])[N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:17][CH2:16][C:14]1[N:15]=[C:10]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)[C:11]2[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][S:18][C:12]=2[N:13]=1
Reactant: OCC1CCNCC1
Reactant: ClCc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OCC1CCN(c2nc(CCl)nc3scc(-c4ccccc4)c23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
4-Piperidinemethanol (0.85 g) was added to a suspension of 4-chloro-2-(chloromethyl)-5-phenyl-thieno[2,3-d]pyrimidine (1.45 g) in ethanol (70 mL). Triethylamine (1.4 mL) was added and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated and the residue was dissolved in water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (1×100 mL), dried (sodium sulfate), filtered and evaporated to give an off-white foam (1.76 g). This was purified by silica chromatography (50 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 50%; collection by UV trigger). Fractions corresponding to the main peak were combined and evaporated to give the target compound as a white foam (1.10 g). m/z [M+H]+373.9/375.9. Retention time 4.67 min (LCMS method+ve 6 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C:11]3[N:15]=[CH:16][C:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)=[CH:18][C:10]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:28]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C:11]3[N:15]=[CH:16][C:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:36]5[CH2:37][CH2:38][CH:33]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)[CH2:34][CH2:35]5)=[O:25])=[CH:21][CH:20]=4)=[CH:18][C:10]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cccnc2Cl)CCN3)cc1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cccnc2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 20 %

Procedure:
4-[1-(2-Chloropyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (38 mg) was reacted with 4-(1-pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid (20% yield). LCMS: m/z=516.89 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.50 (1H, m), 1.80 (5H, m), 1.97 (2H, m), 2.27 (1H, m), 2.58 (4H, m), 3.01 (2H, m), 3.50 (2H, m), 3.67 (2H, m), 3.79 (1H, m), 4.54 (2H, s), 4.95 (1H, bs), 6.58 (1H, d, J=1.5 Hz), 7.23 (1H, m), 7.36 (4H, m), 7.62 (1H, dd, J=7.6, 1.8 Hz), 7.73 (1H, d, J=1.8 Hz), 8.34 (1H, dd, J=4.8, 1.8 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C)C=O.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>>[N:39]1([CH2:38][CH2:37][CH2:36][O:35][C:32]2[CH:33]=[CH:34][C:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)=[CH:24][CH:25]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: C1COCCN1
Reactant: ClCCCOc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(-c2ccc(OCCCN3CCOCC3)cc2)ccc1OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 22.1 %

Procedure:
A suspension of potassium carbonate (138 mg) in a mixture of 1-{3-[4′-(3-chloropropoxy)biphenyl-4-yloxy]propyl}piperidine (100 mg), morpholine (65 mg) and N,N-dimethylformamide (1 mL) is stirred for four days at room temperature. The mixture is filtered, concentrated under reduced pressure and purified by chromatography over silica gel with dichloromethane/methanol 82/2 as eluent. Fractions containing the expected product are pooled and concentrated under reduced pressure to give 25 mg of 4-(3-{[4′-(3-piperidinopropoxy)biphenyl-4-yl]oxy}propyl)morpholine as a off white solid which is salted with 9.4 mg of oxalic acid yielding 15 mg of 4-(3-{[4′-(3-piperidinopropoxy)biphenyl-4-yl]oxy}propyl)-morpholine, dioxalate as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:23])[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=2[CH3:22])[OH:11])[CH2:5]1.[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[OH:11][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][NH:2][CH2:37][C@H:35]([OH:36])[C:26]2[CH:27]=[CH:28][C:29]3[C:30](=[O:34])[O:31][CH2:32][C:33]=3[C:25]=2[CH3:24])([CH3:23])[CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCC(C)(CN)C2)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNCC2(C)CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)C2)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[3-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)-3-methylpyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(R)-2-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 7] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:47]([O:49][CH3:50])=[O:48]>ClCCl>[CH3:50][O:49][C:47](=[O:48])[N:11]([CH2:12][C:13]1[CH:14]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)[CH2:10][C:9]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:8]=1[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:35][CH3:36]
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1C(OC)C1CCCCC1
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine (Example 41, STEP E, 22 mg, 0.042 mmol) in dichloromethane (1 ml) was added diisopropylethyl amine (8.09 mg, 0.063 mmol) followed by methyl chloroformate (3.94 mg, 0.042 mmol) at room temperature and stirred for overnight. Reaction mixture was then concentrated in vacuo and the product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1 CV), 2-20% (10CV), 20% (2CV) to yield the title compound (7 mg, 30%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (m, 6H) 1.4(m, 1H) 1.5(m, 2H) 1.7(s, 1H) 1.9 (d, J=11.2 Hz, 1H) 3.0 (s, 3H) 3.8(s, 3H) 4.0 (d, J=17.9 Hz, 1H) 4.6 (m, 4H) 7.25 (d, J=10.4 Hz, 1H) 7.45 (d, J=7.5 Hz, 1H) 7.53 (m, 3H) 7.7 (s, 1H) 7.8 (s, 1H). MS (ES+) Calc: 585.2, Found: 630.3 (M+45).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@@H:25]1[CH2:29][O:28][CH2:27][C@H:26]1[NH:30][C:31]1[CH2:35][S:34][C:33](=[O:36])[N:32]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][C@H:26]3[C@H:25]([OH:24])[CH2:29][O:28][CH2:27]3)=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2COC[C@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2COC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (649 mg) in 2-propanol (10 mL) were added 4-[trans-(4-hydroxytetrahydrofuran-3-yl)amino]-1,3-thiazol-2(5H)-one (580 mg) and piperidinium acetate (283 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (469 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[CH3:29][O:30][CH2:31][C:32]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:33]
Reactant: COCC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) in THF (4 mL) was added triethylamine (0.12 mL, 0.85 mmol). The mixture was cooled in an ice bath and a solution of methoxyacetyl chloride (0.092 mL, 0.85 mmol) in THF (1 mL) was added dropwise. After stirring for 1 h at room temperature the precipitate was filtered and the organic phase was evaporated. The residue was dissolved in methanol (5 mL), sodium bicarbonate (1 spatula) was added and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was extracted (dichloromethane/water). Then the organic phase was dried over sodium sulfate and concentrated. Chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) afforded the title compound (180 mg, 73%) as a white solid. MS: m/e=355.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[OH-:24].[Na+].OO.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([NH2:23])=[O:24])[CH:19]=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: COc1ncc(Cn2cc(C#N)cn2)cc1-c1cccc(Cl)c1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc(Cn2cc(C(N)=O)cn2)cc1-c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A solution of 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile (Example 170, 25.00 mg, 0.08 mmol) in MeOH (1.54 mL) was heated to 50° C., until the starting material dissolved. Sodium hydroxide (0.23 mL, 1.00 mol/L, 0.23 mmol) and hydrogen peroxide (0.23 mL, 1.00 mol/L, 0.23 mmol) were added and the reaction stirred at 50° C. for 2 h. Water was added (5 mL), and the mixture was filtered and washed with water (3×5 mL) to afford the title compound as a solid (25.0 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=13.69 Hz, 2H), 7.80 (d, J=14.48 Hz, 2H), 7.65-7.37 (m, 5H), 6.95 (br s, 1H), 5.32 (br s, 2H), 3.87 (br s, 3H). [M+H]=343.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH3:26])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].BrCC1C=C[C:34]2C3SC(C(N(C4C=CC=CC=4Cl)C)=O)=CC=3C[CH2:37][O:36][C:35]=2C=1.N1CCOCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:34][CH2:35][O:36][CH2:37][CH2:26]4)=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Reactant: CNCc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Solvent: C1COCCN1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(CN3CCOCC3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure in Example 153 for the synthesis of 243, 8-(bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with morpholine to give 261. MS: (ESI+) 469.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26].[CH:27](O)=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][CH:27]=[O:28])[CH2:23][CH2:24]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26]
Reactant: O=CO
Reactant: O=C1Nc2nc(N[C@H]3CC[C@H](O)CC3)ncc2CN1c1ccccc1Cl
Product: O=CO[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(2-chlorophenyl)-7-(trans-4-hydroxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (300 mg, 0.8 mal) (prepared as described in Example 73) and 96% formic acid (2 mL) was stirred at 60° C. for 3 hours, then concentrated under reduced pressure. The residue was triturated in ether, filtered and dried to give 250 mg of 3-(2-chlorophenyl)-7-(trans-4-formyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1)C1C=CC=CC=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>CO.C(Cl)Cl.[Pd]>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:47])([F:46])[F:48])[CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(NCc2ccc(NC(=O)OCc3ccccc3)cc2)nc2ccccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1nc(NCc2ccc(NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)cc2)nc2ccccc12
Temperature: 50 °C
Reaction time: 41.5 h
Yield: 74.4 %

Procedure:
To a solution of {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-carbamic acid benzyl ester (318 mg, 0.744 mmol) in MeOH (3 mL) was added 5% Pd/C (30 mg). The mixture was stirred at 50° C. under hydrogen atmosphere for 41.5 hr, filtered through a pad of celite, and concentrated. To a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (505 mg, 1.49 mmol) in CH2Cl2 (12 mL) was added PVP (6 mL). To the resulting suspension was added a solution of the above residue in CH2Cl2 (10 mL). The mixture was stirred at ambient temperature for 1.5 days, filtered, poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 33% EtOAc in hexane) to give 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-2-trifluoromethoxy-benzenesulfonamide (330 mg, 74%) as a pale brown solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:12][C:13]([CH2:15]Br)=[CH2:14]>CN(P(N(C)C)(N(C)C)=O)C>[Br:12][C:13](=[CH2:14])[CH2:15][CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: C=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(Br)CC(C(=O)OC)C(=O)OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a suspension of sodium hydride (5.0 g, 125 mmol) in HMPA (50 ml, distilled from calcium hydride) was added a solution of dimethyl malonate (11.7 ml, 100 mmol) in HMPA (5 ml) at 0° C. under argon. The mixture was heated to 50° C. and stirred 1 hour. Following this the solution was again cooled to 0° C., and a solution of 2,3-dibromopropene (122 ml, 100 mmol) in HMPA (5 ml) was added to the reaction mixture. Next, the solution was warmed to 40° C. and stirred for 1 hour. The reaction mixture was quenched with aq. HCl (10%, 88 ml) and extracted with ether (3×45 ml). The organic fractions were collected, dried over MgSO−4, and the solvent was removed in vacuo. The crude oil was purified via silica gel chromatography (eluants: chloroform/hexane) to obtain the titled product as a colorless oil (16.3 g, 65%). 1H-NMR (300 MHz, CDCl3) δ 5.70 (d, J=1.8 Hz, 1H), 5.48 (d, J=1.8 Hz, 1H), 3.63 (t, J=7.5 Hz, 1H), 3.76 (s, 6H), 3.04 (d, J=7.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([N:16]=[N+:17]=[N-:18])[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:21].Cl[CH2:23]Cl.CO>C[Si](C=[N+]=[N-])(C)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([N:16]=[N+:17]=[N-:18])[C:13]([O:15][CH3:23])=[O:14])=[CH:4][C:3]=1[CH3:21]
Reactant: ClCCl
Reactant: Cc1cc(COCCCC[C@@H](N=[N+]=[N-])C(=O)O)ccc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)[C@@H](CCCCOCc1ccc(F)c(C)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of crude (R)-6-(4-fluoro-3-methylbenzyloxy)-2-azidohexanoic acid (0.163 g, 0.552 mmol) in 10 mL of dichloromethane/methanol (4:1), trimethylsilyldiazomethane was added dropwise until the solution became yellow. After stirred at room temperature under N2 for 30 min, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.141 g, 83% yield)
Reaction SMILES: Br[C:2]1[O:11][CH2:10][C:9]2[CH:8]([N:12]([CH3:14])[CH3:13])[CH2:7][C:6]3=[CH:15][N:16]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:17]=[C:4]([C:5]=23)[CH:3]=1.[Li]CCCC.[CH3:33][S:34]SC>O1CCCC1.[Cl-].[NH4+]>[CH3:14][N:12]([CH3:13])[CH:8]1[C:9]2[CH2:10][O:11][C:2]([S:34][CH3:33])=[CH:3][C:4]3=[CH:17][N:16]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])[CH:15]=[C:6]([C:5]=23)[CH2:7]1
Reactant: CSSC
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(Br)OCC3=C2C(=C1)CC3N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSC1=CC2=CN([Si](C(C)C)(C(C)C)C(C)C)C=C3CC(N(C)C)C(=C23)CO1
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml was cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was added dropwise to the solution and the mixture was stirred for 1 h. Then, dimethyldisulfide 185 μl was added and the mixture was stirred for 2 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give the titled compound as colorless crystals, 289.8 mg. Yield 69%. This was recrystallized from hexane to give the titled compound as colorless crystals, m.p. 77-79° C.