Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][C@H:22]([C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=1)[O:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:34](OC(C)(C)C)=O)[OH:23])=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO.C(Cl)Cl>[OH:23][C@@H:22]([C:24]1[CH:43]=[CH:42][CH:41]=[C:26]([O:27][CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[CH3:34])[CH:25]=1)[CH2:21][CH2:20][NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cccc([C@H](O)CCNC(=O)OC(C)(C)C)c1
Reaction time: 4 h

Procedure:
Anhydrous THF (5 mL) was cooled to 0° C. and LiAlH4 (0.016 g, 0.44 mmol) was added. (S)-tert-butyl 2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pyrrolidine-1-carboxylate (0.1 g, 0.22 mmol) was slowly added to reaction mixture and then kept at room temperature for 4 hrs. After completion of reaction as judged by TLC (10% MeOH/CH2Cl2) the reaction mixture was quenched with EtOAc followed by saturated Na2SO4, extracted with EtOAc and organic layer was concentrated under reduced pressure to give tert-butyl ((R)-3-hydroxy-3-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propyl)carbamate as a light yellow oil which was used in the next step without additional purification. Yield (0.060 g, 75%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH2:12][C@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1.[I:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[OH-].[Na+]>CN(C=O)C>[I:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:12][C@H:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[O:27])=[CH:24][CH:23]=1
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(I)cc1
Reaction time: 3 h
Yield: 64.2 %

Procedure:
N,N′-Diisopropylethylamine (1.05 ml, 6.03 mmol) was added to a flask charged with DMF solution mixture of (S)-(−)-3-Aminoquinuclidine dihydrochloride (400 mg, 2.01 mmol) and 4-Iodobenzoyl chloride (616 mg, 2.31 mmol). The clear yellow solution was stirred for 3 hours. The reaction mixture was worked up by addition of 1N sodium hydroxide aqueous solution and extracted twice with ethyl acetate, combined organic layer was washed with saturated brine solution, dried over sodium sulfate, filtered, and concentrated to crude clear oil. The crude oil was purified via preparative HPLC to obtain pure product of (S)-4-iodo-N-(quinuclidin-3-yl)benzamide, (460 mg, 64% yield). 1H NMR (400 MHz, Methanol-D4) δ (ppm): 7.85 (d, J=8 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 4.12 (m, 1H), 3.31 (m, 1H), 2.99 (m, 1H), 2.84 (m, 4H), 2.02 (m, 1H), 1.90 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H). C14H17IN2O=356.04 LCMS (M+H): m/z 357
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27]([N:42]3[CH2:41][CH2:40][CH:39]([C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)[CH2:44][CH2:43]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(F)ccc1F
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(F)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 35.9 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2,5-difluorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.38 g, 3.04 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.70 g, 3.88 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.64 g, 43%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH:5]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:23][CH:24]=[O:25])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: O=Cc1ccc(-n2cccn2)c(F)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-n2cccn2)c(F)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-fluoro-4-(1H-pyrazol-1-yl)benzaldehyde (prepared as described in Reference Example 6) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: [CH:1]([CH:4]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[C:17]([CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>>[CH:1]([CH:4]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:5]([O:7][CH:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
2-Isopropyl-4-(4-fluorophenyl)-3-butenoic acid (1.12 mmol) is reacted via the acid chloride with α-cyano-m-phenoxybenzyl alcohol (1.86 mmol) to yield α-cyano-m-phenoxybenzyl 2-isopropyl-4-(4-fluorophenyl)-3-butenoate, MS m/e 429 (M+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:33]=[C:14]3[CH2:15][CH:16]([N:23]([CH:30]4[CH2:32][CH2:31]4)C(=O)C(F)(F)F)[C:17]4[CH2:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(O)C>[C:1]1([S:7]([N:10]2[CH:33]=[C:14]3[CH2:15][CH:16]([NH:23][CH:30]4[CH2:31][CH2:32]4)[C:17]4[CH2:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CC2=CN(S(=O)(=O)c3ccccc3)C=C3CC(N(C(=O)C(F)(F)F)C4CC4)C(=C23)C1
Solvent: O
Solvent: CCO
Product: O=C1C=CC2=CN(S(=O)(=O)c3ccccc3)C=C3CC(NC4CC4)C(=C23)C1
Reaction time: 23 h
Yield: 96 %

Procedure:
Compound (51) 129 mg was dissolved in ethanol 3 ml. Sodium hydrogenborohydride 42 mg was added to the solution at room temperature and the mixture was stirred for 23 h. Water was added with cooling in ice to the reaction mixture, which was extracted with chloroform. 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 chloroform:hexane (1:1) to give the titled compound as a colorless oil, 98 mg. Yield 96%. The titled compound was treated with 1 eq. of oxalic acid to give the salt, which was recrystallized from isopropanol-ether to give colorless crystals, m.p. 119-122° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][C:6]=1[N+:28]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:28][C:6]1[CH:7]=[C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:9]=[CH:10][C:5]=1[C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccccn2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccccn2)cc1N
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of N-[4-(tert-butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide (100 mg, 0.25 mmol, Example 73), iron powder (69 mg, 1.25 mmol) and NH4Cl (10 mg, 0.17 mmol) in EtOH (0.5 mL) and H2O (0.5 ml) was stirred for 4 h at 80° C. The reaction mixture was filtered, concentrated, and purified through column chromatography to give the product. MS (ES+): 376 M+H); (ES−): 374 (M−H). Calc'd. for C22H25N5O—375.21.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH:21][NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)=[O:32])=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: O=C(CCCCN1CCC(Cc2ccccc2)CC1)NNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)NNC(=O)CCCCN2CCC(Cc3ccccc3)CC2)cc1
Yield: 32.2 %

Procedure:
To a solution of N-(5-(4-benzylpiperidin-1-yl)valeroyl)-N′-(4-nitrobenzoyl)hydrazine (200 mg, 0.456 mmol) in 20 mL of methanol was added 50 mg of 5% Pd/C. The resulting mixture was hydrogenated at 30 psi of hydrogen for 3 hr. The catalyst was removed through a short column of Celite and was washed with methanol (15 mL). The extracts were evaporated in vacuo to give an oil, which was purified by flash chromatography to give the title product as a solid (60 mg, 32%):. mp 163-165° C.; 1H NMR (CDCl3) 1.26 (m, 2 H), 1.59 (m, 9 H), 1.92 (m, 2 H), 2.28 (m, 4 H), 2.52 (m, 2 H), 2.90 (m, 2 H), 3.29 (s, 2 H), 6.83 (d, J=8.1 Hz, 2 H), 7.10 (m, 3 H), 7.20 (m, 2 H), 7.63 (d, J=7.8 Hz, 2 H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:24])[CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br-].[Al+3].[Br-].[Br-]>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:24])[CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCC(C)C(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCCCCC(C)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 40 °C
Reaction time: 11 h
Yield: 54 %

Procedure:
Then, 400 mg (1.2 mmol) of the above 4-methoxy-4'-(2-methyloctanoyl) biphenyl was dissolved in 6 ml of dried toluene in a flask of 50 ml. After the solution was added with 1.3 g (5.0 mmol) of aluminum bromide under ice cooling for 5 minutes, the resulting mixture was stirred under ice cooling for 6 hours, at room temperature for about 60 hours and at 40° C. for 11 hours. After the completion of the reaction, the resulting product was poured into 100 ml of ice water together with 40 ml of toluene. After the separation into two layers, the organic layer was taken out, and the extraction with 40 ml of toluene on aqueous layer was repeated two times. Thereafter, the organic layers were gathered, washed with 40 ml of water and dried on anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the product was concentrated and purified through a silica gel column (toluene→toluene: diethyl ether=5:1 (v/v)] to obtain 200 mg (yield: 54%) of a reddish brown oily substance of 4-hydroxy-4'-(2-methyloctanoyl) biphenyl having the following properties:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:4](=[O:15])[N:3]1[CH2:16][CH2:17]Br.N12CCCC1=NCCC2>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[C:4](=[O:15])[N:3]1[CH:16]=[CH2:17]
Reactant: Cn1c(=S)n(-c2ccc(Cl)cc2)c(=O)n1CCBr
Agent: C1CN=C2CCCN2C1
Solvent: ClC(Cl)Cl
Product: C=Cn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.9 g of 1-methyl-2-(2-bromoethyl)-4-(4-chlorophenyl)-1,2,4-triazolidin-3-one-5-thione (prepared as in Example 3) and 2.1 g 1,5-diaza-bicyclo[4.3.0] non-5-ene in 100 ml chloroform was heated to reflux for 3 hours and stirred overnight at room temperature. The mixture was washed with water, dried (MgSO4), stripped and chromatographed by high-pressure liquid chromatography. Yield: 2.6 g.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[CH:12]=[C:11]([CH2:22][S@:23]([CH3:25])=[O:24])[N:10]=1.[OH-].[Na+]>[Br-].C([N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC)CCCCCCC.CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[CH:12]=[C:11]([C:22]2([S@:23]([CH3:25])=[O:24])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: BrCCOCCBr
Reactant: C[C@@H]1COCCN1c1cc(C[S@](C)=O)nc(Cl)n1
Agent: CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: [Br-]
Product: C[C@@H]1COCCN1c1cc(C2([S@](C)=O)CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.4 %

Procedure:
1-bromo-2-(2-bromoethoxy)ethane (2.323 ml, 18.63 mmol) was added to (R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (1.8 g, 6.21 mmol), sodium hydroxide (16.40 ml, 310.58 mmol) and tetraoctylammonium bromide (0.340 g, 0.62 mmol) in methyl THF (12.34 ml). The resulting mixture was stirred at RT for 24 hours. The reaction mixture was diluted with methyl THF (50 mL), and then washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated onto silica (5 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-(4-((S)-methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (1.461 g, 65%); 1H NMR (400 MHz, CDCl3) 1.34 (3H, d), 1.84-1.94 (1H, m), 2.10 (3H, s), 2.24-2.37 (2H, m), 2.44 (1H, ddd), 3.30 (1H, td), 3.41 (1H, ddd), 3.51-3.64 (2H, m), 3.65-3.73 (1H, m), 3.75-3.82 (1H, m), 3.90-4.08 (4H, m), 4.36 (1H, s), 6.46 (1H, s); m/z: (ES+) MH+, 360.15 and 362.11. b) Iodobenzene diacetate (1.437 g, 4.46 mmol) was added to (R)-4-(2-chloro-6-(4-((S)-methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine (1.46 g, 4.06 mmol), 2,2,2-trifluoroacetamide (0.459 g, 4.06 mmol), rhodium(II)acetate dimer (0.045 g, 0.10 mmol) and magnesium oxide (0.654 g, 16.23 mmol) in DCM (20.29 ml). The resulting suspension was stirred at RT for 48 hours. Further 2,2,2-trifluoroacetamide (0.459 g, 4.06 mmol), magnesium oxide (0.654 g, 16.23 mmol), iodobenzene diacetate (1.437 g, 4.46 mmol) and rhodium(II)acetate dimer (0.045 g, 0.10 mmol) were added and the suspension was stirred at RT for a further 24 hours. The reaction mixture was filtered and then evaporated onto silica (5 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 100% EtOAc in isohexane. Pure fractions were evaporated to afford N-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-X6-(S)-sulfanylidene]-2,2,2-trifluoroacetamide (1.421 g, 74%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, d), 2.19-2.31 (2H, m), 2.72-2.84 (2H, m), 3.11-3.28 (3H, m), 3.40-3.45 (1H, m), 3.46 (3H, s), 3.53-3.61 (1H, m), 3.74 (1H, d), 3.94 (3H, d), 4.12 (1H, s), 4.47 (1H, s), 7.05 (1H, s); m/z: (ES+) MH+, 471.04 and 473.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Cl:13])=[CH:11][NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14](N1C=CN=C1)(=[O:16])[CH3:15]>CCOCC.O>[C:14]([N:10]1[CH:11]=[C:12]([Cl:13])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9]1)(=[O:16])[CH3:15]
Reactant: Clc1cccc(-c2c[nH]cc2Cl)c1
Reactant: CC(=O)n1ccnc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)n1cc(Cl)c(-c2cccc(Cl)c2)c1
Yield: 57.8 %

Procedure:
The mixture of 6.5 g of 3-(3-chlorophenyl)-4-chloropyrol and 10.1 g of N-acetylimidazole was heated for one hour at 100°-110° C. After cooling, the reaction mixture was dissolved in a mixture of 200 ml of ether and 20 ml of water and the resulting ether solution was treated as in Example 4 to obtain 4.5 g of the desired product (colorless crystal, m.p. 88°-90° C.).
Reaction SMILES: [CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17]C#N)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:1]1([N:7]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCN1CCCCC1
Reactant: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCN1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea and N-(2-chloroethyl)piperidine.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([O:15]C(=O)C)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:19][C:20](=[O:22])[CH3:21])(=[O:5])=[O:4].OO.Cl>CN(C)C=O>[CH3:23][N:2]([CH3:1])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:19][C:20](=[O:22])[CH3:21])(=[O:4])=[O:5]
Reactant: CC(=O)Nc1nc2ccc(OC(C)=O)cc2n1S(=O)(=O)N(C)C
Agent: Cl
Agent: OO
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(O)cc2n1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Dimethylaminosulfonyl-2-acetamido-6-acetoxybenzimidazole, 170 mg. (0.50 mmole), was dissolved in 3.0 ml. of dimethylformamide and 2.0 ml. of pH 10.0 buffer was added. One-half milliter of three percent hydrogen peroxide was added to the reaction mixture. The reaction mixture was allowed to stir at room temperature for about 10 minutes. The mixture was poured into 50 ml. of 0.1 N hydrochloric acid. The acid mixture was extracted with chloroform. The extract was washed successively with water and saturated sodium chloride solution. The chloroform solution was dried and evaporated in vacuo to yield 102 mg. of 1-dimethylaminosulfonyl-2-acetamido-6-hydroxybenzimidazole, mp. 175°-176° C., after crystallization
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Cl>O>[F:33][C:34]1[CH:35]=[C:36]([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]3[CH:12]=[C:13]4[C:18]5=[C:19]([CH2:21][CH2:22][N:17]5[C:16](=[O:23])[CH2:15][CH2:14]4)[CH:20]=3)=[O:10])[CH2:5][CH2:6]2)[CH:39]=[CH:40][CH:41]=1
Reactant: Fc1cccc(CCl)c1
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CCC1CCN(Cc2cccc(F)c2)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 55 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A mixture of 600 g of 8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, 6 L of acetonitrile, 0.3 L of water, 345 g (1.3 equivalent) of potassium carbonate and 278 g (1 equivalent) of 3-fluorobenzyl chloride was stirred at about 55° C. and 12 L of water was added dropwise thereto over about 20 minutes while maintaining about 45° C. The mixture was stirred at about 55° C. for 1.5 hours, and at about 20° C. for 3 hours. Precipitated crystals were separated, and washed with 15 L of water. The wet crystals were suspended in 8.0 L of 10% hydrous methanol-denatured ethanol. The material was dissolved at about 70° C., and passed through a dust-removing filter. The filtrate was stirred at about 20° C. for 1.5 hours, 6.9 L of water was added thereto, and the mixture was stirred at about 20° C. for 3 hours. Crystals were separated, washed with 1.8 L of 50% hydrous methanol-denatured ethanol twice and dried to obtain 0.71 kg (yield 88%) of the desired compound as crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N:11]1[C:16]2[N:17]=[C:18](S(C)(=O)=O)[N:19]=[C:20]([C:21]3[CH:22]=[C:23]([NH:28][C:29](=[O:38])[C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=4)[CH:24]=[CH:25][C:26]=3[CH3:27])[C:15]=2[CH2:14][NH:13][C:12]1=[O:43].[CH2:44]([OH:46])[CH3:45]>CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N:11]1[C:16]2[N:17]=[C:18]([O:46][CH2:44][CH3:45])[N:19]=[C:20]([C:21]3[CH:22]=[C:23]([NH:28][C:29](=[O:38])[C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=4)[CH:24]=[CH:25][C:26]=3[CH3:27])[C:15]=2[CH2:14][NH:13][C:12]1=[O:43]
Reactant: CCO
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1nc(-c2cc(NC(=O)c3ccc(C)c(F)c3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Dry ethanol (2 mL) was treated with NaH (0.0056 mg, 0.140 mmol, 60% in mineral oil) under argon and stirred for 10 min. The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide (0.064 g, 0.110 mmol) was added in ethanol (2 mL). The reaction was stirred under argon for 1 h and then warmed to 70° C. for 2 h. The reaction mixture was diluted with EtOAc and the organics washed with water, brine (twice), dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel, eluting with a CH2Cl2—10% EtOAc/CH2Cl2 gradient to afford the title compound as a white solid. mp 257.3-262.5° C.; LC-MS m/z 548 (M+H)+, 2.37 min (ret. time).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.[C:21]([CH2:23][C:24]([NH2:26])=[O:25])#[N:22].C[O-].[Na+]>CN(C=O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[C:4]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[CH:3][C:23]([C:21]#[N:22])=[C:24]([OH:25])[N:26]=2)=[CH:12][CH:11]=1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccncc2)c(-c2ccc(F)cc2)nc1O
Yield: 47.8 %

Procedure:
To a solution of 3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl)prop-2-en-1-one (12.77 g, 47.2 mmol, obtained in reference example 7) in DMF (175 mL), 2-cyanoacetamide (4.41 g, 52.0 mmol) was added under argon atmosphere. Then, sodium methoxide (5.35 g, 99.2 mmol) was added and heated to reflux for 1 hour. The mixture was allowed to cool, concentrated and diluted with water. The pH was adjusted to 4 with 1 N HCl. A precipitate was obtained that was filtered and dried to give 6.57 g of the desired compound as a solid (yield: 48%).