Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[OH-].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O.C(Cl)Cl>[Cl:26][CH2:27][C:28]([N:3]([CH2:4][CH:5]([OH:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:2])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: CNCC(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(CC(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To 55 g of N-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propylamine hydrochloride dissolved in 770 ml of distilled water there was added at room temperature 185 ml of 2 N NaOH and 200 ml of CH2Cl2. At 0° C., slow dropwise addition was made to the mixture of 16.7 ml of chloroacetyl chloride dissolved in 350 ml of anhydrous CH2Cl2. The solution was stirred at room temperature for 3 hours. The organic phase was separated and washed with an aqueous solution of bicarbonate, then with a saturated solution of NaCl, then dried and evaporated to dryness. There was obtained 60 g (Yield 97%) of N-chloroacetyl-N-methyl-3-phenyl-2-hydroxy-3-(2-nitro-phenoxy)-propylamine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[CH:11]=1>ClCCCl>[C:5]([C:16]1[CH:17]=[CH:18][C:19]2[O:20][C:21]3[C:12](=[CH:11][C:10]([Br:9])=[CH:23][CH:22]=3)[S:13][C:14]=2[CH:15]=1)(=[O:7])[CH3:6]
Reactant: Brc1ccc2c(c1)Sc1ccccc1O2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)Sc1cc(Br)ccc1O2
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a suspension of aluminum chloride (1.2 g, 9 mmol) in 1,2-dichloro ethane (20 mL) at room temperature there was added acetyl chloride (0.57 mL, 628 mg, 8 mmol) and the mixture stirred for 10 minutes. There was added 2-bromophenoxathiin (J.A.C.S. 1936, 58, 717) (1.8 g, 6.4 mmol) and the mixture was stirred for 18 hours. After quenching with ice water, the organic portion was collected and the aqueous portion extracted with methylene chloride. The combined organic fractions, after washing 3 times with water and drying over MgSO4, were evaporated to a residue which on crystallization from methanol, followed by column chromatography on silica gel, eluting with a 1:5 mixture of ethyl acetate-hexane, gave the title product as a white solid (247 mg), m.p.: 143°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:28])=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In benzene (4 ml) was dissolved 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (272 mg), and to the solution was added m-chloroperbenzoic acid (267 mg). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (70 ml), saturated sodium hydrogen carbonate solution (30 ml) and sodium nitrite (100 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (205 mg) as pale yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([O:12]C)=O)[C:7]([NH:14][C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:23]=[N:24][N:25]([CH3:31])[C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:21][C:22]3[CH:23]=[N:24][N:25]([CH3:31])[C:26]=3[C:27](=[O:28])[NH:29][CH3:30])=[O:12])[C:7]([NH:14][C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: COC(=O)c1nc(C2CC2)cnc1Nc1cnccn1
Product: CNC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cnccn2)cnn1C

Procedure:
According to the procedure described in step 2 of example 14, methyl 6-cyclopropyl-3-(pyrazin-2-ylamino)pyrazine-2-carboxylate was reacted with 4-amino-N,1-dimethyl-1H-pyrazole-5-carboxamide to give the title compound. Yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([S:10](CCC(OC)=O)(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1.C[O-].[Na+].CC([O-])=O.[Na+].[NH2:27]OS(O)(=O)=O>C1COCC1.O>[Br:1][C:2]1[S:6][C:5]([C:7]([S:10]([NH2:27])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: COC(=O)CCS(=O)(=O)C(C)(C)c1ncc(Br)s1
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(c1ncc(Br)s1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
The product of Step 4 (2.50 g, 7.02 mmol) was taken up in THF (80 mL) at room temperature, and NaOMe (25% in MeOH, 1.52 g, 7.02 mmol) was added. After 30 min at room temperature, the suspension was evaporated to dryness, providing a white solid. The solid was taken up in water (50 mL), and a solution of NaOAc (3.17 g, 38.6 mmol) and hydroxylamine-O-sulfonic acid (3.97 g, 35.1 mmol) in water (25 mL) was added while cooling the reaction (0° C.). The reaction was vigorously stirred at room temperature overnight (a white solid precipitated after 15-30 min). The reaction was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The resulting white residue was triturated with CH2Cl2 and filtered to provide 2-(5-bromo-1,3-thiazol-2-yl)propane-2-sulfonamide (1.58 g, 79%) as a white powder. ESI: [M+H]+ m/z 284.9/286.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6](O)[C:7](=[CH2:12])[CH2:8][O:9][CH2:10][CH3:11])[CH3:2].S(Br)([Br:20])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6]=[C:7]([CH2:12][Br:20])[CH2:8][O:9][CH2:10][CH3:11])[CH3:2]
Reactant: C=C(COCC)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCCl
Product: CCOCC(=CC(NC=O)C(=O)OCC)CBr
Reaction time: 1 h

Procedure:
3.70 g (15.1 mmol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane, and 1.8 ml (22.8 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with 1N potassium hydrogen carbonate solution and with brine, dried over sodium sulfate, filtered and concentrated by evaporation. 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish-brown oil which is reacted further in the crude state.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]([CH3:12])=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.O.[OH-].[Li+:21]>C1COCC1.O>[CH3:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]([CH3:12])=[C:5]([C:7]([O-:9])=[O:8])[N:6]=1.[Li+:21]
Reactant: CCOC(=O)c1nc(C)n(-c2ccccc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)[O-])c(C)n1-c1ccccc1
Temperature: 55 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of ethyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (compound 12a, 4.97 g, 20.3 mmol) in THF/water (15/15 mL) was added lithium hydroxide monohydrate at room temperature. The reaction mixture was stirred at 55° C. for 12 hrs, then the mixture was concentrated in vacuo. The crude solid was washed with diethyl ether to provide the title compound (4.06 g, 90%) as a white solid. The obtained product was used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:23])(=[O:10])=[O:9].[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>N1C=CC=CC=1>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[N:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:10])=[O:9])[C:12](=[O:23])[NH:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1S(=O)(=O)n1c(=O)[nH]c2cc(Cl)ccc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1S(=O)(=O)n1c(=O)[nH]c2cc(Cl)ccc2c1=O
Yield: 66.7 %

Procedure:
22 mg (0.06 mmol) of Compound 2 was dissolved in 200 μl of pyridine, 11.6 μl (0.15 mmol) of methanesulfonyl chloride was added dropwise, then the resultant mixture was stirred at room temperature overnight. An excess amount of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid solution and saturated saline, then dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The crude product was crystallized from diethyl ether to obtain 16 mg (0.04 mmol) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.61 (3H, s), 7.10 (1H, d), 7.20 (1H, d), 7.74 (1H, d), 7.82-7.90 (4H, m), 8.34 (1H, d), 11.70 (1H, s).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.[CH2:13]([N:16]=[C:17]=[O:18])[CH:14]=[CH2:15]>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:13]([NH:16][C:17]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:18])[CH:14]=[CH2:15]
Reactant: ON=C1CCOc2ccccc21
Reactant: C=CCN=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCNC(=O)ON=C1CCOc2ccccc21
Yield: 72.6 %

Procedure:
A solution containing 6.52 g (0.04 mole) of 4-chromanone oxime and 75 ml benzene was stirred and refluxed for 0.50 hrs. using a Dean-Stark apparatus. The solution was cooled to 60° and 6 drops triethylamine and 3.32 g (0.04 mole) allyl isocyanate in 10 ml benzene was added. The solution was stirred and refluxed for 4 hrs., concentrated to dryness, and the residue was recrystallized from 20 ml toluene to give 7.15 g (73%) of the product, m.p. 83°-86°.
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:30][O:29]C(C)(C)[O:27]1)[CH2:3][NH:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:24])(=[O:23])[NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[CH:8][CH:7]=1.Cl>C(O)C.O>[OH:1][CH:2]([CH:26]([OH:27])[CH2:30][OH:29])[CH2:3][NH:4][C:5](=[O:25])[C:6]1[CH:7]=[CH:8][C:9]([S:12](=[O:23])(=[O:24])[NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])=[CH:10][CH:11]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3c(F)cc(F)cc3F)cc2)O1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(NCC(O)C(O)CO)c1ccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4.74 g (10 mmol) of 4-[N-(2,4,6-trifluorophenyl)sulfamoyl]- benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in a mixture of 50 ml of ethanol and 20 ml of water and the solution is acidified to pH 1 with dilute hydrochloric acid. It is stirred at this pH for 4 hours at 60° C. The solution is then adjusted to pH 6.3 with anion exchanger Amberlite IRA 67, filtered and evaporated to dryness in a vacuum. The solid amorphous residue is dried in a vacuum at 50° C. 3.4 g (7.83 mmol)=78.3% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C1(S([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[C:25]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=3)=[CH:24]2)(=O)=O)C=CC=CC=1>>[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:6][C:5]3[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:33]=2)=[CH:24]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc(OC)c1OC
Yield: 34.4 %

Procedure:
Using the procedure of example 1, 3,4,5-trimethoxyaniline (158 mg) was reacted with compound 1f (100 mg) to provide compound 2 (35 mg, 34%). 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=8.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H), 8.31 (d, J=4.8 Hz, 1H), 8.11 (s, 1H), 7.48 (s, 2H), 7.22 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.12 (d, J=4.8 Hz, 1H), 3.86 (s, 9H). MS (ESI) m/z: 378 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:21][CH:22]3[CH2:26][CH2:25][N:24]([C:36](=[O:39])[CH:37]=[CH2:38])[CH2:23]3)[CH:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(Nc3cc(NC4CCNC4)ncn3)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)N1CCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N4-(4-phenoxyphenyl)-N6-(pyrrolidin-3-yl)pyrimidine-4,6-diamine (0.13 g, 0.3 mmol) in THF (1.5 mL) at −60° C. were added DIPEA (0.07 g, 0.5 mmol) and acryloyl chloride (1 M solution in THF, 0.3 mL, 0.3 mmol), and the reaction mixture was stirred at −60° C. for 5 min. The reaction mixture was quenched by adding water and it was extracted with EtOAc (2×5 mL). The combined EtOAc extract was washed with brine (3 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, 230-400, chloroform/methanol:98/2) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyrrolidin-1-yl)prop-2-en-1-one (I-85) as a light green solid. 1H NMR (DMSO-d6) δ ppm: 1.83-1.86 & 1.90-1.94 (m, 1H), 2.07-3.0 & 2.16-2.20 (m, 1H), 3.38-3.86 (m, 4H), 4.2-4.75 & 4.35-4.5 (bs, 1H), 5.65 (dt, J=2 & 10 Hz, 1H), 5.78 (d, J=3.6 Hz, 1H), 6.11 & 6.15 (dd, J=2.4 & 7.0 Hz & dd, J=2.4 & 7.2 Hz, 1H), 6.51-6.64 (m, together 1H), 6.93-7.00 (m, 4H), 7.07-7.18 (m, 2H), 7.36 (t, J=8 Hz, 2H), 7.51 (d, J=8 Hz, 2H), 8.12 (s, 1H), 8.93 (s, 1H); LCMS: m/e 401.8 (M+1).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:30][CH2:29][C:24]5(OCC[O:25]5)[CH2:23][CH2:22]4)[C@@H:17]3[CH2:31][CH2:32][CH2:33][N:34]=[N+:35]=[N-:36])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>O>[N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:30][CH2:29][C:24](=[O:25])[CH2:23][CH2:22]4)[C@@H:17]3[CH2:31][CH2:32][CH2:33][N:34]=[N+:35]=[N-:36])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NCCC[C@@H]1[C@@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)CCN1C1CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=NCCC[C@@H]1[C@@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)CCN1C1CCC(=O)CC1
Yield: 99.6 %

Procedure:
The compound 44 (1.24 g), water (2 mL) and trifluoroacetic acid (18 mL) were stirred at room temperature for 4 hours and then concentrated. The residue was added aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (1.13 g) having the following physical properties.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:37]=[CH:36][N:14]3[C:15](=[O:35])[C:16]([C:21]4[N:22]=[N:23][N:24](CC5C=CC(OC)=CC=5)[N:25]=4)=[C:17]([O:19][CH3:20])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:37]=[CH:36][N:14]3[C:15](=[O:35])[C:16]([C:21]4[NH:25][N:24]=[N:23][N:22]=4)=[C:17]([O:19][CH3:20])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnc(-c3c(OC)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2cc(CCc3nc(C(C)C)cs3)ccn2c(=O)c1-c1nnn[nH]1
Reaction time: 48 h
Yield: 31.3 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-methoxy-3-[2-(4-methoxy-benzyl)-2H-1,2,3,4-tetrazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one (5 mg) obtained in (A) was added with trifluoroacetic acid (0.3 ml) and anisole (0.1 ml) and stirred for 2 days. The solvent was evaporated under reduced pressure, and the residue was added with hexane and ethyl acetate. Insoluble solids were collected by filtration and dried to obtain the title compound (1.2 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH:7]=O)[N:6]=1.[NH2:9][CH2:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]([CH2:27][C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)[CH:17]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[BH4-].[Na+]>CO>[NH:32]1[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[N:29]=[C:28]1[CH2:27][N:16]([CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH:9][CH2:7][C:5]2[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=2)=[CH:38][CH:37]=1)[CH:17]1[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: Cc1nc(C=O)c[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(CNCc2ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc2)c[nH]1
Yield: 52.9 %

Procedure:
Using General Procedure B: A solution of 2-methyl-1H-imidazole-4-carbaldehyde (27.7 mg, 0.25 mmol) and (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (100 mg, 0.25 mmol) in MeOH (2.0 mL) was stirred overnight at room temperature. NaBH4 (18.9 mg, 0.50 mmol) was added and the resultant mixture stirred for an additional 15 minutes. Purification of the crude yellow foam by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 200:3:3) afforded the desired amine (65 mg, 53%) as a white foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([CH3:27])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:24][C:23]([CH3:27])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCN(C)CC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
0.15 g (1.5 mmol) of 1-methyl-piperazine in 10 ml of DMF was added to a solution of 0.45 g (1.275 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml in DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 15:1) and crystallization from EtOH yielded 0.40 g (75%) of 3-benzenesulphonyl-5-methyl-7-(4-methyl-piperazine-1-yl) -2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 209-210°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][NH2:34])[CH2:29]1)[CH3:27]>CS(C)=O.CO>[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][NH:34][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CC[C@@H](CN)C1
Solvent: CO
Solvent: CS(C)=O
Product: CCN1CC[C@@H](CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 120 °C

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic (Intermediate 67, 0.08 g), and ((S)-1-ethylpyrrolidin-3-yl)methylamine (Intermediate 169, 0.8 g) in DMSO (0.2 mL) was stirred and heated at 120° C. for 24 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]-chromene-4-carboxylic acid (0.03 g) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH3:9]I>C1COCC1>[CH3:9][O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](N)CO
Reactant: CI
Solvent: C1CCOC1
Product: COC[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-amino-4-methylpentan-1-ol (0.276 ml, 2.133 mmol) was added to a stirred, ice-bath cooled suspension of KH (267 mg, 2.327 mmol) in THF (10 ml) under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for ˜10 minutes and then treated with MeI (0.121 ml, 1.939 mmol). After stirring for 30 minutes the reaction mixture was quenched by addition of saturated NH4Cl(aq) (˜20 ml) and extracted with EtOAc (25 ml×2). The combined organic phases were dried over MgSO4, filtered under vacuum and the filtrate was evaporated to afford an orange oil. The oil was purified by chromatography on silica eluting with 10% (2M NH3 in MeOH)/DCM to afford the title compound which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)(O)=[O:2].C(Cl)(=O)C([Cl:20])=O>C1C=CC=CC=1>[C:14]1(=[O:15])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([Cl:20])=[O:2])=[CH:5][CH:6]=2)[C:11](=[O:16])[CH:12]=[CH:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(N2C(=O)C=CC2=O)cc1

Procedure:
Para-maleimidobenzoyl chloride was prepared in accordance with the procedure described by Adams et al. in J. Am. Chem. Soc , 42, 599 (1920). The N-(para-carboxyphenyl) maleimide (15 g) was suspended in about 80 ml of benzene with stirring. To this mixture was added 15 ml (a 2.5:1 molar excess) of oxalyl chloride, whereupon some gas was evolved. The mixture was then heated slowly to reflux and maintained at reflux for two hours. Excess oxalyl chloride was removed by distillation. The reaction mixture was then cooled and the yellow product recovered by suction filtration. The resultant product was washed with hexane and dried under vacuum at room temperature.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[N:21]=1>C(O)(C)C>[Br:22][C:20]1[N:21]=[C:16]([NH:14][C:11]2[CH:12]=[N:13][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3nc(Br)cn(C)c3=O)cn2)CC1
Yield: 25.4 %

Procedure:
A mixture of 6-(4-methylpiperazin-1-yl)pyridin-3-amine (1 g, 5.2 mmol) prepared according to US 2009/0318448, 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.7 g, 6.2 mmol), and isopropanol (20 mL) was stirred at reflux for 16 h. After the reaction was completed, the solvent was removed to give 331a as a brown solid (500 mg, 30%). MS: [M+H]+ 379.