Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CO.C(Cl)Cl>[O:11]=[C:10]1[C:4]2[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Nc1ccc2c(c1)C(=O)CCCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc2c(c1)C(=O)CCCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 128A (1.63 g, 9.30 mmol) and K2CO3 (2.57 g, 18.60 mmol) in MeOH (10 ml) under nitrogen atmosphere was cooled to 0° C. The mixture was treated with benzyl chloroformate (1.726 ml, 12.09 mmol), raised to room temperature and stirred for 16 hours. The mixture was diluted with CH2Cl2, washed with water, dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 15% EtOAc/hexanes to provide the title product. 1H NMR (CDCl3) δ 1.75-1.90 (m, 4H), 2.67-2.75 (m, 2H), 2.84-2.92 (m, 2H), 4.70 (d, J=5.76 Hz, 2H), 6.72 (s, 1H), 7.16 (d, J=8.14 Hz, 1H), 7.36-7.39 (m, 5H), 7.49 (d, J=2.71 Hz, 1H), 7.70 (d, J=7.12 Hz, 1H). MS (M+NH4)+ m/z 327.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=O)(C)(C)C.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][C@@H:9]([C:22]([O:24][CH3:25])=[O:23])[NH2:8])=[CH:12]1)[CH3:21]
Reactant: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Reaction time: 17 h
Yield: 74 %

Procedure:
To methylene chloride (175 mL) solution of the compound obtained in Example 140 (4.8 g) was added dropwise 4 mol/L of hydrogen chloride-dioxane solution (17.5 mL) at room temperature, and the mixture was allowed to stir for 17 hours. The crystals precipitated were filtered, and washed with diethyl ether, to give the captioned compound (2.9 g, 74%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:11])[CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[S:6][C:5]([C:7]([C:8](=[CH:14][N:15]([CH3:17])[CH3:16])[C:9]#[N:10])=[O:11])=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccc(Br)s1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)c1ccc(Br)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-(5-Bromothiophen-2-yl)-3-oxopropanenitrile (4g, 17 mmol) was treated with dimethyl formamide dimethylacetal and the mixture heated to 100° C. After 1 h, the mixture was allowed to cool down to room temperature. The yellow solid that precipitated was collected by suction filtration and washed well with diethyl ether. Yield=4.6 g. MS (M+H)+ 284.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH2:10][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CC1=CCC(C(C)CC=O)CC1
Product: CC1=CCC(C(C)CCN2CCCCC2)CC1

Procedure:
The procedure of Example 1 was followed using 50g (0.3 mole) of 3-(4-methyl-3-cyclohexenyl)butyraldehyde and 28g (0.33 mole) of piperdine. Obtained following distillation was 31g of a mixture of N-[3 . . . butyl] piperdine and N-[3-(4-methylcyclohexyl)butyl]piperdine; bp 89- 91° (0.1mm); ir (τ max. film) 3.5 (s), 3.7 (s), 6.9 (s), 7.3 (s), 8.7 (s), 9.0 (s), 9.7 (s), 11.6 (m), 12.6 (w) microns; nmr (δ, CDCl3) 5.37 (m, 1H), 2.95 to 2.55 (m, 6H), 2.0 to 0.8 (m, 22H) ppm; ms (molecular ion) 236 and 238. ##STR2##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)[N:3]=1.[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:12]1[N:8]([C:4]2[N:3]=[C:2]([C:22]#[N:23])[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:11]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(Cl)n2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To a stirred solution of 45 (588 mg, 1.88 mmol) in DMF (12.5 mL) was added zinc cyanide (0.238 mL, 3.75 mmol) followed by Pd(PPh3)4 (217 mg, 0.187 mmol). The resulting suspension was allowed to stir at 95° C. overnight. The residue was purified via ISCO flash chromatography (5% to 35% EtOAc/Hexane; 40G column). The title product 46 (68 mg, 11.9% yield) was isolated as a colorless oil. LRMS (ESI): calc. 304.2; found 305.3 (MH)+.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH2:50])[CH2:44][CH2:43]1.[CH2:51]1[CH:55]([CH2:56][CH2:57][CH2:58][CH2:59][C:60](O)=[O:61])[S:54][S:53][CH2:52]1>O1CCCC1>[S:53]1[CH2:52][CH2:51][CH:55]([CH2:56][CH2:57][CH2:58][CH2:59][C:60]([NH:50][CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][O:42][CH2:43][CH2:44]2)=[O:61])[S:54]1
Reactant: O=C(O)CCCCC1CCSS1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCC1CCSS1)NCCN1CCOCC1
Reaction time: 20 h
Yield: 88 %

Procedure:
4.5 g of hydroxybenzotriazole, 10.5 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 7.8 g of diisopropylethylamine and 3.9 g of 2-morpholino-1-ethylamine are added at room temperature to a solution of 6.2 g of thioctic acid in 180 ml of tetrahydrofuran. After 20 hours, the reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed and then dried over Na2SO4. Concentration under reduced pressure yields 8.4 g of the expected product.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[CH2:20][S:21][CH3:22].C(=O)([O-])O.[Na+]>CO.O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[CH2:20][S:21][CH3:22]
Reactant: COc1ccc([N+](=O)[O-])cc1CSC
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(N)cc1CSC
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
Sodium dithionite (3.264 g) was added to a solution of 1-methoxy-2-methylsulfanylmethyl-4-nitro-benzene (0.8 g), and sodium hydrogen carbonate (1.57 g) in methanol:water (1:1, 200 ml) and stirred at room temperature for 16 h. Solvent was removed at reduced pressure, the residue partitioned between water and ethyl acetate, the organic phase separated, washed with brine dried (Na2SO4) and solvent removed at reduced pressure to give the title compound (0.23 g) as a brown oil. m/z (API+): 184 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][O:28][CH:29]6[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH2:30][CH:29]([O:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:19]3[S:20][C:13]4[C:14](=[N:15][CH:16]=[CH:17][C:12]=4[O:11][C:10]4[CH:40]=[CH:41][C:7]([NH:6][C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:43])=[CH:8][C:9]=4[F:42])[CH:18]=3)=[N:26][CH:25]=2)[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(COC5CNC5)cn4)sc23)c(F)c1)NC1CC1
Reaction time: 4 h
Yield: 84 %

Procedure:
To a suspension of 404 (221 mg, 0.365 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction mixture was stirred for 4 h then concentrated, diluted with water and 1M NaOH to pH 11. The solid was collected by filtration, rinsed with water and dried. The residue was purified by Biotage (SNAP 25 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 10/90 to 30/70), to afford the title compound 405 (155 mg, 84% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77 (s, 1H), 8.55 (brd, J=1.6 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J=7.2 Hz, 1H), 7.91 (dd, J=8.0, 2.4 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.24-7.18 (m, 1H), 6.65 (d, J=5.2 Hz, 1H), 6.62 (brd, J=2.8 Hz, 1H), 4.48 (s, 2H), 4.40-4.41 (m, 1H), 3.56-3.49 (m, 2H), 3.47-3.50 (m, 2H), 2.58-2.51 (m, 1H), 0.68-0.62 (m, 2H), 0.47-0.41 (m, 2H). MS (m/z): 506.14 (M+H).
Reaction SMILES: [F:1][C:2]([F:34])([CH2:31][CH2:32][CH3:33])[C:3](=[O:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([O:12]C2CCCCO2)[CH2:10][C:9](=[O:19])[C@@H:8]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(O)(=O)C.C1COCC1.O>[F:1][C:2]([F:34])([CH2:31][CH2:32][CH3:33])[C:3](=[O:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([OH:12])[CH2:10][C:9](=[O:19])[C@@H:8]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC

Procedure:
The diketone (34) (0.371 g) was dissolved in a mixed solvent of acetic acid, THF and water (1:3:1, 35 ml), and the resultant solution was stirred overnight. The crude product obtained after the usual work-up was chromatographed on a Rober column (ODS) to give the titled compound (35).
Reaction SMILES: F[C:2](F)(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.FC(F)(F)CO[C:20]1[CH:27]=CC(C#N)=C[CH:21]=1>>[CH:3]1([O:4][C:5]2[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=2)[CH2:27][CH2:20][CH2:21][CH2:2]1
Reactant: N#Cc1ccc(OCC(F)(F)F)cc1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Product: CC(N)c1ccc(OC2CCCC2)nc1

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine, step B, starting from 4-(2,2,2-trifluoroethoxy)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28-7.34 (m, 2 H) 6.94-7.00 (m, 2 H) 4.70 (q, J=8.78 Hz, 2 H) 3.95 (q, J=6.53 Hz, 1 H) 1.21 (d, J=6.78 Hz, 3 H). MS (ESI) m/z: 220 [M+H]
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[C:24]([F:32])[CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:17][C:18]4=[N:35][CH:34]=[CH:33][C:19]4=[C:20]([NH:21][C:22]4[CH:23]=[C:24]([F:32])[CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:57][CH2:56][C:53]4[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=4)=[O:30])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Reactant: NCc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(=O)NCc3ccc(F)cc3)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.4 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added [(4-fluorophenyl)methyl]amine (1.01 mL, 8.89 mmol). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure and purified via SiO2. This lead to a yellow solid containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2 M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a 10% ammonium chloride solution, saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide (67 mg, 0.104 mmol) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H), 3.06-3.18 (m, 4 H), 3.76 (s, 3 H), 4.16 (t, J=8.29 Hz, 2 H), 4.51 (d, J=5.86 Hz, 2 H), 6.17 (d, J=1.19 Hz, 1 H), 6.81-7.01 (m, 3 H), 7.13 (t, J=8.84 Hz, 2 H), 7.38 (dd, J=8.29, 5.72 Hz, 2 H), 7.78 (s, 1 H), 8.43 (d, J=11.90 Hz, 1 H), 8.51 (s, 1 H), 9.14-9.25 (m, 1 H), 10.38 (s, 1 H), 11.32 (br. s., 1 H). (ESIMS (M+H)+=645)
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C@H:5]([C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:6].C(N(C(C)C)CC)(C)C.[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:37])=[C:31](F)[C:32]=3[O:34][CH3:35])[C:27](=[O:38])[C:26]3[C:39]([OH:44])=[C:40]([C:42]#[N:43])[S:41][C:25]2=3)[CH2:23][CH2:22]1.Cl>CS(C)=O.CO>[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:37])=[C:31]([N:9]4[CH2:10][CH2:11][C@@H:7]([C@@H:5]([NH:4][CH2:3][CH2:2][F:1])[CH3:6])[CH2:8]4)[C:32]=3[O:34][CH3:35])[C:27](=[O:38])[C:26]3[C:39]([OH:44])=[C:40]([C:42]#[N:43])[S:41][C:25]2=3)[CH2:22][CH2:23]1
Reactant: C[C@H](NCCF)[C@@H]1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(N2CC[C@@H]([C@H](C)NCCF)C2)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Temperature: 110 °C
Yield: 30.7 %

Procedure:
2-Fluoro-N—((S)-1-((R)-pyrrolidin-3-yl)ethyl)ethanamine (0.14 g, 0.87 mmol) and diisopropylethylamine (0.38 mL, 2.18 mmol) are added to a mixture of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile (0.15 g, 0.44 mmol) in DMSO (2 mL). The reaction mixture is heated at 110° C. for 18 h, and cooled to rt. The resulting solution is purified by preparative HPLC using mass-based fraction collection to provide the desired mass only fractions. The fractions containing product were combined and lyophilized. The resulting solid was treated with a solution of 1.25 M HCl in methanol (3 mL), evaporated, and triturated with diethyl ether. This step was repeated three times. The brown solid was dissolved in water and lyophilized to afford the desired product (66.1 mg, 29%, HCl salt) as a brown solid.
Reaction SMILES: [O-][Si]([O-])([O-])[O-].[Mg+2].[Al+3].C(OC)(=O)C(C)=C.[C:15]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:19])[C:16]([CH3:18])=C.[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH:26]=[CH2:27].C(OCCC[Si](OC)(OC)OC)(=O)C(C)=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[CH3:30][CH2:31][CH2:32][CH2:33][CH:22]([CH2:21][O:20][C:15]([CH:16]=[CH2:18])=[O:19])[CH2:23][CH3:24].[CH3:33][CH2:32][CH2:31][CH2:30][O:29][C:25]([CH:26]=[CH2:27])=[O:28]
Reactant: C=C(C)C(=O)OCCCC
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Agent: C=CC(=O)OCCCC
Solvent: O
Product: C=CC(=O)OCC(CC)CCCC
Reaction time: 8 h

Procedure:
On the other hand, magnesium aluminate metasilicate was dispersed in water as inorganic fine particles together with a very small amount of a surfactant (Surfinol 440, mfd. by Nissin Kagaku Kogyo K.K.), and the resulting dispersion, methyl methacrylate, butyl methacrylate, butyl acrylate and 3-trimethoxysilylpropyl methacrylate were mixed in the weight ratio of 3:2:3:2:0.2. The resulting mixture was treated with nitrogen to replace the air, after which potassium persulfate was added and emulsion polymerization was carried out at 60° C. for 8 hours. After completion of the reaction, the concentration was adjusted with water to prepare an (inorganic fine particles)-coated organic fine particles dispersion F (40 wt %) in which magnesium aluminate metasilicate fine particles had been formed on the surfaces of the acrylic copolymer resin fine particles.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CCCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CCCOc1ccc(CO)cc1
Yield: 90.1 %

Procedure:
4-Hydroxybenzyl alcohol (1 g, 8.06 mmol) is treated with 1.73 g (8.86 mmol) of ethyl 4-bromobutyrate, 3.34 g (24.2 mmol) of potassium carbonate and a catalytic amount (120 mg 0.81 mmol) of sodium iodide under the same conditions as described in Preparation 3 to give 1.73 g of 4-[4-(hydroxymethyl)phenoxy]butanoic acid, ethyl ester as a light brown oil (90%). The product is utilized in the next reaction without further purification. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1610, 1580, 1510 cm-1 ; MS (CI) m/e 238, 221, 115.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl.O>[CH3:23][C@:20]12[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:37])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:5]1([NH:4][CH2:3][CH2:2][NH:1][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:22][CH2:21]2
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-aminoethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.026 mmol) and Hunig's Base (0.013 mL, 0.077 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (3.81 mg, 0.033 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with distilled water (3 mL), extracted with dichloromethane (3×3 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a yellow solid (15 mg, 88%). LCMS: m/e 665.55 (M+H)+, 2.44 min (method 11).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22](N(OC)C)=[O:23])[CH2:16][CH2:15]2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]#[N:43])=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[CH3:44][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH2:21][CH:22]([OH:23])[CH3:44])[CH2:18][CH2:19]2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Br
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reaction time: 1 h

Procedure:
To a solution of 2-[(trans-4-{7-butyl-6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.30 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.74 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (6 mL), and sodium borohydride (0.020 g) was added at 0° C. After stirring at 0° C. for 30 min, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.27 g, 98%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:34]([C:31]4[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:36])[F:37])=[CH:29][CH:30]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1ccc(OC(F)(F)F)cc1
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 4-trifluoromethoxy-phenylhydrazine according to the method described for example 43. MS: M=477.1 (M+H)+
Reaction SMILES: OS(O)(=O)=O.[S:6]1[C:10]2[CH:11]=[C:12]([NH:15][C:16]([NH:18][CH2:19][CH:20](OC)OC)=[O:17])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.CO.[OH-].[K+]>C(Cl)(Cl)Cl>[S:6]1[C:10]2[CH:11]=[C:12]([N:15]3[CH:20]=[CH:19][NH:18][C:16]3=[O:17])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: COC(CNC(=O)Nc1ccc2ncsc2c1)OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1[nH]ccn1-c1ccc2ncsc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
1N H2SO4 (2 mL) was added to 1-benzothiazol-6-yl-3-(2,2-dimethoxy-ethyl)-urea (I-142a: 300 mg) and the resulting mixture was stirred at 0° C. for 30 minutes. The reaction mixture was heated to 50° C. for 2 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was cooled to 0° C. and basified with 10% KOH solution. The precipitate was collected, washed with water and dried under reduced pressure to afford 170 mg of 1-Benzothiazol-6-yl-1,3-dihydro-imidazol-2-one (73.59% yield).