Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].Cl.[NH2:25][OH:26]>O.Cl>[F:15][C:16]1[CH:17]=[C:18]([NH:19][C:3](=[O:5])[CH:2]=[N:25][OH:26])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(F)c1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccc(F)c(F)c1
Yield: 42 %

Procedure:
A solution of 18.2 g of chloral hydrate and 260 g of anhydrous sodium sulfate in 400 ml of water was mixed with a solution of 12.9 g of 3,4-difluoroaniline and 22.24 g of hydroxylamine hydrochloride in 160 ml of water and 9 ml of concentrated hydrochloric acid. This reaction mixture was refluxed for 2 hours and then filtered while hot, collecting the solid which was washed well with water and dried. Recrystallization from hot water gave 8.4 g of the desired compound as colorless crystals, mp 148°-150° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH:5]=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][S:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C@@H:21]23)[CH:26]=1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH2:5][NH:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][S:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][NH:33][CH2:34][C@@H:21]23)[CH:26]=1
Reactant: O=Cc1c(C(F)(F)F)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: FC(F)(F)c1cccc(C(F)(F)F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2,6-bis(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 152. LRMS (ES)+: 488.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.CN1C(=O)CCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH:27]1[CH2:29][C:28]1([F:31])[F:30]>C(OCC)(=O)C.O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](=[O:11])[N:10]([CH2:26][CH:27]3[CH2:29][C:28]3([F:31])[F:30])[C:5]2=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)nc2s1
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: O=c1sc2nc(Cl)ccc2n1CC1CC1(F)F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a round bottom flask was added 5-chloro[1,3]thiazolo[5,4-b]pyridin-2(1H)-one (1-4) (3.5 g, 19 mmol), anhydrous NMP (30 mL), anhydrous 1,4-dioxane (60 mL), cesium carbonate (12 g, 37 mmol), followed by 2-(bromomethyl)-1,1-difluorocyclopropane (3.4 g, 20 mmol). The reaction mixture was then heated to 95° C. while stirring in a hot oil bath for 18 hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-40% EtOAc/Hex) to give 5-chloro-1-[(2,2-difluorocyclopropyl)methyl][1,3]thiazolo[5,4-b]pyridin-2(1H)-one (1-5) as a tan solid. HRMS (M+H)+: observed=277.0008, calculated=277.0008.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccco4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes. 2-Furoyl chloride (0.4 g, 3.2 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with CH2Cl2 (60 mL) and 2N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (20 mL) to give furan-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.5 g, 58%) as a white solid: mp 219-221° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.30-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.39-4.49 (m, 3H), 4.53 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=5.0 and 13.1 Hz, 1H, CH), 6.62-6.63 9m, 1H), 7.14 (d, J=3.4 Hz, 1H), 7.47-7.65 (m, 3H, Ar), 7.84 (s, 1H), 8.00 (t, J=5.8 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.18, 38.72, 46.24, 51.58, 111.87, 113.69, 121.70, 128.32, 130.74, 131.61, 134.55, 140.11, 145.15, 147.61, 157.84, 168.05, 171.01, 172.85; Anal. calcd. for C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 61.91; H, 4.64; N, 11.38.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([F:25])([F:26])[F:16])[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1ccccc1C(F)(F)F
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-trifluoromethyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid as a white solid (2.74 g, 95% for the final step); ES+-HRMS m/e calcd for C19H19N2O4F3 [M+H+] 397.1370, found 397.1367. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (br s, 2H), 1.25-1.77 (m, 7H), 1.88-2.05 (m, 1H), 2.09-2.23 (m, 1H), 5.32 (dd, J=10.6, 3.9 Hz, 1H), 5.92 (d, J=2.4 Hz, 1H), 7.52-7.66 (m, 2H), 7.78-7.94 (m, 2H), 8.17 (d, J=2.4 Hz, 1H), 13.06 (br s, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.[CH:25](I)([CH3:27])[CH3:26].O>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH:25]([CH3:27])[CH3:26])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1
Reactant: CC(C)I
Reactant: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (7.0 ml), 4′-chloro-4-ethyl-2′-nitrobenzenesulfonanilide (1.00 g (2.93 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, isopropyl iodide (0.70 ml (7.01 mmol)) was added dropwise and heated at 130° C. for 2 hours with stirring. After being allowed to cool to room temperature, water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with 1% aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent to give 0.41 g (37%) of the title compound as pale red crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3OC)[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.Cl[C:42]1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2)N=1.NC1C=CC=CC=1C(NCC)=O>>[CH2:39]([NH:38][C:37]([C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:33][CH:34]=2)[N:10]=1)=[O:40])[CH3:42]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Agent: CCNC(=O)c1ccccc1N
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC)cc2)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and the commercially available 2-amino-N-ethylbenzamide. MS (ES+): m/z 552.51 (100) [MH+] HPLC: tR=1.05 min (UPLC, purity).
Reaction SMILES: N[C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[C:3]=1[Br:12].N([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C.P(P(O)(O)=O)(O)(O)=O.O>[Br:12][C:3]1[C:4]([F:11])=[C:5]([CH:8]=[C:9]([F:10])[CH:2]=1)[CH:6]=[O:7]
Reactant: Nc1c(F)cc(C=O)c(F)c1Br
Agent: O=N[O-]
Agent: O=P(O)(O)P(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cc(F)cc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
4-amino-3-bromo-2,5-difluorobenzaldehyde (3.4 g, 14.3 mmol) was dissolved in acetic acid (18 mL) before addition of hypophosphoric acid (50% in water, 39 mL). A solution of sodium nitrite (1.4 eq, 1.4 g) in water (8 mL) was then added dropwise under ice-cooling. After stirring at rt for 2 h, the reaction mixture was poured onto a mixture ice/water and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and evaporated. A column chromatography (0 to 10% ethyl acetate in petroleum ether) afforded 3-bromo-2,5-difluorobenzaldehyde (1.3 g, 6.3 mmol, 44%). 1H NMR (d6-DMSO) δ 10.15-10.12 (m, 1H), 8.13 (ddd, J=8.0, 5.0, 3.0 Hz, 1H), 7.66 (ddd, J=8.0, 5.0, 3.0 Hz, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)[N:19]=3)[CH2:11]1)[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:15]1[CH2:14][CH2:13][N:12]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:21]=[C:20]([C:31]2[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=2)[N:19]=3)[CH2:11][C@@H:10]1[CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
Acetic anhydride (0.035 ml, 0.38 mmol) was added dropwise to a methylene chloride solution (6 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (123 mg, 0.25 mmol) and triethylamine (0.069 ml, 0.50 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:5) to give the title compound (92 mg) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:34][CH2:35][CH2:36][CH2:37][OH:38]>CN(C=O)C.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: NCCCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCO)c23)cc1
Yield: 59.6 %

Procedure:
Dissolve 1.00 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 10 ml DMF and add 1.15 g (8.9 mmol) DIEA. Add 0.45 g (5.9 mmol) 3-aminopropanol and then heat the mixture over a period of 2 h to 120° C. After cooling, dilute the mixture with ethyl acetate and wash successively with dilute hydrochloric acid and saturated sodium chloride solution. Dry the organic phase over magnesium sulphate and concentrate by evaporation. Purify the residue by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). 671 mg (60% of theor.) 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}propan-1-ol is obtained in the form of beige crystals.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]([C:20](OC)=[O:21])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1.[CH2:25]([Li])[CH3:26].[CH:28]1C=CC=C[CH:29]=1.C1CCCCC1.[Cl-].[NH4+]>O1CCCC1>[C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]([C:20]([OH:21])([CH2:25][CH3:26])[CH2:28][CH3:29])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1
Reactant: [Li]CC
Reactant: COC(=O)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12
Reactant: c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of methyl 2-(mesitylmethyl)-1-methyl-1H-benzimidazole-7-carboxylate (1.30 g, 4.0 mmol) in tetrahydrofuran (80 mL) was added a solution of ethyllithium in benzene/cyclohexane (90/10) (0.5 M, 32 mL, 16.1 mmol) dropwise at −78° C. The solution was warmed to room temperature over 1 hr followed by addition of saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (100 mL, three times) and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 15-25% ethyl acetate/n-hexane gradient mixture to give the title compound (590 mg, 1.68 mmol, 42%) as a colorless solid. The resulting solid was recrystallized from n-hexane/ethyl acetate to give the title compound (435 mg, 1.24 mmol).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16](OC)=[O:17])=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)#[N:2].[Li+].[OH-:25].CN(C(ON1N=NC2[CH:37]=[CH:38][CH:39]=[N:40]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1>C1COCC1.O.C(OCC)(=O)C>[CH:39]1([NH:40][C:16]([C:15]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[C:3]([C:1]([NH2:2])=[O:25])=[N:4][N:5]=[CH:6]4)[CH:14]=2)=[O:17])[CH2:37][CH2:38]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(C#N)nncc3c2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C(N)=O)nncc2c1
Temperature: 50 °C
Reaction time: 5.5 h

Procedure:
Methyl 3-(1-cyanophthalazin-6-yl)-4-methylbenzoate (120 mg, 396 μmol) was dissolved in THF/water (4:1) (3.96 mL) and LiOH (19 mg, 791 μmol) was added. The reaction mixture was stirred at 50° C. for 5.5 h, concentrated, and lyophilyzed under house vacuum. The reaction mixture was dissolved in DMF (791 μl) and HATU (301 mg, 791 μmol) and cyclopropylamine (277 μl, 3956 μmol) were added and the mixture was stirred at RT for 16 h. The mixture was diluted with 100 mL ethyl acetate, and partitioned with sodium bicarbonate (saturated, aqueous). The organic layers were washed 3×20 mL with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound. MS (ES+): 347 (M+H)+.
Reaction SMILES: [S:1](=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH:6]([C:14]([O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:15])[CH2:5]1)(=[O:3])=[O:2].O.O[Li].O>C1COCC1>[S:1](=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH:6]([C:14]([O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:15])[CH2:5]1)(=[O:2])=[O:3]
Reactant: COC(=O)c1ccc(OC(=O)C2CC(=S(=O)=O)c3ccccc3O2)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(=O)C2CC(=S(=O)=O)c3ccccc3O2)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-[4-sulfonylchromanoyloxy]-2-methoxybenzoate (500 mg, 1.38 mmol) in THF:H2O (18 mL: 2 mL) was added LiOH.H2O (175 mg, 4.14 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a plug of silca gel packed in 50:50 MeOH:CH2Cl2 and eluted with same. The solvent was removed under reduced pressure to afford 4-[4-sulfonylchromanoyloxy]-2-methoxybenzoic acid as a white solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([Cl:15])[CH:6]=1.Cl>CN(C)C=O>[Cl:15][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)cc1Cl
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Sodium thiomethoxide (459 mg) was added to a solution of methyl 4-bromo-2-chlorobenzoate (1.25 g) in N,N-dimethylformamide (10 ml) under ice-cooling, and the mixture was stirred for 2 hr. 1N Hydrochloric acid was added to the reaction mixture and the resulting product was extracted three times with ether. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to give the objective compound (835 mg) as a colorless oil.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH2:35]>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: CN(C)CCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN(C)C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 428 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[NH:6][N:7]=1)[CH3:2].[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:12]=1[OH:18].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:8]2[NH:17][C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:18])[C:11]=3[N:10]=2)[NH:6][N:7]=1)[CH3:2]
Reactant: CCc1cc(C=O)[nH]n1
Reactant: Nc1cccc(O)c1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(-c2nc3c(O)cccc3[nH]2)[nH]n1

Procedure:
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 100 mg of 2,3-diaminophenol, and 153 mg of sodium metabisulphite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm, C18 phase, dimensions: 100×25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07% TFA-water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 16 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[NH:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1>[NH2:8][C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([N:38]2[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCNCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 185 °C
Yield: 96.2 %

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-pyrazolo-[1,5-a]pyrimidin-7-amine (50 mg, 0.09 mmoL), 1,4-diazepan-5-one (36 mg, 0.32 mmoL), EtN(iPr)2 (110 uL, 0.63 mmoL) in NMP (0.8 mL) was heated at 185° C. under microwave condition for 45 min. Purification by prep-LC afforded titled compound (32.3 mg, 85%) as its formic acid salt. LCMS tR=2.49 Min. Mass calculated for, M+ 373.1, observed LC/MS m/z 374.1 (M+H).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:28]\[O:29][CH3:30])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[CH3:30][O:29]/[N:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:50])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: CO/N=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: CO/N=C1\C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 70 %

Procedure:
The title compound II-ao was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6-(E)-methoxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.78 (3H, s), 3.37 (1H, dd), 2.68-1.14 (19H, m), 1.01 (3H, s), 0.98 (3H, s).