Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].CC(O)(C)CN[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[N:17]=[N:18][N:19]=[C:9]2[C:8]=1[N+:20]([O-:22])=[O:21]>O>[N+:20]([C:8]1[C:9]2[N:10]([N:17]=[N:18][N:19]=2)[C:11]2[C:16]([C:7]=1[OH:1])=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:22])=[O:21]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12

Procedure:
Aqueous sodium hydroxide (30 g of 50%) was added to a suspension of 2-methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol (34.0 g, 0.1125 mole, Example 3) in water (500 mL). The mixture was heated on a steam bath and the solid dissolved rapidly. The solution was heated for about 30 minutes and then upon stirring a solid began to precipitate. The mixture was made acidic with 6N hydrochloric acid. The resulting solid was isolated by filtration; washed in succession with water, ethanol and ether; then dried under vacuum at 100 °C. to provide 23.2 g of crude product as a pale yellow/green solid. A sample (3.2 g) was recrystallized initially from methanol/dichloromethane and then from toluene to provide 4-nitrotetrazolo[1,5-a]quinolin-5-ol. Analysis: Calculated for C9H5N5O3: %C, 46.76; %H, 2.18; %N, 30.29; Found: %C, 46.85; %H, 2.23; %N, 29.91.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][NH2:17].[CH2:18]=O>CCOCC>[N:1]1([CH2:18][NH:17][CH2:16][CH2:15][C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=O
Reactant: NCCc1cccs1
Solvent: CCOCC
Product: c1csc(CCNCn2nnc3ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a mixture of 12 g (0.1 mole) benzotriazole and 13 g (0.1 mole) of 2-thiophen-2-yl-ethylamine in 500 mL of ether was added dropwise 7.4 mL (0.1 mole) of 37% aqueous formaldehyde. The reaction mixture was stirred at room temperature overnight. The solution was dried over calcium chloride, filtered and concentrated under pressure. Hexane was added to the residue cooled in an ice bath and the resulting solid was collected by filtration, washing with hexane and then dried to give 26.0 g of benzotriazol-1-ylmethyl-(2-thiophen-2-yl-ethyl)-amine as a light yellow oil (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.P(=O)(O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)cc2s1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3=CCCCC3)c2s1
Temperature: 80 °C
Yield: 91 %

Procedure:
A solution (0.2 M) of methyl 5-(4-chlorophenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in acetic acid was treated with acetic anhydride (2.5 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.1 eq.). The mixture was heated at 80° C. for 3.5 days. After cooling down it was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic layers were washed sequentially with aqueous HCl (1 N), aqueous NaHCO, (saturated solution) and brine then dried and concentrated. The crude was purified by flash chromatography on silica gel (1:9 to 1:4 AcOEt/petroleum ether) affording the title compound (91%) as a solid.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][N:7]([CH3:38])[C:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][CH2:12][C:11](=[CH:14][C:15]([N:17]2[CH2:21][CH2:20][CH:19]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:18]2)=[O:16])[CH2:10][CH2:9]1>CC(CC)=O>[ClH:1].[CH3:38][N:7]([CH3:6])[C:8]1([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:13][CH2:12][C:11](=[CH:14][C:15]([N:17]2[CH2:21][CH2:20][CH:19]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:18]2)=[O:16])[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chlorotrimethylsilane (0.13 ml, 1.01 mmole) was added to a solution of 2-(4-dimethylamino-4-(4-fluorophenyl)-cyclohexylidene)-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]ethanone (300 mg, 0.67 mmole) in ethyl methyl ketone (25 ml) and stirred for 2 hours at RT. The hydrochloride (300 mg, 93%) thereupon precipitated as a diastereoisomer mixture with a melting point of 189°-194° C. in the form of a colourless solid (Example 60).
Reaction SMILES: [C:1]1(OCC(Cl)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:22])([CH3:19])([CH3:18])[CH3:17].[O:29]1CC[CH2:31][CH2:30]1>C(N(CC)CC)C>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:30](=[O:29])[CH2:31][C:3]1[CH:2]=[CH:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C(Cl)COc1cccc2ccccc12
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNC(=O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
11.16 g of naphthoxy acetic acid chloride in solution in 50 ml of tetrahydrofuran were added at 0° C. to +10° C. to a solution of 10.32 g of N-(tert-butoxycarbonyl)-1,4-diamino butane in 110 ml of tetrahydrofuran and 6.7 g of triethylamine. The mixture was stirred for 90 minutes at ambient temperature and the insoluble part was filtered off. The fitrate was evaporated to dryness and the 17.78 g of residue were chromatographed on silica (eluant: hexane-ethyl acetate (1-1)) to obtain 10 g of the expected product melting at 102° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([CH2:21][CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:21]([C:4]1[CH:3]=[C:2]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:7]=[N:6][C:5]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH3:22]
Reactant: CCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)c1
Reactant: C1CCNCC1
Product: CCc1cc(N2CCCCC2)nnc1Cn1ccnc1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-4-ethyl-3-[2-(3-fluoro-phenyl)-imidazol-1-ylmethyl]-pyridazine (55.3 mg, 0.17 mmol) and piperidine (5 mL) is heated at 110° C. for 5 hours. Excess piperidine is removed and the residue is purified by PTLC to give the title compound. LC-MS (M+1) 366.2 (retention time: 0.91 min).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=O.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:8](=[O:10])[CH2:7][O:6][CH2:5][CH2:4][O:3][CH3:2])[C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: COCCOCC(=O)O
Agent: Cl
Product: COCCOCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 26.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-methoxyethoxy)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 88, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(2-methoxyethoxy)acetyl)pyrrolidine-2-carboxamide (8.1 mg, 26.6%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.95 (s, 1H), 7.54 (m, 2H), 7.27 (m, 2H), 7.21-7.15 (m, 7H), 6.93 (m, 2H), 4.47 (m, 1H), 4.08 (m, 2H), 3.62-3.42 (m, 6H), 3.21 (s, 3H), 2.63 (m, 3H), 1.88 (m, 2H). MS (EI) for C29H31FN2O5. found 507.6 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.CN(C=O)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:38](Cl)=[O:39]>O>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:38]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:2][CH2:3]1)=[O:39]
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CCc2c(cccc2N2CCN(C(=O)c3ccc(Cl)c(Cl)c3)CC2)N1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 4 ml of DBU were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 3.0 g of 3,4-dichlorobenzoyl chloride. After completion of addition, the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 1.2 g of 5-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 250°-252° C., colorless powders.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[CH:12][C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH:46]1N=C[N:48]([C:51](N2C=NC=C2)=O)[CH:47]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([N:70](C)[SH:71](=[O:73])=[O:72])C>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:70][S:71]([N:48]([CH2:47][CH3:46])[CH3:51])(=[O:73])=[O:72])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[CH:12][C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: CCN(C)[SH](=O)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(C)S(=O)(=O)NC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4nc(C(C)C)cs4)nc4cc(OC)ccc34)CC1C(=O)N2
Temperature: 65 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A mixture of 17-[2-(4-isopropyl-thiazol-2-yl)-7-methoxy-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (35, 60 mg, 0.095 mmol) and CDI (0.23 mmol) in dry THF (5 mL) was heated at 65° C. in a reflux setup for 1 h, and then cooled to RT. The formation of the stable intermediate 36 was observed. Then, a solution of lithium bis(trimethylsilyl)amide (460 μL of 1.0M in THF) and N-ethyl-N-methylsulfonamide (62.5 mg, 0.45 mmol) in THF (7 mL), was added. After 1 h, the reaction was quenched with water, evaporated, diluted with THF, acidified with HCl in dioxane, and evaporated. Purification by flash chromatography (YMC silica, gradient MeOH/CH2Cl2, 2 to 5%) gave 9.6 mg of the title product as white solids. LCMS: tR=3.51 min, >95%, m/z (API-ES+)=753 (M+1), 1H NMR (400 MHz, CDCl3) major rotamer □ 1.16-1.28 (m, 5H), 1.36 (m, 1H), 1.39 (d, 6H, J=6.4 Hz), 1.42 (m, 1H), 1.62 (m, 1H), 1.70 (m, 1H), 1.87 (dd, 1H, J=8.2 Hz, 5.8 Hz), 2.00 (m, 1H), 2.20-2.31 (m, 1H), 2.33-2.44 (m, 2H), 2.50-2.62 (m, 2H), 2.88-2.94 (m, 4H), 3.04 (s, 3H), 3.17-3.28 (m, 2H), 3.38-3.45 (m, 3H), 3.97 (s, 3H), 4.60 (m, 1H), 5.04 (m, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.23 (s, 1H), 7.04 (d, 1H, J=1.2 Hz), 7.12 (dd, 1H, J=8.8, 2.8 Hz), 7.37 (d, 1H, J=2.8 Hz), 7.51 (m, 1H), 8.03 (d, 1H, J=8.8 Hz), 10.53 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:15](=[O:17])[CH3:16])[CH2:7]2.[H][H].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1.[Ni]>[C:15]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([NH:12][C:20](=[O:22])[CH3:21])[CH:10]=[CH:11][C:2]=2[Br:1])[CH2:7]1)(=[O:17])[CH3:16]
Reactant: [H][H]
Reactant: CC(=O)N1CCc2c(Br)ccc([N+](=O)[O-])c2C1
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)c2c1CN(C(C)=O)CC2
Yield: 96 %

Procedure:
The product from Example 2 (13.05 g, 43.6 mmol) was dissolved in THF (100 mL) and treated with Raney Nickel (2 g). Under the presence of hydrogen (19.8 psi, 23° C.) the mixture was stirred for 19 hours, and evaporated under vacuum. The residue was then washed with diethyl ether and evaporated under vacuum to give a semi-solid. The semi-solid was treated with acetic anhydride (30 mL), THF (30 mL) and stirred. After 2 hours the solvent was evaporated under vacuum. The residue was dissolved in THF, dried with MgSO4, activated charcoal, and passed through a plug of silica gel eluted with ethyl acetate. Upon evaporation under vacuum the desired product was isolated (14.6 g, 96% yield) as a tan solid, mp=127-130° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[C:21]1([CH3:40])[CH:26]=[CH:25][C:24]([O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:23][C:22]1(Br)[CH3:38].[C:41]([O-:44])([O-:43])=O.[K+].[K+]>>[C:4]([OH:27])(=[O:8])/[CH:5]=[CH:18]/[C:41]([OH:44])=[O:43].[C:24]([OH:27])(=[O:8])/[CH:25]=[CH:26]/[C:41]([OH:44])=[O:43].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:38][C:22]5[C:21](=[CH:26][CH:25]=[C:24]([O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:35]([CH3:36])[CH3:37])[CH:23]=5)[CH2:40]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(C)[Si](OC1=CC(C)(Br)C(C)(Br)C=C1)(C(C)C)C(C)C
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)[Si](Oc1ccc2c(c1)CN(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2)(C(C)C)C(C)C
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.52 g, 5.73 mmol), 1,2-dibromo-4-(triisopropylsilyl)oxy-xylene (2.4 g, 5.7 mmol) and K2CO3 (1.8 g, 13 mmol) in acetronitrile (300 ml) was stirred overnight (18 hours) at room temperature. The mixture was filtered and the solvent was stripped. The residue was purified by flash chromatography over a silica gel column (7 gm of SiO2; eluted with 1-3% C;H3OH in dichloromethane. The product thus purified (weight: 900 mg) was converted to the fumarate salt by treatment with fumaric acid (194 mg) in hot ethanol. The crystals were collected and weighed 590 mg, m.p. 208°-210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:49]=[CH:48][C:5]([C:6]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([S:18]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)(=[O:20])=[O:19])[CH:16]=3)[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=2)=[O:7])=[C:4]([N:50]([CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)C(=O)C(F)(F)F)[CH:3]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[CH3:88][N:89]([CH3:94])[CH2:90][C:91](=O)[CH3:92]>ClCCl>[F:27][C:25]1[CH:26]=[C:21]([S:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[NH:8][C:6](=[O:7])[C:5]2[CH:48]=[CH:49][C:2]([NH:1][CH:91]([CH3:92])[CH2:90][N:89]([CH3:94])[CH3:88])=[CH:3][C:4]=2[NH:50][CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)(=[O:19])=[O:20])[CH:22]=[C:23]([F:28])[CH:24]=1
Reactant: Nc1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Reactant: CC(=O)CN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CN(C)C)Nc1ccc(C(=O)Nc2n[nH]c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide (1.56 g, 1.8 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (2.78 mL, 36 mmol), tetramethylammonium triacetoxyborohydride (710 mg, 2.7 mmol) and 1-dimethylamino-propan-2-one (316 microL, 2.7 mmol). The mixture was stirred at room temperature overnight then additional tetramethylammonium triacetoxyborohydride (710 mg, 2.7 mmol) and 1-dimethylamino-propan-2-one (316 microL, 2.7 mmol) were added. The mixture was heated at reflux and stirred for additional 6 hours. After evaporation of the volatiles, the residue was chromatographed on silica gel eluting with dichloromethane/methanol/triethylamine 90:10:0.1 affording 845 mg of N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(2-dimethylamino-1-methyl-ethylamino)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide that was dissolved in methanol (5 mL) and triethylamine (2 mL) and stirred at 50° C. for 6 hours. The mixture was then evaporated to dryness and the residue purified by flash chromatography on silica gel eluting with dichloromethane/methanol/30% NH4OH 92:8:0.5 affording 416 mg of the title compound as pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13]2([CH3:18])OCC[O:14]2)[CH:3]=1>C(O)(=O)C.O>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13](=[O:14])[CH3:18])[CH:3]=1
Reactant: CC1(CCc2cc(O)n3nccc3n2)OCCO1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CCc1cc(O)n2nccc2n1
Temperature: 50 °C
Reaction time: 72 h
Yield: 60.7 %

Procedure:
The compound obtained in step (1) (22 g) was dissolved in 500 ml of acetic acid-water (4:1) and stirred at 50° C. for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the remaining acetic acid-water was azeotropically distilled off with benzene. The residue was recrystallized from ethanol-n-hexane to provide 11 g of 7-hydroxy-5-(3-oxobutyl)pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:13])=[C:9](\[CH3:12])/[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][C@@H](CC1C=CC(O)=CC=1)C(OCC)=O)[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[C:10]([O:16][CH2:14][CH3:15])=[O:11])=[CH:6][CH:7]=1
Reactant: C/C(CO)=C(/C)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)/C(C)=C(/C)c1ccc(Br)cc1
Yield: 141.6 %

Procedure:
The title compound (0.83 g, 87% yield) was prepared from (E)-3-(4-bromophenyl)-2-methyl-but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.C([CH2:20][C:21]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:22])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:20]/[C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])=[CH:11][CH:10]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1
Yield: 86.4 %

Procedure:
Piperidine (0.42 mL, 4.2 mmol) was added to a suspension of 4-methoxybenzaldehyde (0.51 mL, 4.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.83 g, 3.7 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(4-Methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.95 g, 86%) was obtained as a pale yellow crystalline solid; mp 194-195° C., lit. [24] 195-198° C.; δH (500 MHz, DMSO-d6) 3.80 (s, 3H, OCH3), 6.72 (d, J=15.5 Hz, 1H, CH═CHCO), 6.98 (d, J2′,3′=J5′,6′=9.0 Hz, 2H, H3′, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.57 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.68 (d, J2′,3′=J5′,6′=9.0 Hz, 2H, H2′, H6′), 7.99 (d, J3,4=8.0 Hz, 1H, H3), 8.60 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC(c1ccc(NCc2ccc(Cl)cc2Cl)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Oakwoood, 1 g, 3.9 mmol) and 2,4-dichlorobenzaldehyde in methanol (21 mL) was stirred at ambient temperature. After 18 hours, glacial acetic acid (0.24 mL, 4.25 mmol) and sodium cyanoborohydride (388 mg, 4.25 mmol) were added. After stirring an additional 18 hours, the mixture was concentrated in vacuo and the residue dissolved in EtOAc. The organic layer was washed several times with brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded the title compound as a white waxy solid (1.6 g, 99%). MS (ES+) m/z 418 (M+), 420 (M+2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH2:29][CH2:28][C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]3)[CH2:14][CH2:13]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1N(C)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (300 mg, 1.84 mmol) and tert-butyl 9-(methylamino)-3-azaspiro[5.5]undecane-3-carboxylate (573.32 mg, 2.03 mmol) in ethanol (30 mL) was added N,N-diethylethanamine (372.38 mg, 3.68 mmol). The reaction mixture was stirred at 100° C. overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as yellow oil (165 mg, 22%).