Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([OH:37])[C:12]2[C:13](=[O:34])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][C:27]4[O:28]C(C)(C)[O:30][CH:31]=4)[CH:18]=3)[O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.O.[CH2-]C(C)=O>C(O)(=O)C>[OH:37][C:35]1[C:12]2[C:13](=[O:34])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:18]=3)[O:16][C:11]=2[CH:10]=[C:9]([OH:8])[CH:36]=1
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(OCc4ccccc4)cc3o2)cc1OCC1=COC(C)(C)O1
Agent: [CH2-]C(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1OCC(O)CO
Temperature: 0 °C
Yield: 111.9 %

Procedure:
The 36 g of compound obtained in Example 9 are added to 200 ml of a mixture of water and acetic acid (1/1) and the whole is heated at reflux until the mixture becomes homogeneous, after which refluxing is maintained for a further 15 minutes. The disappearance of the acetonide is verified by thin-layer chromatography, then the mixture is cooled to 0° C., and the precipitate formed is filtered and then dried, yielding 30 g of the expected compound of 98% purity. Recrystallisation of that compound from a mixture of isopropanol and water yields the pure product, m.p.: 215°-218° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[C:16]=1[C:25]([OH:27])=O)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:37]1([CH2:40][NH:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH2:39][CH2:38]1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(CC1C2C(=CC=CC=2)NC=1C(O)=O)C1N=NN(C)N=1.C(NCC)C>>[CH:37]1([CH2:40][N:41]([CH2:42][CH:43]2[CH2:45][CH2:44]2)[C:25]([C:16]2[N:17]([CH3:24])[C:18]3[C:23]([C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:35])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:27])[CH2:39][CH2:38]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2c(C(=O)O)n(C)c3ccccc23)n1
Reactant: C1CC1CNCC1CC1
Agent: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2c(C(=O)O)[nH]c3ccccc23)n1
Solvent: CCNCC
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2c(C(=O)N(CC3CC3)CC3CC3)n(C)c3ccccc23)n1
Yield: 62 %

Procedure:
3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-methyl-1H-indole-2-carboxylic acid (0.08 g, 0.156 mmol) and bis cyclopropylmethylamine (0.02 g, 0.156 mmol) were used to synthesize the title compound instead of using 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid and diethylamine in step (ii) of example 131 (0.05 g, yield: 62%).
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:13]([O-])=O.[Na+]>O>[C:1]1([S:7]([N:10]=[N+:11]=[N-:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
26.3 g of benzenesulphonohydrazide, 100 ml of water, 21 ml of 10N hydrochloric acid and 1.3 g of Emulgator [emulsifier] FD (a fatty alcohol/ethylene oxide addition product) are stirred for 30 minutes, 60 g of ice are added, and a solution of 19.5 g of sodium nitrite in 50 ml of water is then added dropwise in the course of about 30 minutes. The batch is stirred for 30 minutes, excess nitrite is then destroyed with a small amount of sulphamic acid, and excess acid is neutralised with about 5 ml of 10N sodium hydroxide solution. An emulsion of benzenesulphonyl azide is obtained.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C:32]=1[C:38]1[NH:42][C:41]2[CH:43]=[C:44](Br)[CH:45]=[C:46]([CH3:47])[C:40]=2[N:39]=1)[CH2:9][O:10]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]1(B(O)O)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl.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>[CH2:1]([C@H:8]([NH:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C:32]=1[C:38]1[NH:42][C:41]2[CH:43]=[C:44]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:45]=[C:46]([CH3:47])[C:40]=2[N:39]=1)[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)Cc4ccccc4)cc[nH]c3=O)nc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Yield: 52.4 %

Procedure:
To a solution of (S)-4-(1-benzyl-2-trityloxy-ethylamino)-3-[6-bromo-4-methyl-1H-benzimidazole-2-yl]-1H-pyridin-2-one (50 mg, 0.072 mmol), phenylboronic acid (13 mg, 0.11 mmol), and 2 M K2CO3 (0.108 mL, 0.22 mmol) in THF (5 mL) was added Pd(PPh3)4 (8.3 mg, 0.007 mmol). The mixture was heated to reflux 14 h. Upon cooling, the reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was used for the next step without purification. LCMS (M+H)+ m/z 693 (t=2.82 min.). The crude product was treated with 4 N HCl dioxane solution (5 mL) at room temperature for 6 h. After concentration in vacuo, the residue was purified by prep. HPLC to yield the title compound (17 mg, 34%) as a white solid. 1H NMR (300 MHz, CD3OD) δ7.13–7.67 (13H, m), 6.15 (1H, d, J=7.4 Hz), 3.99–4.11 (1H, m), 3.74–3.77 (2H, m), 3.16 (1H, dd, J=5.4, 13.6 Hz), 2.97 (1H, dd, J=7.8, 13.6 Hz), 2.69 (3H, s). LCMS (M+H)+ m/z 451 (t=2.04 min.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Temperature: 100 °C

Procedure:
0.202 g (1.0 mmol) of 1-bromo-4-nitrobenzene and 0.20 ml of piperidine (2.0 mmol) were dissolved in 3 ml of dimethylsulfoxide. 0.207 g (1.5 mmol) of potassium carbonate was added and the reaction mixture was heated to 100° C. After 2 h 100 ml of water was added, and the mixture was extracted a few times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to obtain crude 4-(piperidin-1-yl)-1-nitrobenzene. Following the procedure outlined in Step 2 of Example 1, but substituting 4-piperidin-1-yl-1-nitrobenzene for 1-methyl-4-(4-nitrophenyl)piperazine, afforded 4-piperidin-1-ylaniline, which was reacted with 9-chloroacridine (according to Step 4 in the procedure of Example 1) to obtain the title compound with 6% overall yield.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5]
Reactant: CCOC(=O)Cl
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a stirred suspension of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (200 mg) in pyridine (2 ml) was added a solution of ethyl chloroformate (68.8 mg) in dichloromethane (0.5 ml) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was diluted with dichloromethane. The mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-ethoxycarbonylhydrazino)quinoline (115 mg).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=[CH2:4].P(Br)(Br)[Br:16]>>[Br:16][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(C)CCCC
Product: CCCCC(C)=CCCC(C)=CCBr

Procedure:
By the procedure described in Example 13, from 6-methyl-5-decen-2-one and vinyl-magnesium bromide there is obtained 3,7-dimethyl-1,6-undecadien-3-ol; nD26 = 1.4618, boiling point 116° C./9 mm Hg. This alcohol is reacted with phosphorus tribromide by the procedure of Example 13 to give 1-bromo-3,7-dimethyl-2,6-undecadiene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-:3])=[O:2].C(O[C:49]1[CH:57]=[CH:56][C:52](C(O)=O)=[CH:51][CH:50]=1)CCCCCCCCCCCCC.OC1C=CC(C(OC[C@@H](C)CC)=O)=CC=1.ClC1C=C(O)C=CC=1C(OC[C@@H](C)CC)=O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:49]3[CH:57]=[CH:56][CH:52]=[CH:51][CH:50]=3)=[O:32])=[CH:27][CH:26]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: CC[C@H](C)COC(=O)c1ccc(O)cc1
Agent: CC[C@H](C)COC(=O)c1ccc(O)cc1Cl
Product: CCCCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccccc3)cc2)cc1[N+](=O)[O-]

Procedure:
The procedure of Example 1 was followed except using 3'-nitro-4'-tetradecyloxybiphenyl-4-carboxylic acid instead of said 4-tetradecyloxybenzoic acid and (S)-2-methylbutyl 4-hydroxybenzoate instead of said (S)-2-methylbutyl 2-chloro-4-hydroxybenzoate. There resulted 4--(S)-2-methylbutyloxycarbonyl]phenyl 3'-nitro-4'-tetradecyloxybiphenyl-4-carboxylate].
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:16])=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=1>CC(O)C>[F:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([C:4]1[O:3][C:2]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=3)=[N:6][CH:5]=1)=[CH:15]2
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2cc(F)ccc21
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(C)(=O)=O)c3)o2)cc2cc(F)ccc21
Temperature: 80 °C
Yield: 24.2 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-5-fluoro-1H-indole-1-carboxylate 50 (0.314 g, 0.934 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.174 g, 0.934 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 5-fluoro-2-(2-((3-(methylsulfonamido)phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 52 (0.11 g, 25% yield) as solid. MS (ES) m/z 487 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH3:7][CH:8]([CH3:14])[CH2:9][C:10](=[O:13])[CH:11]=[CH2:12]>>[CH2:9]([C:10]([CH:11]1[CH2:12][CH2:5][C:4]([CH3:6])=[C:2]([CH3:1])[CH2:3]1)=[O:13])[CH:8]([CH3:14])[CH3:7]
Reactant: C=C(C)C(=C)C
Reactant: C=CC(=O)CC(C)C
Product: CC1=C(C)CC(C(=O)CC(C)C)CC1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
45.3 g of 2,3-dimethylbutadiene are added to 47.5 g of 5-methyl-hex-1-en-3-one at initially 100° C., at a rate such that the temperature does not drop below 90° C. The mixture is then kept for 1 hour at 100° C. and 30 minutes at 115° C., the excess dimethylbutadiene is distilled off, and the residue is distilled under reduced pressure. 64 g of 3,4-dimethylcyclohex-3-en-1-yl isobutyl ketone, of boiling point 99°-101° C./3 mm Hg, are obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@H:17]([N:18]([CH3:28])[C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:5][CH:4]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1>C(Cl)Cl>[C:31]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@H:17]([N:18]([CH3:28])[C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:29][CH:30]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc(N)cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(O[C@H]2CC[C@H]3[C@@H]4CC[C@H]5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 17β-(4-aminophenoxy)-4-methyl-5α-4-azaandrostan-3-one hydrochloride (7 mg) in CH2Cl2 (100 μl) was added acetic anhydride (30 μl) followed by adding pyridine (50 μl). The mixture was stirred at room temperature for 1 hr and then concentrated to dryness. The residue was purified via a silica gel plate developed with 5% MeOH-EtOAc (Rf=0.3) to give the title product, mp. 340° C.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[CH:11]=[CH:10][C@@H:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.[C:30](=O)(OC(Cl)(Cl)Cl)[O:31]C(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:30](=[O:31])[N:8]2[CH2:7][C@H:6]1[CH:11]=[CH:10][C@H:9]2[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@@H]1C=C[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C=C[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.6 %

Procedure:
To a stirred solution of O-allyl-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 128, 2.0 g, 6.70 mmol) in acetonitrile (560 mL), N-ethyl-N-isopropylpropan-2-amine (4.67 ml, 26.80 mmol) was added. Bis(trichloromethyl) carbonate (0.795 g, 2.68 mmol) dissolved in 40 mL CH3CN was added via a syringe pump (at a rate 0.1 ml/min) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. It was then allowed to stir at room temperature overnight. The mixture was then concentrated and diluted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column (12 g, 0-25% Hex/EA) to give the desired product as a colorless oil (1.64 g).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C1CO1.OCC1OCCN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C1.[C:41]1([CH:51]2[CH2:53][O:52]2)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1.[CH:54]([N:56]1[CH2:61][CH2:60][N:59]([CH:62]=[O:63])[CH2:58][CH:57]1[CH2:64][OH:65])=[O:55]>>[CH:54]([N:56]1[CH2:61][CH2:60][N:59]([CH:62]=[O:63])[CH2:58][CH:57]1[CH2:64][O:65][C:51]([C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1)([OH:52])[CH3:53])=[O:55]
Reactant: O=CN1CCN(C=O)C(CO)C1
Reactant: c1ccc2c(C3CO3)cccc2c1
Agent: OCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Agent: c1ccc2cc(C3CO3)ccc2c1
Product: CC(O)(OCC1CN(C=O)CCN1C=O)c1cccc2ccccc12

Procedure:
The same procedure as in (1) of Production Example 16 was repeated, except that the 2-(2-naphthyl)oxirane and the 2-hydroxymethyl-4-tritylmorpholine were replaced by 2-(1-naphthyl)oxirane and 1,4-diformyl-2-piperazinyl methanol, respectively, to obtain oily 2-[(1,4-diformylpiperazin-2-yl)methoxyl-1-(1-naphthyl)ethanol (compound No. 270).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:10]=2)[CH2:25][CH2:24]1
Reactant: O=CCCc1cc(-c2nccs2)no1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3nccs3)no2)CC1
Yield: 92.1 %

Procedure:
About 2 min after dissolving 3-(3-(1,3-thiazol-2yl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol)and 1-(2-methoxyphenyl)piperazine (9.2 mg, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 15.5 hr and followed the same processes as in Example 1 to obtain 17.7 mg (95.9%) of the target compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=O.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[N:24]([C:23]2[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=2)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: CSc1ccc(C(=O)CCC(=O)C(F)(F)F)cc1
Product: CSc1ccc(-c2ccc(C(F)(F)F)n2-c2ccc(F)cc2)cc1
Yield: 42 %

Procedure:
Following a procedure similar to that described in Example 43(iii), but using 5,5,5-trifluoro-1-(4-methylthiophenyl)pentane-1,4-dione [prepared as described in step (ii) above] and 4-fluoroaniline as starting materials, the title compound was obtained as a pale brown oily substance (yield 42%).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[F:11][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[F:11][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[C:17]([CH:4]=[O:5])[C:16]([CH3:20])=[N:15]1
Reactant: Cc1cc(C)n(CCF)n1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(CCF)c(C)c1C=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
To DMF (56 g, 0.75 mol) was added POCl3 (74.55 mL, 0.8 mol) at 0° C. After 30 minutes, to the formed Vilsmaier reagent was added 1-(2-fluoroethyl)-3,5-dimethyl-1H-pyrazole (88 g, 0.62 mol), and the reaction mixture was heated for 16 h at 80° C. The reaction mixture was diluted with dichloromethane (400 mL) and treated with potassium carbonate (600 g) in water (2 L) at 0° C. The organic layer was separated, passed through silica gel (10×10 cm), and evaporated. The liquid residue was crystallized from a mixture of hexane (100 mL) and ether (200 mL), separated by filtration, and dried in vacuo using an oil pump to give 26.3 g (24.9%) of the title product. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 3H), 2.48 (s, 3H), 4.36 (dt, J=28 Hz, J=5 Hz, 2H), 4.74 (dt, J=44 Hz, J=5 Hz, 2H), 9.85 (s, 1H). GC-MS calcd for C8H11FN2O: 170.09, found (M+): 170 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:18])[NH:15][CH2:16][CH2:17][C:12]=3[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:26][C:27]([OH:29])=[O:28]>CN(C=O)C>[C:12]([O:29][C:27](=[O:28])[CH2:26][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:19]([F:22])([F:20])[F:21])=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[C:14]1=[O:18])([CH3:17])([CH3:13])[CH3:11]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)NCC3)cc1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CC(=O)OC(C)(C)C)CC3)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Part A: 1-(4-Methoxy-phenyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (2.0 g, 6.43 mmol) was stirred in dry DMF (8 mL) at 0° C. NaH (60%, 0.35 g, 8.75 mmol, 1.4 eq) was added. Bromoacetic acid and t-butyl ester (1.0 mL, 6.77 mmol, 1.1 eq) were added dropwise. The mixture was stirred at 0° C. for 2 h and at rt overnight. The reaction was quenched with H2O, extracted with EtOAc, washed with brine, concentrated, and purified by silica gel chromatography (1:1 EtOAc:hexanes) to give pure [1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-acetic acid tert-butyl ester (2.73 g, yield: 99%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[N:5]=[CH:4][CH:3]=1.[CH3:16][NH:17][CH2:18][CH3:19].[OH-].[Na+].Cl>CC#N.CCO.O>[CH2:18]([N:17]([CH3:16])[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[N:5]=[CH:4][CH:3]=1)[CH3:19]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn2c(Cl)ccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: CCN(C)c1ccnc2c(C(=O)O)cnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (68 mg, 0.30 mmol) in CH3CN (1 mL) was added N-methylethanamine (18 mg, 0.30 mmol) and the mixture was stirred at ambient temperature for 16 h. The mixture was evaporated and the residue was purified by column chromatography (0-10% MeOH in dichloromethane) to give a solid. The solid was taken up in EtOH (0.5 mL) and water (0.1 mL) before NaOH (12 mg, 0.30 mmol) was added. The mixture was stirred at 50° C. for 4 h. The pH of the mixture was adjusted to 4 with conc. HCl, and the solvents were removed. The residue was co-evaporated with MeOH (3×) to provide 7-(ethyl(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. ESI-MS m/z calc. 220.1, found 221.5 (M+1)+; Retention time: 0.29 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][NH:24]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH:24]1[C:25]2[C:21](=[C:20]([C:2]3[CH:3]=[C:4]([NH2:11])[C:5]4[CH:6]=[N:7][NH:8][C:9]=4[CH:10]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 115 °C
Yield: 109.3 %

Procedure:
6-Bromo-1H-indazol-4-amine (10 g, available from Sinova Inc.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (16.05 g, available from Frontier Scientific, Europe Ltd) were dissolved in 1,4-dioxane (60 ml) and water (60 ml). 2M sodium carbonate (70.7 ml) and Pd(dppf)Cl2-DCM adduct (1.93 g) were added and the mixture was heated at 115° C. for 18 hr. The reaction mixture was diluted with dichloromethane (200 ml) and the organic and aqueous layers were separated by hydrophobic frit. The aqueous layer was extracted with further quantities of dichloromethane (2×200 ml), using a hydrophobic frit to separate the layers. The organic layers were combined and silica (80 g) was added. The solvent was removed in vacuo to give a crude material that was purified by chromatography on silica gel (750 g cartridge, Flashmaster II) eluting with 0-100% ethyl acetate in cyclohexane over 60 minutes. The oil was dried in vacuo on a drying rack overnight. The resultant yellow foam was dissolved in dichloromethane (3×400 ml), removing the solvent in vacuo after each dissolution. Ethyl acetate (50 ml) was then added and the solvent was removed in vacuo. The solid obtained was dried in a vacuum oven to afford the title compound (12.8 g) as a yellow foam.