Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[O:21]C)[CH2:9]1)(C)(C)C.ClC1[S:26][C:27]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=2[N:29]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[F:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:6]([NH:7][C@H:8]3[CH2:9][C@H:10]([N:12]4[C:16]5=[N:17][CH:18]=[CH:19][CH:20]=[C:15]5[NH:14][C:13]4=[O:21])[CH2:11]3)[S:26][C:27]=2[CH:33]=1
Reactant: COc1nc2cccnc2n1[C@H]1C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: Fc1ccc2nc(Cl)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=c1[nH]c2cccnc2n1[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Temperature: 90 °C

Procedure:
To a glass microwave reaction vessel was added 3-(trans-3-aminocyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (intermediate 43, 0.1288 g, 0.465 mmol), 2-chloro-6-fluorobenzo[d]thiazole (0.087 g, 0.465 mmol), and diisopropylethylamine (0.283 ml, 1.627 mmol) in dry dimethylsulfoxide (1.549 ml). The vial was sealed and heated at 90° C. for 14 hours. It was allowed to cool to room temperature and the crude product purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in acetonitrile/water, gradient 10% to 90% over 12 min) to give the desired 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (26.2 mg, 0.074 mmol, 15.86% yield). M+1: 355.99. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37-2.47 (m, 2 H) 3.25-3.34 (m, 1 H) 4.55 (d, J=5.28 Hz, 1 H) 5.20 (quin, J=8.41 Hz, 1 H) 6.99-7.12 (m, 2 H) 7.32 (dd, J=7.63, 1.17 Hz, 1 H) 7.41 (dd, J=8.80, 4.89 Hz, 1 H) 7.64 (dd, J=8.80, 2.74 Hz, 1 H) 8.00 (dd, J=5.18, 1.27 Hz, 1 H) 8.56 (d, J=6.06 Hz, 1 H) 11.15 (s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.Cl.[CH2:13]([O:17][NH2:18])[CH:14]([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>C1COCC1.O.CCOC(C)=O>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:18][O:17][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH:4]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CC(C)CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CONC(=O)c1cc(Cl)ccn1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of 4-chloropicolinoyl chloride hydrochloride (1.0 g, 5.68 mmol, 1.0 eq) in 25 ml of THF were added O-isobutylhydroxylamin hydrochloride (785 mg, 6.25 mmol, 1.1 eq) and N,N-diisopropylethylamine (2.97 ml, 17.0 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred for 30 min and diluted with water (25 mL) and EtOAc (50 mL). The separated organic layer was washed with brine (25 mL), saturated sodium bicarbonate solution (2×25 mL) and dried over sodium sulfate. Concentration under reduced pressure gave the title compound as colorless solid (870 mg, 67%), which was used without further purification. ES/MS m/z 229.0 (MH+), Rt=2.61 min.
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:30]=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[CH:30]([C@@H:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1)=[O:2]
Reactant: C[C@]12CCCCC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
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: C[C@]12CCC(=O)CC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
6α-Formylandrostane-3,17-dione was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6α-formylandrostane (Prepn. 14) 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 to give 6α-formylandrostane-3,17-dione. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 9.50 (1H, d), 2.56-0.82 (21H, m), 1.16 (3H, s), 0.88 (3H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:7][CH:8]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of N-(4-methylthiophenyl)-1-phenyl-1-H-pyrazol-3-amine (1.4 g) in dichloromethane (100 ml) at 0° was added a solution of 3-chloroperbenzoic acid (0.9 g) in dichloromethane (20 ml) and the mixture stirred and allowed to reach room temperature over 1 hour. The solution was washed with dilute sodium hydroxide solution, dried over magnesium sulphate, filtered and evaporated to an oil. The oil was dissolved in hot ether and gradual evaporation to a small volume gave the title compound as a colourless solid (1.2 g), collected by filtration, mp 123°-124°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:3]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN)(=O)=O)(C)C.[C-:38]#[N:39].[K+].CO>O1CCCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2([CH2:16][C:38]#[N:39])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:3]1
Reactant: [C-]#N
Reactant: Cn1cc(C2(C=O)CCCC2)c2ccccc21
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C2(CC#N)CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.9 g (0.0134 mol) of 1-(1-methyl-3-indolyl)-cyclopentanecarbaldehyde and 5 g (0.0166 mol) of 2,4,6-triisopropylbenzenesulphonohydrazide dissolved in 30 cm3 of tetrahydrofuran are stirred at room temperature for 3 hours. The tetrahydrofuran is thereafter evaporated off completely and 2.6 g (0.0402 mol) of potassium cyanide and 30 cm3 of methanol are added to the residue. The mixture is heated to reflux for 4.5 hours and then cooled, water is added and the mixture is extracted with dichloromethane. In succession, the organic extract obtained is washed with aqueous sodium hydrogen carbonate solution, dried over sodium sulphate and filtered and the solvent is evaporated off. The crude product thereby isolated is purified by chromatography on a silica gel column in dichloromethane and then, where appropriate, by flash chromatography using a 3:1 hexane/ethyl acetate mixture as eluent.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:45]3[CH2:46][CH2:47][N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH2:43][CH2:44]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOC)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-(2-methoxy-ethyl)-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C35H45N6O3Cl2 [(M+H)+] 667.2925, observed 667.2919.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](Cl)[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O-:29])(=[S:28])[CH3:27].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:28][C:26](=[O:29])[CH3:27])[CH2:10][C@@H:9]1[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Cl)C[C@H]1COCc1cc(F)c(F)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@H](COCc2cc(F)c(F)cc2F)N(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 88.8 %

Procedure:
A solution of 0.873 mg (2 mmol) (2S,4S)-4-chloro-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 20 ml DMF and after the addition of 0.343 mg (3 mmol) potassium thioacetate heated for 2.5 h at 100° C. Evaporation and flash-chromatography on silica gel (toluene/CH3CN 95:5) gave 0.745 g (89%) of (2R,4S)-4-acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 420 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]=[C:26]1[CH2:29][CH:28]([C:30]([OH:32])=O)[CH2:27]1.N(CC)(CCC)CCC.O[N:43]=[C:44]([C:46]1[CH:47]=[CH:48][C:49]([CH3:64])=[C:50]([NH:52][C:53]([C:55]2[N:59]3[CH:60]=[CH:61][CH:62]=[CH:63][C:58]3=[N:57][CH:56]=2)=[O:54])[CH:51]=1)[NH2:45]>CN(C=O)C>[CH3:64][C:49]1[CH:48]=[CH:47][C:46]([C:44]2[N:43]=[C:30]([CH:28]3[CH2:27][C:26](=[O:25])[CH2:29]3)[O:32][N:45]=2)=[CH:51][C:50]=1[NH:52][C:53]([C:55]1[N:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]2=[N:57][CH:56]=1)=[O:54]
Reactant: O=C1CC(C(=O)O)C1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: CCCN(CC)CCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
HATU (1.41 g, 3.72 mmol) was added in one portion to a stirred solution of 3-oxocyclobutanecarboxylic acid (0.405 g, 3.55 mmol) and Pr2NEt (0.62 mL, 3.7 mmol) in dry DMF (5 mL). After 10 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (1.0 g, 3.23 mmol) was added in one portion and continued to stir for another 30 minutes. The resulting solution was heated (110° C.) for 30 minutes and then cooled to room temperature. The solvent was evaporated and the residue was partitioned with saturated NH4Cl and EtOAc. The organic layer was dried with MgSO4 and filtered. The residue was purified on silica gel using 10% MeOH in dichloromethane to obtain N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10). 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1 H), 9.53-9.51 (m, 1 H), 8.71 (s, 1 H), 8.08 (d, J=1.6 Hz, 1 H), 7.91-7.88 (m, 1 H), 7.85 (dd, J=2.0, 8.0 Hz, 1 H), 7.72-7.68 (m, 1 H), 7.51 (d, J=8.4 Hz, 1 H), 7.34-7.30 (m, 1 H), 4.12-4.04 (m, 1 H), 3.70-3.53 (m, 4 H), 2.37 (s, 3 H). MS m/z 388.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1.[CH2:36]([Zn]CC)[CH3:37]>C1(C)C=CC=CC=1>[CH2:36]([C:9]1[CH:8]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:6]=[C:5]([O:4][C:3]2[CH:23]=[CH:24][C:25]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:26][C:2]=2[F:1])[CH:10]=1)[CH3:37]
Reactant: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Product: CCc1cc(CC(=O)O)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared as described in example 76 step (iii) but instead using the product of example 76 step (ii) and 2.0M diethylzinc in toluene.
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.BrC1C=CC(F)=CC=1.[Mg].Cl>C1(C)C=CC=CC=1.CCOCC>[C:1]([CH:3]([CH:9]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C(C#N)=Cc1ccc(C)cc1
Agent: Cl
Agent: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C(c1ccc(C)cc1)c1ccc(F)cc1

Procedure:
A solution of 860 grams of ethyl α-cyano-4-methylcinnamate in 1500 milliliters of hot toluene was added to a solution of 4-fluorophenyl magnesium bromide prepared from 860 grams of 4-bromofluorobenzene and 130 grams of magnesium turnings in 2500 milliliters of ether, under simultaneous distillation of the ether, until a final temperature of 80 degrees Centigrade was reached in the reaction mixture. The reaction mixture was then refluxed for 1 hour, whereupon it was hydrolysed with ice and 450 milliliters of concentrated hydrochloric acid. The mixture was then extracted with ether, washed with water, dried over anhydrous magnesium sulfate, treated with active carbon and evaporated in vacuo to give 1275 grams of crude ethyl α-cyano-3-(p-fluorophenyl)-3-(p-tolyl)-propionate.
Reaction SMILES: [CH3:1][N:2]([CH:18]([CH3:20])[CH3:19])[C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[K+]>CO.O>[CH3:1][N:2]([CH:18]([CH3:20])[CH3:19])[C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)C(C)C)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (2.5 g, 9.08 mmol) in methanol (20 ml) was added potassium hydroxide (2.5 g, 44.56 mmol) in water (5 ml). The resulting solution was stirred overnight at 50° C. and then concentrated in vacuo. The reaction was quenched water (100 ml). The pH was adjusted to 5 with HCl (3N). The product was precipitated from water and collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylic acid as a white solid (2.1 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[CH:10]=2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Reactant: COc1cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)no2)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1c(OC)cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)no2)cc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 75.2 %

Procedure:
2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenol (29b) (387.38 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (34d) (546 mg, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](OCC)=[O:15].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][OH:15]
Reactant: CCOC(=O)c1cnoc1-c1ccc(F)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of ethyl 5-(2,4-difluorophenyl)isoxazole-4-carboxylate (3.85 g) in tetrahydrofuran (60 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 33 ml) at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 5-(2,4-difluorophenyl)-4-isoxazolylmethanol (2.70 g, yield 84%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 60–61° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-].C(OCC)(=O)C.O>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([O:1][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:7][CH2:6]3)[C:9]3[N:10]([N:33]=[CH:34][CH:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.63 g) and rhodium acetate (dimer, 0.12 g) in methylene chloride (20 mL) was added dropwise a solution of ethyl diazoacetate (2.6 g) in methylene chloride (10 mL), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then 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 (2.17 g, 70%).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]([O:15][CH3:16])[N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=2)[CH:12]=1
Reactant: COc1c2cc(Cl)ccc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2cc(Cl)ccc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (57 mg, described in Example 118) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (96 mg, 95%). MS (ES): M/Z [M+H]=469. 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 4.19 (s, 3H), 4.77 (d, 1H), 4.90 (d, 1H), 7.16 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.4 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.92-8.01 (m, 3H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[C:12](=[O:13])[CH:11]3[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]3[C:9]2=[O:18])=[C:6]([F:19])[CH:5]=[C:4]([Cl:20])[C:3]=1[OH:21].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:3]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:4]([Cl:20])[CH:5]=[C:6]([F:19])[C:7]=1[N:8]1[C:12](=[O:13])[CH:11]2[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]2[C:9]1=[O:18]
Reactant: Nc1c(O)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1c(OC2CCCC2)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O

Procedure:
A mixture of 2-amino-6-chloro-4-fluoro-3-(tetrahydrophthalimido)phenol (0.31 g), cyclopentyl bromide (1.3 ml), potassium carbonate (0.14 g), and acetonitrile (5 ml) was heated under reflux for 2 hr. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the title product (0.17 g).
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]1[CH:40]=[CH:39][C:8]([CH2:9][C:10]2([C:35]([O:37]C)=[O:36])[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[C:22]4[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=3)=[O:18])[CH2:11]2)=[CH:7][CH:6]=1.Cl>CO.C1COCC1>[F:4][C:5]1[CH:40]=[CH:39][C:8]([CH2:9][C:10]2([C:35]([OH:37])=[O:36])[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[C:22]4[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=3)=[O:18])[CH2:11]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C1(Cc2ccc(F)cc2)CCCC(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(Cc5ccc(F)cc5)(C(=O)O)C4)cc23)ccn1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide in water (4 M solution, 1 ml, 4 mmol) was added into a solution of methyl 1-(4-fluorobenzyl)-3-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)cyclohexanecarboxylate (0.32 mmol) in methanol (0.5 ml) and THF (2 ml). The reaction solution was stirred at 70° C. for 16 h, and 1.0 N HCl solution was added dropwise to adjust pH to 4. The resulting solution was extracted with EtOAc (10 ml, twice). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified using HPLC to give the titled compound. LC-MS: 487.21 [M+11]. LC/MS RT=2.36 min.