Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:21]O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[CH2:21][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Oc1cncc(Br)c1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as an orange oil. MS: 357.3 and 359.3 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH:7]=[C:8]([OH:10])[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:53])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)[C:34]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:26]>CC(C)=O.CN(C=O)C>[CH2:25]([O:27][C:28](=[O:53])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:10][C:8]2[CH:7]=[C:6]([O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=2)[C:34]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:26]
Reactant: CC(=O)c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OS(=O)(=O)C(F)(F)F)cc(C(C)=O)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-acetyl-5-hydroxy-phenyl ester (1.0 g) in a mixture of acetone and DMF (2:1, 80 mL) were added potassium carbonate (2.4 g) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.8 g). The resulting mixture was stirred at 75° C. for 3 h. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 1.7 g of the title compound (72% yield). HRMS calcd for C32H41O10S1F3 [M+H]+ 675.2446, observed 675.2440.
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:10]2[C@@H:6]([O:7]C(C)(C)[O:9]2)[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[O:4]1)#[CH:2]>C(O)(=O)C.O>[CH:23]1([NH:22][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[C:19]=2[N:20]=[CH:21][N:13]3[C@H:5]2[C@H:6]([OH:7])[C@H:10]([OH:9])[C@@H:3]([C:1]#[CH:2])[O:4]2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CC(=O)O
Solvent: O
Product: C#C[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A solution of [9-((1R,2R,4R,5R)-4-ethynyl-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)purin-6-yl]cyclopentylamine (0.28 g) was dissolved in 20 ml of a mixture of acetic acid:water (80:20) and stirred overnight at 75° C. Solvent was removed under reduced pressure, and the residue purified by preparative TLC, eluting with methanol:methylene chloride (1:8), to yield (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-ethynyloxolane-3,4-diol, a compound of Formula I.
Reaction SMILES: Br[C:2]1[C:11](OC)=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]3[O:14][CH:9]32)=[C:4](OC)[CH:3]=1.FC(F)(F)C(O)=O.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:7]1[C:8](=[O:14])[CH2:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH2:6]1
Reactant: COc1cc(Br)c(OC)c2c1CCC1OC21
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of epoxide (2C) (0.494 g, 1.73 mmol) in 7 ml of chloroform was added 3.5 ml of trifluoroacetic acid. The solution was refluxed for 2 hrs. under argon, and then allowed to stand at room temperature overnight. The solution was once again refluxed for 1 hr. and then allowed to cool to room temperature. Washing the solution with 10 ml of water, drying over sodium sulfate, and evaporating the solvent yielded a yellow oil. Subjecting the product to medium pressure liquid chromatography using hexane-ethyl acetate::7.:3 yielded 0.250 g (51%) of the β-tetralone 44:mp 88°-89° C. 1H NMR (CDCl3) δ2.43 (2H, t, J=6 Hz,ArCH2CH2CO), 2.96, (2H, t, J=6 Hz, ArCH2CH2), 3.50 (2H, ArCH2CO,s), 3.70 (3H, s, ArOCH3), 3.73 (3H, s, ArOCH3), 6.76 (1H, s, ArH); IR (CHCl3) 3030, 2980, 2905, 2840, 2400, 2250, 1780, 1710, 1575, 1510, 1470, 1430, 1400, 1375 (sh), 1335, 1285, 1210 (br), 1170 (sh), 1140, 1080, 1040, 1010 cm-1 etc.; mass spectrum m/e/ (rel. intensity) 286 (M+ +2, 100%), 284 (M+, 100%), 271 (M+ +2-CH3. 25%), 269 (M+ -CH3, 25%), 244 (M+ +2-CH2 =C=O, 31%), 242 (M+ -CH2 =C=O, 38%), 229 (M+ +2,CH3 --CH2 =C=0, 69%), 277 (M+ -CH3 -CH2 =C=O, 69%), etc.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[O:18].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])=[O:10])=[CH:11][CH:12]=1
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(O)COc1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)COc2ccc(I)cc2)c1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To (4-iodo-phenoxy)acetic acid (83.5 mg, 0.3 mmol), 3-amino-benzamide (61.3 mg, 0.45 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (86.3 mg, 0.45 mmol) and 1-hydroxybenzotriazole (HOBt) (61.3 mg, 0.45 mmol) in DMF (3 ml) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.08 ml, 0.45 mmol). The mire was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=6:1) to give 3-[2-(4-iodo-phenoxy)acetyl-amino]-benzamide as a white solid (105.1 mg, 88.4% yield).
Reaction SMILES: [O:1]1[CH:6]([OH:7])[CH2:5][C@@H:4]([CH:8]([CH3:10])[CH3:9])[CH2:3][CH:2]1[C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[CH:20]([CH2:21][CH:22]([OH:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[C:15](=[O:33])[CH2:14]1)[CH3:12].[OH-].[K+]>CO>[O:1]1[CH:6]([OH:7])[CH2:5][C@@H:4]([CH:8]([CH3:10])[CH3:9])[CH2:3][CH:2]1[C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[CH:20]([CH2:21][CH:22]([OH:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[C:15](=[O:33])[CH2:14]1)[CH3:12]
Reactant: CC(C)[C@@H]1CC(O)OC([C@@H](C)[C@H]2CC(=O)[C@H]3[C@@H]4CCC5CC(O)CC[C@]5(C)[C@H]4CC[C@]23C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H]1CC(O)OC([C@@H](C)[C@H]2CC(=O)[C@@H]3[C@@H]4CCC5CC(O)CC[C@]5(C)[C@H]4CC[C@]23C)C1

Procedure:
Epimerization of compound 248 at the C14 position using KOH in MeOH yields 22,29-epoxy-3,29-dihydroxy-1 4β-stigmastan-15-one (260). Compound 248 is dissolved in MeOH and a solution of KOH in MeOH (25 mg/ml) is added. The mixture is refluxed for 15 minutes then cooled to room temperature. Water is added and the aqueous slurry is extracted with chloroform and then dried over MgSO4. Filtration and concentration gives the crude product that contains an epimeric mixture of compounds 248 and 260. Separation of 248 and 260 is achieved using column chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH:17](=[O:19])[CH3:18]>>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([CH:17]([OH:19])[CH3:18])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Reactant: CC=O
Product: CC(O)c1cc2c(N3CCOCC3)nc(Cl)nc2s1

Procedure:
2-chloro-4-morpholinothieno[2,3-d]pyrimidine (300 mg) was reacted with acetaldehyde via General Procedure D to give 1-(2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)ethanol. This crude intermediate was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 via General Procedure A to yield 100.2 mg of 308 following reverse phase HPLC purification. MS (Q1) 382.1 (M)+
Reaction SMILES: [C:1]([NH:4][C:5]#[N:6])(=[O:3])[CH3:2].[Na].[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>CN(C)C=O>[CH2:8]([N:4]([C:5]#[N:6])[C:1](=[O:3])[CH3:2])[CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)NC#N
Reactant: CCCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCN(C#N)C(C)=O
Temperature: 70 °C

Procedure:
221 g (2.085 mols) of sodium acetylcyanamide are dissolved in 500 ml of dimethylformamide at 90° C., the mixture is allowed to cool to 70° C. and 285.6 g (2.085 mols) of n-butyl bromide are then added dropwise at 70° C. in the course of 11/2 hours. The mixture is allowed to after-react at 70° C. for 10 hours, and the NaBr which has precipitated is filtered off with suction and the entire distillable constituent is removed from the filtrate by vacuum distillation. Fractional distillation of this distillate over a packed column 60 cm high gives 216.4 g (74.1% of theory) of pure product of boiling point 105° C./34 mbar.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1)=[O:4].[NH2:19][C@H:20]([CH2:23][CH3:24])[CH2:21][OH:22]>C(OCC)(=O)C>[OH:22][CH2:21][C@H:20]([NH:19][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1)=[O:4])[CH2:23][CH3:24]
Reactant: CC[C@@H](N)CO
Reactant: CS(=O)(=O)c1cc(NC(=O)CCl)cc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CC[C@H](CO)NCC(=O)Nc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
2-Chloro-N-(3-methanesulfonyl-5-nitro-phenyl)-acetamide (750 mg; 2.56 mmol) was diluted in 40 of ethyl acetate, (R)-(−)-2-amino-1-butanol (1.01 ml; 10.25 mmol) was added and the reaction mixture was stirred at 75° C. overnight. The solvent was concentrated under vacuum and the crude was purified by flash chromatography (Isolute Silica cartridge 10 g; eluent: Dichloromethane:MeOH=99:1). 380 mg (1.10 mmol; 43% yield) of the desired 2-((R)-1-Hydroxymethyl-propylamino)-N-(3-methanesulfonyl-5-nitro-phenyl)-acetamide were obtained.
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3](OC)=O.[C:18]1([C:24]2[N:29]=[N:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]([F:17])([C:3]1[N:28]2[N:29]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:25]=[CH:26][C:27]2=[N:30][N:31]=1)[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(-c3ccccc3)nn12
Temperature: 150 °C

Procedure:
A mixture of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (0.50 g, 2.1 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.39 g, 2.1 mmol) and p-toluenesulfonic acid monohydrate (0.20 g, 1.1 mmol) in 5 mL of dioxane was heated at 150° C. for 1 hour in a microwave tube in the microwave. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give yellow solid as desired product 6-(difluoro(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline. MS (ESI pos. ion) m/z: 374.1 (M+H). Calc'd Exact Mass for C21H13F2N5: 373.1.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
Dimethyl sulfoxide (20.80 ml, 22.90 g, 29.3 mmol) in dichloromethane (75 ml) was added dropwise to a cooled (-70° C.) solution of oxalyl chloride (13.95 ml, 20.30 g, 160 mmol) in dichloromethane (350 ml). The mixture was stirred at -70° C. for 15 minutes, then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 36.91 g, 133 mmol) in dichloromethane (150 ml) was added dropwise. The mixture was stirred at -70° C. for 20 minutes, then allowed to warm to -30° C. The mixture was cooled to -50° C. and triethylamine (55.95 ml, 40.45 g, 400 mmol) was added slowly. The mixture was allowed to warm to 0° C. and diluted with ice-cooled dichloromethane (250 ml). The mixture was washed with ice cold aqueous citric acid solution (5%, 2×300 ml) and water (300 ml), dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (42.3 g), which was used immediately without further purification. 1H NMR (250 MHz, CDCl3) δ 7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s).
Reaction SMILES: O1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:11]/[OH:12])/[CH2:3]C1.[N:13]1C=CC=C2C(=O)CCC=12>>[N:13]1[CH:8]=[CH:7][CH:6]=[C:5]2/[C:4](=[N:11]\[OH:12])/[CH2:3][CH2:9][C:10]=12
Reactant: O/N=C1\CCOc2ccccc21
Reactant: O=C1CCc2ncccc21
Product: O/N=C1/CCc2ncccc21

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 6,7-dihydro-5H-cyclopenta[b]pyridin-5-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, DMSO-d6) δ) 11.11, 8.50, 7.89, 7.27, 3.04, 2.81; HRMS (EI) calcd for C8H8N2O 148.0637, found 148.0628.
Reaction SMILES: [O:1]=[Sb:2]([O:4][Sb:5](=[O:7])=[O:6])=[O:3].[N+]([O-])([O-])=[O:9].[In+3:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=O>O>[OH-:1].[In+3:12].[OH-:9].[OH-:14].[O:1]=[Sb:2]([O:4][Sb:5](=[O:7])=[O:6])=[O:3]
Reactant: O=[N+]([O-])[O-]
Agent: O=[Sb](=O)O[Sb](=O)=O
Agent: [In+3]
Solvent: O
Product: [OH-]
Temperature: 25 °C

Procedure:
900 g of water was added to 600 g of the diantimony pentoxide sol (specific gravity: 1.198, Sb2O5 concentration: 18.4 wt %) prepared in Preparation Example 1 for dilution. Then, an aqueous indium nitrate solution having 242.2 g of indium nitrate (In(NO3)3.3H2O, In2O3 content: 39.1 wt %, guaranteed reagent, manufactured by Mitsuwa Kagaku Yakuhin K. K.) dissolved in 200 g of water, was added thereto with stirring at room temperature. Then, the mixture was heated at 90° C. for 6 hours to obtain a mixed slurry of indium hydroxide and diantimony pentoxide. This slurry had an In2O3 concentration of 4.9 wt %, a Sb2O5 concentration of 5.7 wt % and an In2O3 /Sb2O5 molar ratio of 1.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](=O)[C:14](=[CH:17][N:18](C)C)[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.[NH2:25]N>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]3=[N:25][NH:18][CH:17]=[C:14]3[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)C(=CN(C)C)CCC2
Reactant: NN
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2c1-c1n[nH]cc1CCC2

Procedure:
The title compound is prepared in analogous fashion to Example 8 using 5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester and hydrazine acetate. The crude product mixture is carried into the next step without purification. Electrospray mass spectrum: m/z 246 [M+1]; 1H NMR (DMSO-d6, 300 MHz) δ>13.0 (br s, 1H), 11.65 (br s, 1H), 7.49 (s, 1H), 7.20 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.91 (m, 2H), 2.76 (m, 2H), 1.84 (m, 2H) 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:24])([S:20]([CH3:23])(=[O:21])=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(C2=CCCCC2)cn1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@](C)(CCn1cc(C2CCCCC2)cn1)S(C)(=O)=O
Yield: 72 %

Procedure:
A solution of ethyl (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (120 mg, 0.339 mmol, 1.0 eq) in MeOH (5 mL) was subjected to hydrogenation conditions (8-bar pressure, room temperature) on a Thales Nano H-cube using a 10% Pd/C catcart, (catalyst cartridge). The solution was then concentrated to give ethyl (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoate (87 mg, 72% yield). LC-MS M+H+357.1.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([NH2:18])=[O:17])[CH2:2][CH3:3].[CH3:19][C:20]([CH3:22])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:19][C:20]1([CH3:22])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16](=[O:17])[NH:18]1
Reactant: CC(C)=O
Reactant: CCCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 70 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
A mixture of 3-(propylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.130 g, 0.500 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 2 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexane to ethyl acetate), then washed with ethyl acetate to afford the title compound (0.094 g, 62%) as a yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[C:15]([CH3:24])=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[OH:25].Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:25][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][CH:8]=[C:7]2[O:13][C:14]1[C:15]([CH3:24])=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
7-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (25 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. 1-Bromo-2-chloroethane (54 mg) and potassium carbonate (52 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give 6-(2-chloroethoxy)-7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (24 mg, yield 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:3]=1.[I:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[F:9][CH:8]([F:10])[C:6]1[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:3]=[C:2]([N:25]2[CH:26]=[C:22]([I:21])[N:23]=[CH:24]2)[N:7]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.3) (1.24 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure Ia. Obtained as a light brown solid (1.77 g, 95%). MS (ISP) 468.0 [(M+H)+]; mp 173° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10]C=[N:8][C:7]=2C(OC)=O)=[CH:2]1.[ClH:15]>>[ClH:15].[S:1]1[CH:5]=[CH:4][C:3]([C:6]([CH2:7][NH2:8])=[O:10])=[CH:2]1
Reactant: COC(=O)c1ncoc1-c1ccsc1
Agent: Cl
Product: NCC(=O)c1ccsc1
Reaction time: 4 h
Yield: 91 %

Procedure:
A mixture of 20.9 g of 5-(3-thienyl)-4-methoxycarbonyloxazole and 100 ml of 6N hydrochloric acid is stirred at 80° to 90° C. for 4 hours. Then, the reaction mixture is condensed under reduced pressure, and the residue is crystallized with acetone. 16.2 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride are thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([NH2:19])[C:15]([CH3:20])=[N:14]1.[CH3:21][N:22]=[C:23]=[O:24]>O1CCCC1.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([NH:19][C:23]([NH:22][CH3:21])=[O:24])[C:15]([CH3:20])=[N:14]1
Reactant: CN=C=O
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(C)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1c(C)nn(-c2cc(OC(C)C)c(Cl)cc2F)c1C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 1-(2-fluoro-4-chloro-5-isopropoxyphenyl)-3,5-dimethyl-4-aminopyrazole (29.8 g) in tetrahydrofuran (100 ml) was added one drop of triethylamine and then added dropwise a solution of methyl isocyanate (6.0 g) in tetrahydrofuran (50 ml). After the completion of addition, the reaction mixture was left to stand at room temperature for one hour. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (34.7 g) as a white crystalline solid. Recrystallization of the solid from a mixture of cyclohexane/acetone provided a white crystalline solid. m.p. 184°-185° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12](OCC)=[O:13])=[CH:9]2)=[N:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][OH:13])=[CH:9]2)=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1ccc2nn(CC)cc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1cc2cc(CO)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
To a solution of ethyl 2-ethyl-2H-indazole-5-carboxylate (step-1 of Example 13, 150 mg, 0.69 mmol) in THF (10 mL) was added LiAlH4 (26 mg, 0.69 mmol) at 0° C. The mixture was stirred at room temperature for 1 hr. The mixture was quenched with saturated aqueous NH4Cl. The precipitate was filtered off. The filtrate was concentrated to give the titled compound (131 mg, quant) as an orange colored oil.