Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[C:27]([C:35](=O)[CH2:36]Br)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[F:23][C:24]([F:39])([F:40])[C:25]1[CH:26]=[C:27]([C:35]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:36]=2)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(O)c1cc(-c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 32 %

Procedure:
4-[4-(3,5-Bis-trifluoromethyl-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (110 mg, 32%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3′,5′-bis(trifluoromethyl)-2-bromoacetophenone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.79 (s, 1H), 8.72 (s, 2H), 8.55 (s, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.12-8.17 (m, 2H), 7.79 (t, J=7.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.41-7.50 (m, 2H).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[C:15]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=4[F:30])=[C:16]([F:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=3[N:10]=[CH:9]2)[CH2:4][O:3]1.S(=O)(=O)(O)O>C(O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])=[C:16]([F:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1
Reactant: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Combine (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (24.75 g, 45.58 mmol) and ethanol (250 mL). Add aqueous 9N sulfuric acid (50 mL) over 5 minutes. Heat to 75° C. After 2 hour, cool to ambient temperature and then cool in an ice bath to give a solid. Collect the solid by filtration, rinse with ethanol (3×30 mL), and dry to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ10.24 (s, 1H), 8.52 (s, 1H), 7.69 (dd, 1H, J=10.4, 1.8 Hz), 7.52 (d, 1H, J=8.6 Hz), 6.98 (m, 1H), 5.14 (brs, 1H), 4.83 (brs, 1H), 4.32 (dd, 1H, J=12.9, 2.5 Hz), 3.76 (m, 1H), 3.67 (dd, 1H, J=13.1, 12.9 Hz), 3.58 (s, 3H), 3.46 (ddd, 1H, J=10.9, 5.3, 5.1 Hz), 3.38 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ161.3 (d, J=4.0 Hz), 155.6 (d, J=22.8 Hz), 154.6 (d, J=250 Hz), 152.0, 150.6, 134.3 (d, J=231 Hz), 133.8 (d, J=7.1 Hz), 133.1 (d, J=3.0 Hz), 127.8 (d, J=10.3 Hz), 125.3 (d, J=7.0 Hz), 123.9 (d, J=21.5 Hz), 95.0 (d, J=4.0 Hz), 87.1 (d, J=7.8 Hz), 68.0, 63.8, 50.1, 28.8; 19F NMR (376 MHz, DMSO-d6) δ-124.4, −149.8; MS (M+H)+m/z calcd 505.0. found 505.0.
Reaction SMILES: [CH2:1]([C@H:5]([CH2:8][C:9]#[N:10])[C:6]#[N:7])[CH:2]([CH3:4])[CH3:3].C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2>O>[CH2:1]([CH:5]([CH2:8][C:9]#[N:10])[C:6]#[N:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@@H](C#N)CC#N
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CC(C#N)CC#N
Yield: 84 %

Procedure:
The racemization of (R)-2-isobutyl-succinonitrile was carried out on material recovered from bioconversion of racemic 2-isobutyl-succinonitrile with NIT-102 C2. A mixture of (R)-2-isobutyl-succinonitrile (1.36 g, 10 mmol, 69% ee), toluene (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.076 g, 5 mmol) was refluxed for 2 h. Water (10 mL) was added to the reaction and the resulting mixture extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed sequentially with 5% HCl (20 mL) and saturated aqueous sodium chloride (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give racemic 2-isobutyl-succinonitrile (1.14 g, 84%). Enantiomeric purity was determined by GC using a Chiraldex™ G-TA column (30 M×0.25 mm ID, 125 micron film thickness).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.CN(C)CC(O)=O>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(O)cc1
Reactant: CS(=O)(=O)Nc1ccc(I)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
A mixture of N-(4-iodo-phenyl)-methanesulfonamide (0.45 g, 1.52 mmol) from Step A, 4-methoxyphenol (0.28 g, 2.28 mmol), Cs2CO3 (0.99 g, 3.04 mmol), N,N-dimethylglycine HCl salt (31.8 mg, 0.23 mmol) and CuI (14.5 mg, 0.076 mmol) in dioxane (4 mL) under N2 was heated to 100 C overnight. The reaction was diluted with EtOAc and brought to the usual work-up. The residue was purified by chromatography (silica gel, 30% EtOAc/hexanes) to give the desired product. MS (EI) 294 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11]3=[CH:20][C:21]([C:23]([N:25]([CH3:27])[CH3:26])=O)=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1.O1CCCC1.CSC.B>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:11]3=[CH:20][C:21]([CH2:23][N:25]([CH3:27])[CH3:26])=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: C1COCCO1
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Yield: 97.7 %

Procedure:
1 g of compound 12a (2.7 mmol) and 50 mL of tetrahydrofuran or dioxane were added into a 150 mL two-neck flask and refluxed under nitrogen atmosphere. 2 M of borane-dimethyl sulfide solution (10.8 mmol) was slowly added dropwise and refluxed for 2 hours. The reaction mixture was quenched with methanol and purified by column chromatography with dichloromethane to give white solid 13a (930 mg, 96.7%). m.p. 205° C. (decomposition). 1H NMR (300 MHz, DMSO-d6): δ 7.92 (d, J=8.5 Hz, 2H), 7.86 (s, 1H), 7.05 (s, 1H), 6.60 (d, J=8.5 Hz, 2H), 5.48 (br s, 2H), 4.02 (t, J=4.5 Hz, 4H), 3.92 (s, 2H), 3.77 (t, J=4.5 Hz, 4H), 2.42 (s, 6H). MS (EI) m/e (%): 352 (M+, 24).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:21][CH2:22][CH2:23][N:24]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH3:25]>CN(C)C=O>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:7])=[O:6])[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: CC(C)NS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCN(C(C)C)S(=O)(=O)c2cccc(C(F)(F)F)c2)cc1OC
Reaction time: 2 h
Yield: 43.3 %

Procedure:
N-isopropyl-3-trifluoromethylbenzenesulfonamide (5.362 g, 0.02 mol) in dimethylformamide (30 mL) was treated with sodium hydride (60% in mineral oil), (0.802 g) and stirred for 2 hours. Then N-(3-chloropropyl)-3,4-dimethoxy-N-methylphenethylamine (5.436 g, 0.02 mol) was added and the reaction heated overnight. Filtration and removal of solvent provided the crude product (6.95 g). Column chromatography and high pressure liquid chromatography provided the pure product (4.35 g) as a gum. 1H NMR (CDCl3) 1.15 (d, 6, J=3.5H, Me2) 2.25 (s, 3, N--Me) 3.84 (d, 6, (OMe)2) 6.76 (m, 3, Ar) 7.25 (m, 3, Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:14][O:15][C:16](=[O:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:14][O:15][C:16](=[O:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:26])(=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Yield: 60.5 %

Procedure:
To a mixture of aniline (0.33 g, 3.53 mmol) and pyridine (1 ml) a solution of 3-(2-chlorosulfonylphenyl)acrylic acid methyl ester (33) (0.45 g, 1.72 mmol) in dichloromethane (3 ml) was added and the resultant solution was stirred at 50° C. for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with ethyl acetate-chloroform (1:7, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.33 g, 60%). 1H NMR (CDCl3, HMDSO), δ: 3.86 (3H, s); 6.27 (1H, d, J=16.0 Hz); 6.69 (1H, br s); 6.87-7.67 (8H, m); 7.94-8.13 (1H, m); 8.49 (1H, d, J=16.0 Hz).
Reaction SMILES: [Si:1]([C:8]1[N:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])[CH:10]=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:10]1[N:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:15])[CH3:16])[C:8]([Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[N:12][CH:11]=1
Reactant: BrCCCCCCCCBr
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(CCCCCCCCBr)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 2-(tert-butyldimethylsilyl)-1-(N,N-dimethylsulfamoyl) imidazole (Example 29 step a) (2.62 g, 9.05 mmol) in dry tetrahydrofuran (30 ml) was cooled under an atmosphere of argon to -78° C. n-Butyl lithium (1.5M in hexanes) (7.25 ml, 10.9 mmol) was added over 15 min and the solution stirred for a further 30 min. A solution of 1,8-dibromooctane (2.55 ml 13.6 mmol) in dry tetrahydrofuran (5 ml) was added over 10 min. The solution was stirred for 2 h, allowed to warm to room temperature and stirred for 18 h. Saturated ammonium chloride solution (30 ml) and diethyl ether (30 ml) were added and the ethereal extract was washed with brine and dried over sodium sulfate. Filtration, evaporation of the filtrate and purification by flash column chromatography (silica; 20%; ethyl acetate/hexane) to afford the product (Rf 0.43) as a white solid (2.36 g, 54%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([NH2:20])[CH:3]=1.[OH-].[Na+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([N:20]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc(N)cc21
Reactant: BrCCOCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc(N3CCOCC3)cc21
Temperature: 110 °C
Yield: 17.3 %

Procedure:
Into a 100 ml round bottomed flask with 4-bromo-1-(3-chloro-2-methylbenzyl)-1H-benzo[d]imidazol-6-amine (2.33 g, 6.64 mmol), tetrabutylammonium iodide (0.123 g, 0.332 mmol) was added 6N sodium hydroxide (16.61 ml, 100 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.657 ml, 13.29 mmol). The reaction was heated to 110° C. for 2 h, cooled to room temperature and the mixture was extracted with EtOAc. The combined organic phase was washed with Brine (20 mL) and concentrated. The residue was purified by reversed phase HPLC and was eluted with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (30-65%) over 12 minutes. The appropriate fractions were collected and evaporated to yield 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-1H-benzo[d]imidazol-6-yl)morpholine (483 mg, 1.148 mmol, 17.28% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.37 (s, 3H) 3.14-3.22 (m, 4H) 3.84-3.93 (m, 4H) 5.48 (s, 2H) 6.71 (d, J=2.02 Hz, 1H) 6.91 (d, J=7.58 Hz, 1H) 7.16 (t, J=7.83 Hz, 1H) 7.34 (d, J=2.02 Hz, 1H) 7.44 (d, J=7.58 Hz, 1H) 8.84 (br. s., 1H); LC/MS: MS (ES+) m/e 421 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:20]([C:39]([F:42])([F:41])[F:40])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:44]>C(O)C>[ClH:44].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:32][CH:33]=2)=[C:20]([C:39]([F:40])([F:41])[F:42])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(OC(F)(F)F)cc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 52-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (600 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([O:11]CC)=[CH2:10])[N:5]=[CH:4][N:3]=1.Cl>CC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([C:9](=[O:11])[CH3:10])[C:7]=1[CH3:8]
Reactant: C=C(OCC)c1ncnc(Cl)c1C
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1ncnc(Cl)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
4-Chloro-6-[1-(ethyloxy)ethenyl]-5-methylpyrimidine (Intermediate 42, 1.49 g, 7.50 mmol) was dissolved in acetone (75 ml), treated with 2M aqueous hydrochloric acid solution (11.25 ml, 22.50 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was neutralised with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure to give the title compound as a yellow oil (947 mg);
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)C1(CCc2ccncc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccncc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-15; 0.8 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.9 mmol), potassium carbonate (3.1 mmol) in DMF (5 mL). The product was triturated from Et2O, mp 140-155° C. MS (APCI): 470 (M+H).
Reaction SMILES: C1(S(O[CH2:11][CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=O)=O)C=CC=CC=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].CN(C)C=O>O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH:16]=[CH:15][CH:14]=[C:13]2[CH2:12][CH2:11][N:29]2[C:28](=[O:30])[C:27]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]3[C:25]2=[O:35])=[CH:18][CH:19]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc2cccc(CCOS(=O)(=O)c3ccccc3)c2c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cccc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
The compound IV (14 g, 0.041 mol) produced as described above and potassium phthalimide (12.3 g, 0.0656 mol) were added into a reaction vessel, and dimethylformamide (200 ml) was added. The mixture was heated and refluxed for 2 hours. After cooling it to room temperature, 200 ml of water was added, and the mixture was stirred and filtered. The filter cake formed was washed with water and dried, to produce 12.3 g of N-[2-(7-methoxy-1-naphthyl)ethyl]phthalimide (II). The yield was 92.3%. The melting point was 160-161° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([O:23]C)=O)[N:13]=2)[CH:9]=[N:8]1.CCO.O.[NH2:31][NH2:32]>>[CH3:26][Si:2]([CH3:1])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([NH:31][NH2:32])=[O:23])[N:13]=2)[CH:9]=[N:8]1
Reactant: COC(=O)c1cc2nccn2c(-c2cnn(COCC[Si](C)(C)C)c2)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2nc(C(=O)NN)cc3nccn23)cn1
Yield: 92.7 %

Procedure:
In a 20 mL flask, methyl 5-(1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (Example 122; Step C) (50 mg, 0.13 mmol) was dissolved in EtOH (540 μL, 0.13 mmol). To this was added a large excess of hydrazine hydrate (104 μL, 3.3 mmol). The reaction mixture was refluxed for 1 hour, and then concentrated down to dryness. The residue was diluted in EtOAc and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to afford 5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carbohydrazide (45 mg, 90% yield) as a yellow oil. MS (apci) m/z=374.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].CC(O)=O.N1CCCCC1>C1CCCCC1.CCOC(C)=O>[C:12]([C:11](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)[C:10]([O:16][CH2:17][CH3:18])=[O:15])(=[O:13])[CH3:14]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCCCC1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cccc(Cl)c1)C(C)=O
Yield: 116.5 %

Procedure:
A mixture of 3-chlorobenzaldehyde (2 g), ethyl acetoacetate (1.94 g), AcOH (0.23 ml), piperidine (0.23 ml) in cyclohexane (40 ml) was refluxed azeotropically for 2 hours. After cooling, the reaction mixture was diluted with EtOAc. The organic layer was washed with water, saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4 and concentrated in vacuo to give ethyl 2-acetyl-3-(3-chlorophenyl)acrylate (4.19 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:12])[C:6]2=[O:11].[BH4-].[Na+].[OH-].[K+].CI.Br[C:20]1C=CC=C2C=1CC(C)C2O>C1COCC1.CO.CS(C)=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:12])[CH:6]2[O:11][CH3:20]
Reactant: CC1Cc2c(Br)cccc2C1O
Reactant: CC1Cc2c(Br)cccc2C1=O
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: COC1c2cccc(Br)c2CC1C
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of 149.5 g (0.664 mol) of 4-bromo-2-methyl-1-indanone in 900 ml of THF-methanol (2:1, vol.), 37.6 g (0.995 mol) of NaBH4 was added in small portions with vigorous stirring over 1.5 hours at 5° C. This mixture was stirred at room temperature for 12 hours and then added to 2 L of cold water. The hydrogenation product was extracted with 5×200 ml of dichloromethane, and the combined extract was evaporated to dryness. To 149 g (2.65 mol) of KOH in 420 ml of DMSO, 188 g (82.5 ml, 1.33 mol) of MeI, and a solution of the crude 4-bromo-2-methylindan-1-ol in 220 ml of DMSO were added. This mixture was stirred for 2 hours at ambient temperature; then, 92.0 g (40.4 ml, 0.664 mol) of MeI was added, and the mixture was additionally stirred for 2 hours. The resulting mixture was added to 2.5 L of cold water. The crude product was extracted with 5×200 ml of dichloromethane. The combined extract was dried over Na2SO4, and then evaporated to dryness. Fractional distillation gave a mixture of two diastereomeric compounds, b.p. 108° C./3 mm Hg. Yield, 148.5 g (93%) of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:23]=[N:22][C:21]([N:24]2[CH:28]=[C:27]([CH2:29][OH:30])[N:26]=[CH:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:23]=[N:22][C:21]([N:24]4[CH:28]=[C:27]([CH2:29][OH:30])[N:26]=[CH:25]4)=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: OCc1cn(-c2ccc(Cl)nn2)cn1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: OCc1cn(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 180 °C

Procedure:
To a mixture of 6-fluoro-1-(piperidin-4-yl)indoline (100 mg, 0.4 mmol) and (1-(6-chloropyridazin-3-yl)-1H-imidazol-4-yl)methanol, prepared as in STEP 1 above (63 mg, 0.3 mmol) in DMSO (1.5 mL) was added DIPEA (0.16 mL, 0.9 mmol). The resulting mixture was sealed and heated at 180° C. for 1.5 h under microwave irradiation. The resulting mixture was then poured into H2O (30 mL) and the aqueous layer was extracted with 10% CH2Cl2/Et2O (80 mL×4). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by column using EtOAc then 3-5% MeOH/EtOAc as the eluent to yield (1-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-imidazol-4-yl)methanol.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[NH:27][C:26](=[O:28])[N:25]2[C:29]([CH3:35])=[N:30][C:31]([CH2:32][CH2:33][CH3:34])=[C:24]2[N:23]=1)[CH3:10]>ClCCl>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[NH:27][C:26](=[O:28])[N:25]2[C:29]([CH3:35])=[N:30][C:31]([CH2:32][CH2:33][CH3:34])=[C:24]2[N:23]=1)[CH3:10]
Reactant: CCN1CCNCC1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
83 mg (0.73 mmol) of N-ethylpiperazine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a]-[1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 104 mg (87%) of 2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one are obtained.