Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23](C)(C)[CH3:24])[C:17](=[S:19])[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](OC(OCC)CBr)[CH3:29].[CH3:37][C:38](C)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][CH2:23][CH2:24][CH2:37][CH3:38])[C:17]2[S:19][CH:28]=[CH:29][N:18]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CCOC(CBr)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=S
Product: CCCCOC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)c1nccs1
Temperature: 65 °C
Reaction time: 14 h
Yield: 42 %

Procedure:
To a solution of tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-thiocarbamoylethyl]carbamate (250 mg, 0.647 mmol) in acetone (5 ml) was added bromoacetaldehyde diethyl acetal (149 μl, 0.970 mmol), and the mixture was stirred at 65° C. for 14 hr. The mixture was further heated to 75° C. and stirred for 5 hr. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give text-butyl (S)-[2-(4-benzyloxyphenyl)-1-(thiazol-2-yl)ethyl]carbamate (112 mg, yield 42%).
Reaction SMILES: [OH:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].[OH-].[Na+].[Cu+2:9]>O>[OH:1][CH:2]([PH:4](=[O:5])[O-:6])[CH3:3].[Cu+2:9].[OH:1][CH:2]([PH:4](=[O:5])[O-:6])[CH3:3]
Reactant: CC(O)[PH](=O)O
Agent: [Cu+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)[PH](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of α-hydroxyethylphosphinic acid (18 g) in distilled water (30 ml) previously adjusted to pH 8 with an aqueous solution of sodium hydroxide, a solution of copper(II) (10.7 g) in distilled water (70 ml) was added, followed by stirring for 30 minutes. After elimination of water by distillation, anhydrous ethanol (300 ml) was added thereto, and stirring was continued for 30 minutes. The by-produced sodium chloride was separated by filtration. The filtrate was concentrated to give copper(II) α-hydroxyethylphosphinate (Compound No. 11) (21.45 g) as pale green crystals. M.P. ~105° C. (decomp.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:18])[CH2:13][NH:14][CH2:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1.O>[C:7]([O:11][C:12](=[O:18])[CH2:13][N:14]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:15][CH2:16][OH:17])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Potassium carbonate (33.0 g; 0.19 mol) is added to a solution of the product from Example 4 (32.15 g; 0.18 mol) in dioxane (1.0 l) and water (0.5 l). A solution of benzyl chloroformate (27.3 ml; 0.19 mol) in dioxane (0.2 l) is slowly added dropwise at room temperature. The solution is stirred at room temperature for 3.5 h and subsequently concentrated. The residue is taken up in dichloromethane (3.0 l) and extracted by shaking with water (1.0 l). The aqueous phase is re-extracted five times with dichloromethane. The organic phases are combined, dried (magnesium sulphate) and concentrated. Yield: 24.47 g (43%), pale yellow oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].Br[CH2:29][C:30]1[O:34][C:33](=[O:35])[O:32][C:31]=1[CH3:36]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[C:15]([O:17][CH2:36][C:31]1[O:32][C:33](=[O:35])[O:34][C:30]=1[CH3:29])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OCc1oc(=O)oc1C
Yield: 5.3 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (19) (1.5 g, 3.5 mmol) dissolved in 15 mL of anhydrous toluene was reacted with 1.4 g (7.0 mmol) of commercially available 5-bromomethyl-4-methyl-1,3-dioxolen-2-one in the presence of 1.4 g (5.3 mmol) of silver carbonate (Ag2CO3). After work-up and further purification by mass-guided preparative HPLC, 0.1 g (5.3% yield) of the title compound (48a) was obtained as a colorless, viscous oil. Rf=0.62 (EtOAc/MeOH=19:1). MS (ESI) m/z 538.14 (M+H)+, 560.13 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])C)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.Cl>>[C:13]([NH:12][CH2:11][CH2:10][N:8]([C:41]([CH2:40][CH2:39][C:38]([OH:43])=[O:44])=[O:42])[CH3:1])([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]
Reactant: CN(CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)CCC(=O)O
Reaction time: 1 h

Procedure:
Boc-NMe-CH2CH2—NH-Fmoc (520 mg, 1.31 mmol) was treated with TFA-water (15 ml, 95:5, v/v) for 1 hour at ambient temperature, when TLC analysis showed complete Boc-deprotection. TFA-water was removed under reduced pressure and the resulting oil dissolved in DCM (30 mL). To this solution, succinic anhydride (131 mg, 1.31 mmol) was added followed by DIPEA (to pH ˜10 by moist pH paper). The mixture was then stirred for 30 min. The reaction mixture was then acidified (pH=1) with HCl (1 M) and extracted with EtOAc (100 mL×3). The combined EtOAc layers were washed with brine (100 mL×2) and dried over Na2SO4. The EtOAc was removed under reduced pressure to give the title compound as a colorless oil. ES-MS (MeOH-direct infusion) Calculated MH+ (C23H26N2O5H+)=411.10, Observed MH+411.09.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[N:30]=[CH:29][N:28](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:27]=5)[CH:24]=4)[N:19](C4CCCCO4)[N:18]=3)[CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[NH:28]1[CH:29]=[N:30][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:13]2[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:16]=[CH:15][CH:14]=2)=[N:27]1
Reactant: O=C(CC1CCCCC1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC1CCCCC1)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
2-Cyclohexyl-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)acetamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.034 g, 34% yield over 2 steps): 1H NMR (CD3OD) δ 8.75 (s, 1H), 8.38 (br s, 2H), 8.20 (s, 1H), 8.10 (d, 1H), 7.76 (td, 2H), 7.70 (d, 1H), 7.51 (t, 1H), 2.30 (d, 2H), 1.90 (m, 1H), 1.78 (m, 4H), 1.3 (m, 4H), 1.07 (m, 2H); ES-MS (m/z) 401 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Br[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[N:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:10]([C:5]2[NH:6][C:7]([CH2:8][CH3:9])=[C:3]([Cl:2])[N:4]=2)=[O:11])[C@H:14]([O:19][CH2:20][CH3:21])[CH2:15]1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: Brc1nc2ccccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(c2nc3ccccc3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 64.7 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-bromobenzothiazole (95 mg, 0.44 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 83.4 mg of the title compound as a colorless oily substance (65%).
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[C:36]([C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CCCCCC.CS(C)=O>[C:37]1(/[C:36](/[C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[CH:16]/[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1cccnc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=C(O)CCCCCCCCC/C=C(/c1ccccc1)c1cccnc1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.7 g, 68 mmoles) was washed with hexane and, after removal of the hexane under reduced pressure, dimethyl sulfoxide (40 ml) was added and the mixture was stirred with heating at 85° C. for an hour. After cooling, a dimethyl sulfoxide solution (20 ml) containing 10-carboxydecyltriphenylphosphonium bromide (18.0 g, 34 mmoles) was added dropwise to the mixture. After 10 minutes, a solution of 3-benzoylpyridine (6.2 g, 33.8 mmoles) in dimethyl sulfoxide (10 ml) was added. The reaction was allowed to proceed for an hour and, following addition of water (200 ml), the reaction product was washed with toluene. The aqueous layer was acidified with 2N hydrochloric acid to pH 5.2, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and distilled under reduced pressure to remove the solvent. The residue was then subjected to silica gel column chromatography using ethyl acetate as the developing solvent to give (Z)-12-phenyl-12 -(3-pyridyl)-11-dodecenoic acid (Compound Id-8, 3.2 g), after fractional recrystallization from isopropylether.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C@@H:30]1([CH2:40]O)[C@@H:39]2[N:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:40][C@H:30]5[C@@H:39]6[N:34]([CH2:35][CH2:36][CH2:37][CH2:38]6)[CH2:33][CH2:32][CH2:31]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC[C@H]1CCCN2CCCC[C@H]12
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN2CCCC[C@H]12

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1S,9aR)-octahydro-2H-quinolizin-1-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(1S,9aR)-octahydro-2H-quinolizin-1-yl]methanol following General Procedure J.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH2:29][CH:26]2[CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NCC1CC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC3CC3)c2c1N

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and cyclopropylmethanamine as a pale-yellow solid (80%). 1H NMR (400 MHz, DMSO-d6) δ 0.12-0.13 (m, 2H), 0.29-0.31 (m, 2H), 0.90 (m, 1H), 1.27 (s, 6H), 1.33 (t, J=8.0 Hz, 3H), 2.56 (s, 3H), 2.97 (t, J=8.0 Hz, 2H), 4.14 (s, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.91 (t, J=4.0 Hz, 1H), 8.11 (s, 2H). MS 400 (MH+).
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][S:8][C:9]1[C:18]([C:19]([O:21]CC)=[O:20])=[C:17]([OH:24])[C:16]2[C:11](=[C:12]([F:27])[C:13]([F:26])=[C:14]([F:25])[CH:15]=2)[N:10]=1)(=O)C>S(=O)(=O)(O)O>[F:25][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:27])[C:13]=1[F:26])[N:10]1[C:6]([CH2:5][OH:4])=[CH:7][S:8][C:9]1=[C:18]([C:19]([OH:21])=[O:20])[C:17]2=[O:24]
Reactant: CCOC(=O)c1c(SCC(=O)COC(C)=O)nc2c(F)c(F)c(F)cc2c1O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(=O)c2cc(F)c(F)c(F)c2n2c(CO)csc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
Concd. sulfuric acid (300 ml) was added to ethyl 2-(3-acetoxy-2-oxopropylthio)-6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylate (36.0 g) and the mixture was stirred at room temperature for 45 minutes and then at 85° C. for 19 hours. After adding ice-water (250 g) with cooling, the mixture was stirred at room temperature for 3 hours and the reaction mixture was then poured into ice-water. After precipitated crystal was filtered and washed with water, the resultant was recrystallized from a mixed solvent of chloroform - methanol to give the title compound (14.2 g) as light brown crystals, m.p. 220° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:22][CH3:21])=[O:24])[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1cccc(-c2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 3-(N-methylaminocarbonyl)phenyl boronic acid (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 111. NMR (CDCl3): 3.11 (3H, d), 4.34 (3H, s), 6.25 (1H, br), 7.56 (1H, m), 7.63-7.70 (2H, m), 7.84 (1H, d), 7.87 (1H, s), 7.90 (1H, d), 8.00 (1H, d), 8.21 (1H, s), 8.27 (1H, s), 8.97 (1H, s). MS: MH+ 383.09 (100%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O>ClCCl.C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([NH:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCNc1ncccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCCNc1ncc(Br)cc1Cl
Reaction time: 1.5 h
Yield: 103.6 %

Procedure:
2.1 g of 2-(3-chloro-2-pyridinylamino)ethanol was dissolved in 25 mL dichloromethane, and 2.3 g N-bromosuccinimide was added little by little thereto at 0° C. and stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous saturated sodium bicarbonate and brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed, whereby 3.17 g of the title compound (yellow oil) was obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1.B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(O)cc1O
Temperature: 85 °C
Reaction time: 1.75 h

Procedure:
A mixture of resorcinol (100 g, 0.908 mol), 4-chlorophenylacetic acid (170 g, 0.999 mol) and boron trifluoride etherate is stirred mechanically at 85° C. for 1.75 h. The dark red-brown reaction mixture is allowed to cool to room temperature and then poured slowly into aqueous sodium acetate (1 l, 30% w/v). The suspension is stirred overnight at room temperature. The orange brown precipitate is removed by filtration, dried in vacuo and then triturated with isopropyl ether/hexane (1:9) to give a yellow solid. This solid is washed with hexane and dried in vacuo to provide the title compound. A further three crops of material are obtained from the sodium acetate work-up mixture.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:31]=[CH:30][C:11]([C:12]([N:14]2[CH2:29][CH2:28][N:17]3[C:18]4[N:27]=[CH:26][CH:25]=[CH:24][C:19]=4[NH:20][C:21](=O)[CH2:22][CH:16]3[CH2:15]2)=O)=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:31]=[CH:30][C:11]([CH2:12][N:14]2[CH2:29][CH2:28][N:17]3[C:18]4[N:27]=[CH:26][CH:25]=[CH:24][C:19]=4[NH:20][CH2:21][CH2:22][CH:16]3[CH2:15]2)=[CH:10][CH:9]=1
Reactant: O=C1CC2CN(C(=O)c3ccc(F)cc3)CCN2c2ncccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Reaction time: 0.17 h

Procedure:
Solid LiAlH4 (357 mg, 9.41 mmol) was added to a vigorously stirred solution of the product of Example 64B (528 mg, 1.55 mmol) in tetrahydrofuran (40 mL). The resulting gray suspension was heated at reflux under nitrogen for 1 hour and then cooled in ice. The reaction was quenched by successive addition of ethyl acetate (5 mL), water (0.35 ml), 15% NaOH (0.35 mL) and water (1.05 mL). The resulting slurry was stirred for 10 minutes, filtered (tetrahydrofuran (15 mL) and ethyl acetate (15 mL) rinse), and the filtrate was concentrated to provide the title compound, sufficiently pure for use in the next step: 1H NMR (300 MHz, CDCl3) δ ppm 1.78-1.90 (m, 1H), 1.92-2.03 (m, 1H), 2.19-2.31 (m, 1H), 2.44-2.62 (m, J=8.7 Hz, 2H), 2.72-2.85 (m, J=10.7 Hz, 1H), 3.26 (ddd, J=12.1, 5.6, 3.8 Hz, 1H), 3.38-3.62 (m, 6H), 6.67 (dd, J=7.5, 4.5 Hz, 1H), 6.74 (dd, J=7.5, 2.0 Hz, 1H), 6.94-7.06 (m, 2H), 7.28-7.39 (m, 2H), 7.78 (dd, J=4.8, 1.6 Hz, 1H); MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=[O:10])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.Cl.S([S:21]([O-:23])=[O:22])([O-])=O.[Na+].[Na+].[OH2:26]>>[S:21]([OH:23])([OH:10])(=[O:22])=[O:26].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(N2CCOCC2)n1
Reactant: O=S([O-])S(=O)[O-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: Nc1nc(N)c(N)c(N2CCOCC2)n1
Product: O=S(=O)(O)O
Temperature: 50 °C

Procedure:
2.5 gm of 2,4-diamino-6-morpholino-5-nitroso-pyrimidine was suspended in 15 ml of water, and 2 N HCl (5 ml) was added until the substance just dissolved. The mixture was heated to 50° C; and sodium dithionite (Na2S2O4) was added until the violet color solution took on a yellow color. Then, the solution was filtered, cooled, and adjusted to a pH 2 by means of sulfuric acid (1 : 1). After a short time, the pyrimidine derivative precipitated as pyrimidine sulfate; the yield was 2.6 gm which was 76.4% of theory.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:17]=[O:18])=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)=[O:27]
Reactant: CSc1c2ccccc2c(C=O)c2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1c2ccccc2c(C=O)c2ccccc12
Temperature: 25 °C
Yield: 93 %

Procedure:
A 1 L RB flask fitted with addition funnel and stirring bar was charged with 10-methylthio-9-anthracenecarbaldehyde (example 3A, 12.0 g, 48 mmol) and 450 mL of CH2Cl2. The resulting solution was cooled to 5° with an ice bath. A solution of m-chloroperbenzoic acid (MCPBA) (Aldrich (85%), 9.64 g, 48 mmol) in 350 mL of CH2Cl2 was then added dropwise to the flask over 1 h. The reaction mixture was allowed to warm to RT over 1 h and then was washed with 5% NaHCO3 solution (2×500 mL), dried (Na2SO4), filtered, concentrated to 500 mL, and passed through a plug of SiO2 (250 g) using PhCH3 (5 L) as the eluting solvent. The desired material was then eluted from the SiO2 using EtOAc (2 L) as solvent. The solvent volume was reduced to 100 mL and then diluted to 700 mL with hexane. The resulting yellow solid was filtered and dried at 50° to give 11.98 g (94%) of 10-methylsulfinyl-9-anthracenecarbaldehyde mp 182°-184°, (C, H, S).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>O1CCCC1>[F:37][C:35]([F:36])([F:38])[C:33]1[CH:32]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH3:9])=[O:41])[CH:30]=[C:29]([C:28]([F:27])([F:45])[F:46])[CH:34]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a solution of 180 mg (0.711 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine in 7 ml dry tetrahydrofuran 0.86 ml of a 0.91 M solution (0.78 mmol) of potassium hexamethyldisilazide in tetrahydrofuran was added at room temperature under an atmosphere of argon. After 45 min 295 mg (0.924 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added. The reaction mixture was stirred at room temperature for 3 h. Quenching with water was followed by dilution with tert-butyl methyl ether and washing with 2 M aqueous sodium carbonate solution and brine. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated. Flash chromatography gave 254 mg (67%) of the title compound as a light yellow solid.