Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:31]1[C@H:35]([CH2:36]Br)[CH2:34][CH2:33][C:32]1=[O:38].CCN(C(C)C)C(C)C>C(#N)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:36][C@H:35]3[NH:31][C:32](=[O:38])[CH2:33][CH2:34]3)[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C1CC[C@@H](CBr)N1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O[C@H]1CC[C@@H](NC[C@@H]2CCC(=O)N2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To a solution of non-racemic 1-(S)-(1-(R)-(3,5-bis(trifluoro-methyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(amino)cyclopentane from Example 39 in 0.5 mL of acetonitrile was added 50 mg of (2-pyrrolidon-5-(S)-yl)methylbromide and 0.10 mL of DIPEA. The reaction was heated in a sealed vial at 90° C. for 60 h and then evaporated. The residue was purified on a 2×1 mm preparative silica gel plates eluted with 2% TEA in methanol to afford 50 mg of title compound as a white solid. Mass spec (NH3 /CI): 533 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:25]1([O:30][C:31](=[O:38])[C@H:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:33][C@H:32]([C:31]([O:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC1CCN(C(=O)OC(C)(C)C)C1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-tert-butoxycarbonyl-3-pyrrolidinone (0.382 g, 4.76 mmol) in dichloroethane (20 mL) was added L-leucine cyclopentyl ester tosylate (1.96 g, 5.3 mmol) and sodium triacetoxyborohydride (2.65 g, 12.5 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (150 mL) and quenched with saturated ammonium chloride solution (50 mL) and washed with saturated sodium hydrogen carbonate solution (3 times 30 mL). The organic extracts were dried (MgSO4), concentrated and purified by flash column chromatography (7:3 ethyl acetate:heptane) to yield the desired product. LC/MS: m/z 369.25 [M+H]+
Reaction SMILES: S([CH:5](C)[C:6]([O:8][C:9](=[O:16])[CH:10]([S:12]([OH:15])(=[O:14])=[O:13])[CH3:11])=[O:7])(O)(=O)=O.O1[C:22](=O)[CH2:21][CH2:20]S1(=O)=O.C(C1C(=O)OS(=O)(=O)C1)C(C)C.CC1C(=O)OS(=O)(=O)C1>>[CH2:11]([C:10]1([S:12]([OH:15])(=[O:13])=[O:14])[CH2:5][C:6](=[O:7])[O:8][C:9]1=[O:16])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1CCS(=O)(=O)O1
Reactant: CC(C(=O)OC(=O)C(C)S(=O)(=O)O)S(=O)(=O)O
Agent: CC(C)CC1CS(=O)(=O)OC1=O
Agent: CC1CS(=O)(=O)OC1=O
Product: CCCCC1(S(=O)(=O)O)CC(=O)OC1=O

Procedure:
sulfopropionic anhydride, i.e., 1,2-oxathiolane-5-one-2,2-dioxide of the formula: ##STR7## 4-methyl-1,2-oxathiolane-5-one-2,2-dioxide 4-isobutyl-1,2-oxathiolane-5-one-2,2-dioxide
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:63])([F:62])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[C:51]([C:58]([O:60][CH3:61])=[O:59])[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:55][CH2:54][N:53]2[C:49]([C:48]([F:63])([F:47])[F:62])=[N:50][C:51]([C:58]([O:60][CH3:61])=[O:59])=[C:52]2[CH2:57]1)=[O:5]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 22.7 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (568 mg, 1.50 mmol), crude methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (300 mg, 1.50 mmo) and N,N-diisopropylethylamine (0.4 mL, 2 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate 3 (120 mg, yield 23.0%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]=[CH:19][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: COc1ccc(CNc2cc(Br)ccc2N)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: COc1ccc(Cn2cnc3ccc(Br)cc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 886.7 %

Procedure:
To a solution of 5-bromo-N-(4-methoxybenzyl)benzene-1,2-diamine (550 mg, crude) in HC(OMe)3 (20 mL) was added TsOH.H2O (30 mg, 0.16 mmol). The mixture was stirred at 100° C. for 4 h. The reaction solution was then concentrated and the residue was washed with water and extracted with EtOAc. The organic layer was concentrated to give the desired product (450 mg, 79% yield) and the crude product used in next step without further purification. LCMS (m/z): 318.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]2=[N:32][C:33](=[O:35])[N:34]=[C:30]2[CH:29]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COCCC(C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
70 mg (186 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate), 27.7 mg (186 μmol, 1.0 eq.) of 5-aminobenzimidazolone, 26.4 mg (186 μmol) of Oxima and 28.9 μl (186 μmol) of DIC in 3.9 ml of dimethylformamide were reacted according to General Method 5. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/0.1% formic acid and acetonitrile/0.1% formic acid, gradient 10% acetonitrile to 90% acetonitrile) and then subjected to basic extraction (aqueous sodium hydroxide solution/ethyl acetate). Yield: 44 mg (47% of theory)
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[C:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])#[N:28].C(OCC)C.Cl>C(OCC)(=O)C.C(OCC)C>[ClH:25].[C:27]([C:29]1[CH:30]=[C:31]([NH:32][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:33]=[CH:34][CH:35]=1)#[N:28]
Reactant: N#Cc1cccc(N)c1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCCCC3)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1c[nH]c2c(Nc3cccc(C#N)c3)ncc(C(=O)N3CCCCC3)c12
Yield: 26.5 %

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-(1-piperidin-1-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (90 mg) and using 3-cyanoaniline (56 mg) instead of 3-bromoaniline and heating for 15 rather than 30 minutes. Isolated by MDAP rather than trituration with diethyl ether and then suspended in ethyl acetate (10 ml) and treated with a solution of 1M hydrochloric acid in diethyl ether (10 drops). The mixture was evaporated and dried at 40° C. under vacuum to afford the title compound (25 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:30])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][C:3]=1[Cl:30]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
To a solution of 1-(4-aminophenyl)-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (118 mg, 0.400 mmol) in DMF (3 mL) was added NCS (51 mg, 0.38 mmol). The mixture was stirred at room temperature for 20 h, diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (1:1 hexane/EtOAc) to afford the title compound as a tan solid (60 mg, 0.18 mmol, 45%), mp: 256°-258° C. 1H NMR (CDCl3) 8.50 (s, 1H), 7.54 (s, 1H), 7.32(d, J=8.3, 1H), 6.82 (s, 1H), 6.77 (d, J=8.3, 1H), 6.69 (s, 1H), 6.04 (s, 2H), 4.33 (s, 2H), 3.42 (s, 2H).
Reaction SMILES: [H-].[Na+].CC1C=CC(S(O[CH2:14][C@@H:15]2[O:17][CH2:16]2)(=O)=O)=CC=1.[F:18][C:19]1[CH:34]=[CH:33][C:22]2[C:23]([C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)=[N:24][O:25][C:21]=2[CH:20]=1>CN(C)C=O.O>[F:18][C:19]1[CH:34]=[CH:33][C:22]2[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:14][C@H:15]4[CH2:16][O:17]4)[CH:27]=3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Oc1cccc(-c2noc3cc(F)ccc23)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Yield: 75 %

Procedure:
The title compound is prepared from a mixture of sodium hydride in dimethylformamide, 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol in dimethylformamide and (2R)-(−)-glycidyl tosylate in dimethylformamide essentially as described above except that the reaction mixture is diluted with water, extracted with ethyl acetate, washed with water (twice), dried (MgSO4), concentrated and purified by column (silica) chromatography eluting with a graded solvent mixtures of toluene to 1% ether in toluene to give the title compound as a white solid (9.29 g, 75% Yield). NMR and microanalysis (C, H, N) are consistent with the final, desired compound. Chiral HPLC, 16.92 minutes, [Chiralcel OD (250×4.6 mm), 98:2 heptane/ethanol @ 0.8 mL/min, UV @ 285 nm, 18.14] shows the title compound as 95.5% e.e. mp=84-85° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3OCCO3)[CH:13]=2)=[N:5][C:4]([NH2:23])=[N:3]1.Cl.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=2)=[N:5][C:4]([NH2:23])=[N:3]1
Reactant: C1CCNCC1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(C2OCCO2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-N5 -[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (106 mg) in tetrahydrofuran (2 ml) was stirred with 2N hydrochloric acid (0.2 ml) for 1/2 h at room temperature. The mixture was treated with piperidine (0.5 ml), stirred at room temperature for 1 h, and then treated with sodium borohydride (75 mg). After a further 1 h, the mixture was diluted with water, and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo. The resulting oil was crystallised from a mixture of benzene and cyclohexane to yield the title compound (60 mg) m.p. 93°-4°. TLC silica (methanol:ammonia 80:1) Rf 0.5.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7](O)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C:6]([CH3:20])=[CH:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: CN(C)c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC1=CO[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of dihydroartemisinin (500 mg, 1.86 mmol) in dichloromethane (28 ml) at 0° C. under nitrogen was added 4-(N,N-dimethylamino)pyridine (37 mg) and trifluoroacetic anhydride (0.79 ml, 5.58 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The solution was then concentrated in vacuo. The residue was purified by flash chromatography (SiO2; ether:hexane from 0.5:9.5 to 1.5:8.5) to give 9,10-anhydro-10-deoxoartemisinin (9,10-anhydroartemisinin) (180 mg, 25%) as a white solid. M.p. 100° C.; [α]D20.5 +155.74° (c. 0.0101 in CHCl3); νmax (film): 2948, 2922, 2862, 2850, 1684, 1432, 1372, 1334, 1198, 1178, 1158, 1142, 1114, 1078; 1028, 1016, 992, 954, 944, 904, 880, 828, 812; δH: 6.18 (1H, s, H-10), 5.54 (1H, s, H-12), 2.40 (1H, ddd, J=17.1, 13.2, 4.14 Hz, H-9), 2.00-2.09 (2H, m), 1.88-1.95 (1H, m), 1.07-1.73 (8H, m), 1.58 (3H, d, J=1.37 Hz, H-16) 1.42 (3H, s, H-14), 0.98 (3H, d, J=5.98 Hz, H-15); m/z (EI): 380 (M+); Anal. Calc. for C15H22O4: C, 67.67; H, 8.27. Found: C, 67.63; H, 8.51.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C([S-])C.[Na+].[CH2:26]([N:28](CC)CC)[CH3:27].CN(C)C=O>O>[CH2:26]([NH:28][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:27]
Reactant: CCN(CC)CC
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3C2=O)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC1=C(c2ccc(OC)cc2)C(=O)c2cc(OC)ccc21
Temperature: 80 °C
Yield: 89 %

Procedure:
A mixture of 3-Bromo-6-methoxy-2-(4-methoxyphenyl)-1H-inden-1-one (150 mg, 0.4345 mmol), sodium ethanethiolate (91.4 mg, 1.09 mmol), and triethyl amine (0.5 ml) in N,N, dimethyl formamide (3 mL) was heated at 80° C. for 24 h. The reaction was cooled to room temperature was poured into water and extracted with ethyl acetate. The organic extracts were washed with brine and were dried over MgSO4. Evaporation and flash chromatography (10% ethyl acetate/petroleum ether) gave (126 mg, 89% yield) of the product as a dark red solid: mp 88-90° C.; MS m/e 327 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[OH:7][C:8]([CH3:19])([CH3:18])[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:19][C:8]([OH:7])([CH3:18])[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: Nc1nc[nH]n1
Reactant: CC(C)(O)COC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(O)COC1CCC(Nc2nc[nH]n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.3 %

Procedure:
To a solution of 3-amino-1H-1,2,4-triazole (1.46 g) and 4-(2-hydroxy-2-methylpropoxy)cyclohexanone (3.25 g) in acetic acid (30 mL) was added sodium triacetoxyborohydride (5.53 g), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/10→06/94 (volume ratio)] to give colorless amorphous 2-methyl-1-{[4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol (2.84 g, 64%) as a diastereomixture.
Reaction SMILES: [CH3:1][C:2]([C:5](=[N:10][NH:11][C:12](=[O:34])[C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[Cl:33])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].CI.[C:37](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:4][C:2]([C:5](=[N:10][N:11]([CH3:37])[C:12](=[O:34])[C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[Cl:33])[C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:1])[CH3:3]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)NN=C(C(C)(C)C)C(C)(C)C)c(Cl)cc2F)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN(N=C(C(C)(C)C)C(C)(C)C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 20.3 %

Procedure:
A mixed solution of 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid, 2-[1-(1,1-dimethylethyl)-2,2-dimethylpropylidene]hydrazide (0.48 g), excess of methyl iodide and potassium carbonate (0.132 g) in acetonitrile (20 ml) was heated at reflux temperature overnight. The mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and brine. The organic phase was washed with brine (×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluted with a mixed solvent of ethyl acetate and hexane (1:4 to 1:2) to give the titled compound (0.25 g) along with its, 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid, 2-[1-(1,1-dimethylethyl)-2,2-dimethylpropylidene]-1-methylhydrazide (0.1 g, Compound No. 6-8)
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[Cl-].[Ca+2].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=1>C1C2C(=CC=CC=2)CCC1.C1(C)C=CC=CC=1>[CH3:24][C:19]1[CH:18]=[C:17]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=2)[CH:22]=[CH:21][C:20]=1[CH3:23]
Reactant: Cc1cccc(N)c1
Reactant: Cc1ccc(N)cc1C
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccc2c(c1)CCCC2
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccc(C)c(C)c2)c1
Temperature: 0 °C
Yield: 42.7 %

Procedure:
In a 500-ml four-necked flask were charged 56 ml of 1,2,3,4-tetrahydronaphthalene (boiling point: 207° C.) as a solvent and 45.0 g (0.42 mol) of m-toluidine, followed by the addition of 25.6 g (0.23 mol) of anhydrous calcium chloride and 30.8 g (0.23 mol) of anhydrous aluminum chloride under stirring. After stirring at an internal temperature of 100 to 120° C. for 30 minutes under a nitrogen atmosphere, the reaction mixture was added with 50.9 g (0.42 mol) of 3,4-xylidine. The resulting mixture was reacted at an internal temperature of 210 to 220° C. for 3 hours. After cooling, the reaction mixture was added with 126 ml of toluene, followed by charging in 160 g of ice water. The resulting mixture was stirred and then, allowed to stand, whereby a water layer was separated out. The organic layer was washed successively with 150 ml of a 5% aqueous solution of hydrochloric acid, 100 ml of a 5% aqueous solution of sodium bicarbonate and 100 ml of water. From the organic solvent, the distillate at 134 to 135° C. and a vacuum degree of 0.4 to 0.5 Torr was collected, whereby 37.9 g (yield: 42.7%) of the title compound was obtained as a slightly yellow oil. As a result of HPLC. analysis (column: YMC-A-312, detection UV: 280 nm, flow rate: 1.0 ml/min, eluent: acetonitrile/water=8/2), the compound was found to have a purity of 99.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[C:37]2[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:35][CH:36]=2)[N:31]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:30]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[N:8]([CH2:28][C:29]2[C:37]3[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=4)=[CH:35][CH:36]=3)[N:31]([CH2:48][C:49]3[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=3)[N:30]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(Cl)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridine-2(1H)-one (0.400 g, 1.23 mmol) and potassium carbonate (0.171 g, 1.23 mmol) suspended in dimethylformamide (5 mL) was added 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-6-amine (0.522 g, 1.23 mmol) as a solution in dimethylformamide (2 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound as a solid. 1H NMR (DMSO-d6) δ 7.90 (d, J=7.3 Hz, 1H), 7.75-7.67 (m, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.07-7.03 (m, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 6.59 (d, J=7.3 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 5.31 (s, 2H), 5.29 (s, 2H), 4.48 (d, J=4.3 Hz, 2H), 3.71 (s, 3H), 3.69 (s, 3H). HRMS (M+1)=710.1557.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[CH3:16][S:17]SC.CI>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([S:17][CH3:16])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CSSC
Reactant: Clc1ncnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CSc1cc2ncnc(Cl)c2s1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 20 (shown in the scheme 4) (200 mg, 1.18 mmol) in THF (11 mL) was added n-BuLi (566 μL, 1.42 mmol, 2.5M in THF) very slowly at −78° C. and the mixture was stirred for 15 min at the same conditions. A solutions of dimethyl disulfide (160 uL, 1.77 mmol) and MeI (110 μL, 1.77 mmol) in THF (1 mL) was added drop wise. The reaction mixture was stirred for 2 h at −78° C., quenched with saturated aqueus NH4Cl solution, and extracted with DCM. The extract was dried over anhydrous Na2SO4 and concentrated to afford the title compound 280 (210 mg, 82% yield) as a yellowish solid. MS (m/z): 217.0(M+H) (found).