Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.[Br:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.CO.[OH-].[Na+]>O1CCOCC1>[Br:33][C:34]1[CH:35]=[C:36]([C:20]2[S:21][C:17]3[C:16]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)=[C:15]([C@H:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:8][OH:7])[C:24]([CH3:25])=[CH:23][C:18]=3[N:19]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 90 °C
Yield: 35.9 %

Procedure:
To a solution of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (310 mg, 0.577 mmol) in dioxane (5 mL), was added 3-bromophenylboronic acid (173 mg, 0.865 mmol), Ph(PPh3)4 (33 mg, 0.029 mmol) 2N K2CO3 (850 μL) in sealed tube. The reaction mixture was heated at 90° C. for 3hs. Then the reaction was cooled down and to the mixture was added MeOH (5 mL), 2N NaOH (1.5 mL) and heated at 45° C. After the reaction was finished, the reaction was washed by water, extracted by EtOAc. The organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product (110 mg, 36%). LCMS-ESI+: calc'd for C26H25BrClNO2S: 530.0 (M+H+); Found: 530.2 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15].[CH3:17]O>>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (6 mL) was added dropwise to a solution of 2-bromo-4-fluorophenylacetic acid (5.0 g) in methanol (50 mL), and the reaction solution was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate. The solution was filtered through a silica gel pad (carrier: Chromatorex NH), and the filtrate was concentrated under reduced pressure to obtain methyl 2-bromo-4-fluorophenylacetate (5.53 g). A solution of methyl 2-bromo-4-fluorophenylacetate (2.0 g) in DMF (5 mL) was added to a suspension of sodium hydride (containing mineral oil at 40%, 356 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (1.82 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature for three hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Hydrazine monohydrate (8 mL) was added to a solution of the resulting crude purified methyl 5-chloro-2-(2-bromo-4-fluoro)phenylpentanoate (2.75 g) in ethanol (20 mL), and the reaction solution was heated under reflux for 3.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 1.157 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28].C1(C2OC3C=CC=CC=3C=2C(=O)C2C=CC(O)=CC=2)C=CC=CC=1.C(N(CC)CCCCl)C>>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([C:13]2[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[O:10][C:9]=2[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:22])=[CH:20][CH:19]=1)[CH3:28]
Reactant: Cc1cc(C)cc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)c1
Reactant: CCN(CC)CCCl
Agent: CCN(CC)CCCCl
Agent: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3cc(C)cc(C)c3)oc3ccccc23)cc1

Procedure:
Reaction of 2-(3,5-dimethylphenyl)-3-(4-hydroxybenzoyl)benzofuran with 2-diethylaminoethyl chloride by the procedure described in Example 1 for 2-phenyl-3-(4-hydroxybenzoyl)benzofuran and 3-diethylaminopropyl chloride gives 3-[4-(2-diethylaminoethoxy)benzoyl]-2-(3,5-dimethylphenyl)-benzofuran.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]1>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:58][CH:59]4[CH2:60][CH2:61][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:63][CH2:64]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[5-(Cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid from example D.c1 (3.98 g; 8.0 mmol), triethylamine (2.43 g; 24.0 mmol) and HOBt (1.08 g; 8.0 mmol) is stirred in dry dichloromethane (40 mL) for 30 min, before addition of EDC (1.84 g; 9.6 mmol). The reaction mixture is stirred for one hour at ambient temperature. After addition of tert-butyl 4-amino-piperidine-1-carboxylate hydrochloride (2.27 g; 9.6 mmol) the reaction mixture is stirred at ambient temperature until the starting material is consumed according to LC-MS and chromatographed on silica gel (ethylacetate/cyclohexane—1:1) to yield the title compound as colorless foam.
Reaction SMILES: Br[C:2]1[C:3]([NH:18][C@@H:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[OH:28])=[N:4][C:5]([O:16][CH3:17])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1.[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC.[F-].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([CH:29]=[CH2:30])[C:3]([NH:18][C@@H:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[OH:28])=[N:4][C:5]=1[O:16][CH3:17]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1nc(-c2ccc(Cl)cc2Cl)c(OC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 120 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of (1R,2S)-1-{[3-bromo-5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (150 mg, 0.31 mmol) in DMF (1.6 mL) is added Pd(PPh3)4 (7 mg, 6 μmol), and tributyl vinyl tin (114 mg, 0.36 mmol). The reaction is heated at 120° C. overnight. Sat. aq. KF (15 mL) is added and the mixture is stirred at rt for 1 hr. Extract with CH2Cl2 (5×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 15% ethyl acetate/hexanes) to afford 132 mg (38%) of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxy-3-vinylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol as a solid: 1H NMR (CDCl3) δ 3.08-3.12, 3.28-3.34, 3.93, 4.82, 5.46-5.49, 5.54-5.67, 6.09-6.13, 6.77-6.84, 7.28-7.50; MS (ESI+) for C20H17Cl2N3O2 m/z 402 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH:12]2[CH2:14][CH2:13]2)[CH:7]=1)=[O:5])[CH3:2].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:37]I>C(#N)C.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH:12]2[CH2:13][CH2:14]2)[C:7]=1[I:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C2CC2)nn1C
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(I)c(C2CC2)nn1C
Temperature: 25 °C
Yield: 103.3 %

Procedure:
A solution of 500 mg (2.57 mmol) of ethyl-3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylate (prepared from ethyl-3-cyclopropyl-1H-pyrazole-5-carboxylate in accordance with Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824) in 5 ml of acetonitrile is admixed with 706 mg (1.28 mmol) of ammonium cerium(IV) nitrate and 392 mg (1.53 mmol) of iodine and heated under reflux for three hours and afterstirred overnight at room temperature. The reaction mixture is diluted with water and ethyl acetate, and the organic phase is washed with saturated sodium thiosulphate solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. Chromatographic purification gives 506 mg of ethyl-3-cyclopropyl-4-iodo-1-methyl-1H-pyrazole-5-carboxylate (66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]3[CH2:13][CH2:14][CH:9]2[CH2:10][CH2:11]3)=[CH:4][C:3]=1[O:15]COC.[ClH:19].O1CCOCC1>C1COCC1.CO>[ClH:19].[CH:12]12[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([OH:15])[CH:4]=3)[CH:9]([CH2:14][CH2:13]1)[CH2:10][CH2:11]2
Reactant: COCOc1cc(N2C3CCC2CC3)ccc1F
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Oc1cc(N2C3CCC2CC3)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(4-fluoro-3-(methoxymethoxy)phenyl)-7-azabicyclo[2.2.1]heptane (D81) (423 mg, 1.683 mmol) in THF (10 mL) and MeOH (1 mL) was added 4M solution of HCl in 1,4-dioxane (2.104 mL, 8.42 mmol). The mixture was stirred overnight at RT. The reaction mixture was evaporated in vacuo to give the title compound (427 mg), which was carried over to next step without purification. LCMS (A): m/z [(M−HCl)+H]+ 208, Cl2H14FNO.HCl requires 243 (acidic).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([F:10])[CH:3]=1.CC(O)=[O:13].OO.C([O-])(O)=O.[Na+].[OH2:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:9])(=[O:13])=[O:22])=[C:4]([F:10])[CH:3]=1
Reactant: CC(=O)O
Reactant: O
Reactant: CSc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a 50 ml sealable tube is introduced 4-Bromo-2-fluoro-1-methylsulfanyl-benzene (as obtained in preparation 63, 5 g, 22.6 mmol) followed by 4.6 ml AcOH. 9.3 ml of a 30% H2O2 solution in H2O is added at RT. The tube is sealed and the resulting colorless biphasic solution is stirred at 100° C. for 2 h. After cooling, the pH of the medium is set basic with solid NaHCO3 and then extracted with CH2Cl2 several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The title compound is obtained as a colorless solid, Rt=0.916 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([O:13][C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=O)=[CH:2]1.O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:13])=[CH:2]1
Reactant: O=C1OC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Reactant: NCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C(=O)N1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of 2,3-bis(1H-indol-3-yl)maleic anhydride (100 mg, 0.3 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) and dissolved in DMF (10 mL) and water (10 mL) was added benzylamine (0.13 mL, 1.2 mmol), and the whole was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DMF, and the concentrate was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 2,3-bis(1H-indol-3-yl)-N-benzylmaleimide (110 mg, 86.6%) as red solids.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1)[CH3:3].S(Cl)([Cl:14])=O>ClCCl>[ClH:14].[CH3:1][N:2]([CH2:4][C:5]1[O:11][C:8]([CH2:9][Cl:14])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)Cc1ccc(CCl)o1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine 5-[(dimethylamino)methyl]-furfuryl alcohol (25 g) and dichloromethane (100 mL). Cool to 0° C. Add dropwise, thionyl chloride (20 mL) at such a rate that the reaction does not rise above 5° C. After 0.5 hours, evaporate in vacuo to give a residue, Recrystallize the residue from ethanol to give the title compound: mp; 164°-165° C. (dec).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[N:3]=1.[O-:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>O>[CH3:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[N:3]=[C:2]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1
Reactant: [O-]c1ccccc1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)cc(OC)c1OC
Agent: [Na+]
Solvent: O
Product: COc1cc(Nc2nc(C)cc(Oc3ccccc3)n2)cc(OC)c1OC
Yield: 12.9 %

Procedure:
4-Chloro-6-methyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine (0.30 g, 0.97 mmol) was added to a solution of sodium phenoxide (0.97 mmol) [prepared from phenol (0.091 g, 0.97 mmol) and NaH (60% in mineral oil; 0.039 g, 0.97 mmol)], and heated to 80° for 17 h with stirring. Water was added and the mixture was extracted with CH2CH2 (2×30 ml), the organic phases were dried (MgSO4) and evaporated to a yellow oil. The residue was subjected to chromatography (silica, 2% methanol/CH2CH2) to give the title compound (0.046 g). A portion was recrystallised from methanol to give an off white crystalline solid m.p. 175°. δH (CDCl3) 2.38 (3H, s), 3.64 (6H, s), 3.77 (3H, s), 6.19 (1H, s), 6.78 (2H, s), 6.95 (1H, s), 7.15 (2H, d, J 7.5 Hz), 7.23 (1H, m) and 7.39 (2H, t, J 7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[F-:19].[Cs+]>C1S(=O)(=O)CCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][F:19])[N:3]=1
Reactant: [F-]
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Agent: [Cs+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CF)n1
Temperature: 100 °C

Procedure:
To a solution of 2,4-diamino-6-bromomethyl-5-(2,4-dichlorophenyl) pyrimidine (1.04 g) in tetramethylene sulphone (4.5 ml) was added cesium fluoride (1 g). The mixture was stirred and heated at 100° C. for 4 hours, cooled, diluted with water and extracted with chloroform. The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (silica: 19:1:0.1 dichloromethane/methanol/triethylamine) to give the title compound, which was recrystallised from ethanol. 0.19 g, mp. 210°-211° C.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH2:29][C@H:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:25]=[CH:26][C:27]=1[F:28])=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:29][C@H:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CCOC(=O)[C@@H](C)Cc1ccc(F)c(NC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@@H](C)Cc1ccc(F)c(NC(=O)[C@@H](N)C(C)C(F)(F)F)c1
Reaction time: 8 h

Procedure:
2.60 g (5.07 mmol) of ethyl (2S)-3-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorophenyl]-2-methylpropanoate (Example 36A, mixture of 4 isomers) were dissolved in a mixture of 10.7 ml of ethanol and 10.7 ml of THF. The solution was inertized with argon, and 322 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen overnight. After filtration through kieselguhr and washing with dichloromethane/methanol, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1) and separated. This gave 1.39 g of the title compound as diastereomer mixture 1 (72.4% of theory).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[C:8]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:7][N:6]=[C:5]2[O:13][CH2:14][CH2:15][C:4]=12.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.C(OCC)C>[CH3:17][Si:2]([CH3:1])([CH3:16])[C:3]1[C:8]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:7][N:6]=[C:5]2[O:13][CH2:14][CH2:15][C:4]=12
Reactant: C[Si](C)(C)c1c(CCCO)cnc2c1CCO2
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: CCOCC
Product: C[Si](C)(C)c1c(CCC=O)cnc2c1CCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
A mixture of 3-[4-(trimethylsilyl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl]propan-1-ol (6.54 g, 26.0 mmol) and orthoiodoxybenzoic acid (9.47 g, 33.8 mmol) in dimethyl sulfoxide (80 mL) was stirred at room temperature for 5 hr. The reaction solution was diluted with diethyl ether, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→70/30) to give the title compound (5.69 g, yield 87%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=1)[C:22]#[N:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([NH:18][C:19]1[CH:20]=[C:21]([C:22]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:23]=2)[CH:24]=[CH:25][N:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCCCCNc1cc(C#N)ccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCNc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Yield: 18.1 %

Procedure:
Methyl thiosalicylate (0.44 g, 2.6 mmol) and 2-(hexylamino)isonicotinonitrile (0.26 g, 1.3 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.40 ml, 2.9 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs, subjected to a silica gel (50 g) chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.08 g, 18%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C([Li])CCC.[Br:16]C(Cl)(Cl)C(Br)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[Br:16][C:9]1[N:4]2[N:3]=[C:2]([CH3:1])[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc2ccccn2n1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 2-methylpyrazolo[1,5-a]pyridine (Reference; Chem. Pharm. Bull., 1983, 31, 4568–5572) (1.0 g) dissolved in tetrahydrofuran (20 mL) was added n-butyllithium (2.66 M hexane solution; 3.7 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (2.7 g) in tetrahydrofuran (5 mL) dropwise, and stirring was continued for 30 minutes. After adding saturated aqueous ammonium chloride to the obtained reaction mixture, the temperature was raised to room temperature, water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic extract was separated, then washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (1.34 g) was obtained as a yellow oil from the n-hexane:ethyl acetate (10:1) fraction.
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].O.[C:8]([OH:12])(=[O:11])[CH:9]=O.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1]([N:2]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1)[CH2:9][C:8]([OH:12])=[O:11])=[O:6])[CH3:5]
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=CC(=O)O
Reactant: CCOC(N)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N(CC(=O)O)n1nnc2ccccc21
Temperature: 15 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Ethyl carbamate (69.0 g, 774.5 mmol), glyoxylic acid hydrate (71.3 g, 774.5 mmol) and benzotriazole (92.0 g, 774.5 mmol) were dissolved in toluene (2.3 1) and the mixture was heated with distillation for 3 h to precipitate the product. The mixture was diluted with toluene (totally 2.3 1) and stirred at 15° C. overnight. The resultant precipitate was collected by filtration, washed with toluene (160 ml) and dried to afford the title compound (196.06 g, 96%): mp. 189°-192° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C1CCN2C(=NCCC2)CC1.[Cl:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[N:31]=[C:32]=[O:33]>ClCCCl.C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[N:31]1[C:7](=[O:9])[CH:2]2[CH2:3][O:4][CH2:5][CH2:6][N:1]2[C:32]1=[O:33]
Reactant: O=C(O)C1COCCN1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1C2COCCN2C(=O)N1c1ccc([N+](=O)[O-])cc1Cl
Temperature: 160 °C
Yield: 54.2 %

Procedure:
To a stirred solution of 3-morphline carboxylic acid (0.100 g; 0.627 mmol), DBU (187 μL; 1.25 mmol) in 1,2-dichloroethane (2.8 mL) was added 2-chloro-4-nitrophenylisocyanate (0.149 g; 0.752 mmol) and the resulting mixture was heated at 160° C. in the microwave for 10 min. The reaction was diluted with methylene chloride (15 mL), washed with 1N HCl (10 mL), sat. NaHCO3 (10 mL) and concentrated under vacuum to give the crude product. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 40% to give 106 mg of 2-(2-chloro-4-nitrophenyl)tetrahydro-1H-imidazo[5,1-c][1,4]oxazine-1,3(2H)-dione, 1.1.21, (54%).