Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5](=[O:8])[N:6]([CH2:20][CH3:21])[CH:7]=1
Reactant: CCI
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(Br)cc(C(F)(F)F)c1=O
Temperature: 25 °C
Yield: 67 %

Procedure:
In a round bottom flask equipped with a stir bar and purged with nitrogen was added 5-bromo-3-(trifluoromethyl)pyridin-2-ol (1.0 equiv.), potassium carbonate (2.0 equiv.) and DMF (0.2 M). The mixture was stirred at room temperature and iodoethane (1.2 equiv.) was added via syringe. The mixture was warmed to 35° C. for 4 hours at which time LCMS indicated full conversion. The reaction was worked up by partitioning between water and ethyl acetate, the aqueous phase was extracted 3 more times with ethyl acetate, the organics were combined, washed with brine, dried with sodium sulfate, filtered and concentrated to yield 5-bromo-1-ethyl-3-(trifluoromethyl)pyridin-2(1H)-one (67%). 1H NMR (400 MHz, <cdcl3>) δ ppm 1.32-1.50 (m, 3H) 4.04 (q, J=7.17 Hz, 2H) 7.63 (br. s., 1H) 7.78 (br. s., 1H). LCMS (m/z) (M+H)=269.1/271.1, Rt=0.72 min
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.[CH2:32]([NH2:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>>[CH2:32]([NH:34][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1)[CH3:33]
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCNc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCOCC3)cc2OC)o1
Yield: 86 %

Procedure:
As described for example 106, 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine (100 mg, 0.23 mmol) using ethylamine instead of dimethylamine hydrochloride and potassium carbonate was converted to the title compound (88 mg, 86%) which was obtained as a white solid. MS: m/e=448.3 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[C:4](OCOC)[C:3]=1[C:16](=[O:18])C>C(O)C>[CH3:6][O:8][CH2:9][O:10][C:5]1[CH:4]=[C:3]([CH:2]=[CH:7][C:6]=1[O:8][CH2:9][O:10][CH3:11])[CH:16]=[O:18]
Reactant: COCOc1cc(O)c(C(C)=O)c(OCOC)c1
Solvent: CCO
Product: COCOc1ccc(C=O)cc1OCOC
Yield: 218.6 %

Procedure:
In 260 ml of ethanol were dissolved 33.37 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone obtained in Production Example 11 and 32.20 g of the 3,4-bis(methoxymethoxy)benzaldehyde obtained in Production Example 24, and 300 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution and the mixture was stirred for 24 hours to effect a reaction. After the reaction, the pH value of the reaction liquid was adjusted to about 6 by 6N hydrochloric acid, and the formed precipitate was recovered by filtration, washed with water and dried to obtain 53.17 g (yield=87.9%) of 2'-hydroxy-3,4,4',6'-tetrakis(methoxymethoxy)chalcone.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([SH:15])[CH2:13][SH:14]>CCO>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]2[S:15][CH2:12][CH2:13][S:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: SCCS
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C2SCCS2)cc1
Yield: 85.1 %

Procedure:
Following the general procedure employed in Example 1, 38.58 gm (0.255 moles) of 4-nitrobenzaldehyde and 24.71 gm (0.262 moles) of 1,2-ethanedithiol gave, after crystallization from absolute EtOH, 49.23 gm (0.2169 moles) of an orange colored solid (85% yield) m.p. 80°-82° C. Elemental analysis for C9H9NO2S2 :
Reaction SMILES: C([Li])CCC.C1COCC1.[CH3:11][NH:12][CH3:13].C1COCC1.Cl[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([OH:26])[CH:25]=1>C(O)C>[CH3:11][N:12]([CH3:13])[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([OH:26])[CH:25]=1
Reactant: Oc1cncc(Cl)c1
Reactant: CNC
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)c1cncc(O)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At −70° C., a 1.59 M normal-butyllithium/THF solution (14.6 ml) was added to s 2 M dimethylamine/THF solution (11.6 ml), followed by stirring for 10 minutes. This was warmed to 0° C., and 3-chloro-5-hydroxypyridine (1.00 g) was added thereto, followed by stirring overnight at room temperature. Ethanol (15 ml) was added, and the solvent was evaporated under reduced pressure. Water was added to the residue, followed by extraction with chloroform. The organic layer 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 column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain 3-dimethylamino-5-hydroxypyridine (176 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH2:27]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: OCc1cnccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2cnccn2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
To a mixture of (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (0.57 g, 2.0 mmol), pyrazin-2-yl-methanol [CAS 6705-33-5] (0.25 g, 2.3 mmol), and triphenylphosphine (0.57 g, 2.2 mmol) in THF (20 mL) is added DEAD (0.36 mL, 2.3 mmol). The mixture is stirred at room temperature overnight and partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (2×), and the combined organic phase is dried (Na2SO4) and concentrated. The crude material is purified by SCX chromatography followed by silica gel chromatography eluting with 20% (10% 2M MeOH/CH2Cl2)/80% CH2Cl2 to 70% (10% 2M MeOH/CH2Cl2)/30% CH2Cl2 to yield 12 mg of the title compound. MS (ES+) 367.3
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][C:51]=1[NH:52][C:53](OC1C=CC([N+]([O-])=O)=CC=1)=[O:54])[C:45]([O:47][CH3:48])=[O:46].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:53]([NH:52][C:51]2[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][C:42]=2[Cl:41])=[O:54])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(Cl)c1
Reaction time: 8 h
Yield: 131.8 %

Procedure:
To a solution of 181 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.114 mL of triethylamine in 3.0 mL of THF was added 171 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate at room temperature, followed by stirring overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 352 mg of methyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)-3-chlorobenzoate as a crude product. ESI+: 656
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.[CH3:12][CH:13]([NH2:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:15][CH:13]([CH3:14])[CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)N
Reactant: Clc1nc2ccc(Br)cc2s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2ccc(Br)cc2s1
Yield: 64 %

Procedure:
A microwave reaction vial was charged with 6-bromo-2-chlorobenzo[d]thiazole (300 mg, 1.21 mmol), propan-2-amine (75 mg, 1.27 mmol), triethylamine (183 mg, 1.81 mmol) and 2.4 mL DMF. The vial was sealed, and the mixture was irradiated in the microwave for 20 min at 150° C. The reaction mixture was concentrated twice from toluene and purified by silica gel chromatography (0-50% 90/10 CH2Cl2/MeOH in CH2Cl2), which provided 6-bromo-N-isopropylbenzo[d]thiazol-2-amine (210 mg, 64%) as a white solid. MS (ESI pos. ion) m/z calc'd for C10H11BrN2S: 271.2/273.2. found 271.0/273.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][CH:21]=[C:22]([Cl:25])[CH2:23]Cl>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]([CH2:23][C:22]([Cl:25])=[CH:21][Cl:20])[C:14]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Reactant: ClC=C(Cl)CCl
Product: Cc1c(C)n(CC(Cl)=CCl)c2c(OCc3ccccc3)nncc12
Yield: 8 %

Procedure:
The title compound was prepared as ocherous powdery crystals in 8.0% yield in a similar procedure to that described in Example 41 by using 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine and 1,2,3-trichloro-1-propene.
Reaction SMILES: Cl.C([N:9]1[CH2:18][CH2:17][C:16]2[C:15]([C:19]3[CH:23]=[C:22]([CH3:24])[S:21][CH:20]=3)=[N:14][C:13]([CH:25]([CH3:27])[CH3:26])=[N:12][C:11]=2[CH2:10]1)C1C=CC=CC=1.[Cl:28]C(OC(Cl)=O)C>ClCCCl>[ClH:28].[CH:25]([C:13]1[N:14]=[C:15]([C:19]2[CH:23]=[C:22]([CH3:24])[S:21][CH:20]=2)[C:16]2[CH2:17][CH2:18][NH:9][CH2:10][C:11]=2[N:12]=1)([CH3:27])[CH3:26]
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1cc(-c2nc(C(C)C)nc3c2CCN(Cc2ccccc2)C3)cs1
Agent: Cl
Solvent: ClCCCl
Product: Cc1cc(-c2nc(C(C)C)nc3c2CCNC3)cs1
Temperature: 95 °C

Procedure:
A solution of 7-benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride (0.133 g) in 1,2-dichloroethane (7 mL) was treated with 1-chloroethylchloroformate (0.105 mL). The mixture was heated at 95° C. for 16 h, concentrated, dissolved in MeOH, and heated at 50° C. for an additional 2 h. The mixture was concentrated and chromatographed on SiO2 (2 M NH3 in MeOH/CH2Cl2). MS (ESI): exact mass calcd. for C15H19N3S, 273.13; m/z found, 274.3 [M+H]+. 1H NMR (MeOH-d4): 7.81-7.80 (m, 1H), 7.36-7.35 (m, 1H), 4.42 (s, 2H), 3.55 (t, J=6.0, 2H), 3.25 (t, J=6.0, 2H), 3.19 (m, 1H), 2.55 (s, 3H), 1.35 (d, J=7.2, 6H).
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([OH:20])=O)[CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N+:44]([C:47]1[CH:48]=[CH:49][C:50]([O:53][C:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=2)=[N:51][CH:52]=1)([O-:46])=[O:45]>CN(C=O)C>[N+:44]([C:47]1[CH:48]=[CH:49][C:50]([O:53][C:54]2[CH:59]=[CH:58][C:57]([NH:60][C:18](=[O:20])[CH2:17][N:14]3[CH2:13][CH2:12][N:11]([CH2:1][C:2]4[CH:10]=[CH:9][C:8]5[O:7][CH2:6][O:5][C:4]=5[CH:3]=4)[CH2:16][CH2:15]3)=[CH:56][CH:55]=2)=[N:51][CH:52]=1)([O-:46])=[O:45]
Reactant: O=C(O)CN1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(Cc2ccc3c(c2)OCO3)CC1)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (4-piperonylpiperazin-1-yl)acetic acid (13.9 g, 50 mmol) was suspended in DMF (400 mL), and to the resulting suspension were added 1-hydroxybenzotriazole monohydrate (8.42 g, 55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.5 g, 55 mmol) and 4-(5-nitropyridin-2-yloxy)phenylamine (11.6 g, 50 mmol) under ice cooling. The resulting solution was stirred for 6 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate, and washed with a saturated sodium bicarbonate solution and brine. The organic layer was left for standing overnight at room temperature, and the resulting precipitated crystals were collected by suction filtration, to thereby yield 12.8 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7]Cl)[CH2:4][CH3:5])[CH3:2].CN(CCCCl)C.[CH3:16][C:17]1[CH:35]=[C:20]2[NH:21][C:22](=[O:34])[C:23]3[CH:28]=[N:27][C:26]4[N:29]([CH3:33])[N:30]=[C:31]([CH3:32])[C:25]=4[C:24]=3[N:19]2[N:18]=1>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:21]1[C:22](=[O:34])[C:23]2[CH:28]=[N:27][C:26]3[N:29]([CH3:33])[N:30]=[C:31]([CH3:32])[C:25]=3[C:24]=2[N:19]2[N:18]=[C:17]([CH3:16])[CH:35]=[C:20]12)[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: Cc1cc2[nH]c(=O)c3cnc4c(c(C)nn4C)c3n2n1
Agent: CN(C)CCCCl
Product: CCN(CC)CCn1c(=O)c2cnc3c(c(C)nn3C)c2n2nc(C)cc12

Procedure:
By substituting diethylaminoethyl chloride for the dimethylaminopropyl chloride and utilizing the 2,8,10-trimethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one product of Example 12 instead of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]- pyrido[3,4-e]pyrimidin-5(8H)-one in the procedure of Example 4, 4-[2-(diethylamino)ethyl[-2,8,10-trimethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.[CH:18]1([C:21]2[C:22]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:31]3[CH2:36][CH2:35][N:34]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[CH3:16])=[O:13])[CH2:33][CH2:32]3)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=2)[CH2:19][CH2:20]1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 76.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (255 mg) described in Preparation Example 29 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (271 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 87, the title compound (390 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:13][CH2:14][CH3:15])[C:10]([NH2:12])=[S:11].C(N(CC)CC)C.Br[CH:24]([CH3:35])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=O>C(O)C>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:10]([N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:14][CH3:15])[S:11][C:24]=1[CH3:35]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCN(C(N)=S)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)c1ccc(Cl)cc1Cl
Temperature: 78 °C

Procedure:
To 1.07 g of N-(2,4-dichlorophenyl)-N-propylthiourea (Compound 10-1) in 6 ml of ethanol, there is added 1 ml of triethylamine followed, dropwise, by 1.3 g of 2-bromo-1-(2,4-dichlorophenyl)propan-1-one (Compound 1-1). The reaction mixture is heated for 3 hours at 78° C., it is evaporated to dryness and then the residue is taken up in dichloromethane. The organic phase is washed with water, dried over sodium sulphate and evaporated to dryness under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][S:12]([CH:15]([CH:20]([CH3:22])[CH3:21])[C:16](OC)=[O:17])(=[O:14])=[O:13])[N:4]=1.C([NH2:25])=O.C[O-].[Na+].Cl>CN(C)C=O.O.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][S:12]([CH:15]([CH:20]([CH3:22])[CH3:21])[C:16]([NH2:25])=[O:17])(=[O:14])=[O:13])[N:4]=1
Reactant: NC=O
Reactant: COC(=O)C(C(C)C)S(=O)(=O)Nc1nc(OC)cc(OC)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(NS(=O)(=O)C(C(N)=O)C(C)C)n1
Temperature: 100 °C

Procedure:
A solution of the product of Example 1 (3.0 g) and formamide (1.22 g) in dimethylformamide (10 ml) was heated to 80° C. Sodium methoxide (3.3 ml of a 25% w/v methanol solution) was slowly introduced with stirring. The reaction mixture was maintained at about 100° C. for 4 hours prior to addition to water (150 ml) and acidification (hydrochloric acid). The product was extracted into ethyl acetate, the ethyl acetate solution being washed with water (twice), dried over magnesium sulfate and run down under vacuum. The residual oil was triturated with a mixture of diethyl and diisopropyl ethers to yield a white solid. The solid was washed thoroughly with the ether mixture and dried. The yield was 1.1 g (39%), mp 147°-50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[O:34])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)c(C)c1
Yield: 55 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (26 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 41 mg (yield 55%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:23])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)(methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 39) (273 mg, 0.70 mmol)and N-methylmorpholine (85 μl, 0.77 mmol) in anhydrous dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (100 μl, 0.77 mmol) and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. O-(Trimethylsilyl)hydroxylamine (250 μl, 2.10 mmol) was then added and the mixture stirred under a nitrogen atmosphere for 1 hour, being allowed to warm to room temperature over this time. The mixture was then quenched with methanol (10 ml) and stirred for 10 minutes. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLCa to afford the title compound as a colourless oil (187 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH:20]1([CH:26]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+].Cl>CCO>[CH:20]1([CH2:26][NH:1][CH2:2][C:3]2[CH:19]=[CH:18][C:6]([O:7][C:8]3[CH:17]=[CH:16][C:11]4[B:12]([OH:15])[O:13][CH2:14][C:10]=4[CH:9]=3)=[CH:5][CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OB1OCc2cc(Oc3ccc(CNCC4CCCCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (150 mg, 0.59 mmol, 1.0 eq.) in EtOH (5.0 mL) was added cyclohexanecarbaldehyde (280 μL, 2.36 mmol, 4.0 eq.). The mixture was stirred at room temperature for 30 minutes. After cooling to 0° C., NaBH4 (89 mg, 0.36 mmol, 4.0 eq.) was added in portions and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was carefully treated with dilute HCl (5 mL) and aqueous phase was extracted with EtOAc (3×10 mL). Combined organic extracts was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 5-{4-[(cyclohexylmethyl-amino)-methyl]-phenoxy}-3H-benzo[c][1,2]oxaborol-1-ol as a white solid. LCMS (m/z) 352 (M+H); 1H NMR (DMSO-d6) δ: 9.08 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.30-7.37 (m, J=8.5 Hz, 2H), 6.95-7.02 (m, 2H), 6.88-6.95 (m, 2H), 4.89 (s, 2H), 3.64 (s, 2H), 2.31 (d, J=6.6 Hz, 2H), 1.67-1.77 (m, 2H), 1.56-1.66 (m, 3H), 1.30-1.44 (m, 1H), 1.02-1.23 (m, 3H), 0.77-0.91 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:3]=1)[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15]
Reactant: O=C1CCC(=O)O1
Reactant: Oc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1cc(Cl)ccc1O
Yield: 49 %

Procedure:
4-Chlorphenol was reacted with succinic anhydride and aluminium chloride in a similar manner to the procedure described in Example 8 (i) to give 3-(5-chloro-2-hydroxybenzoyl)propionic acid (49%, m.p. 172°-173° C). (Found: M+, 228/230. C10H9Cl O4 requires: M, 228/230). (ii) 3-(5-Chloro-2-hydroxybenzoyl)propionic acid was esterified with methanol-hydrogen chloride in a similar manner to the procedure described in Example 1 (i) to give methyl 3-(3-chloro-2-hydroxybenzoyl)propionate (75%).
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:5]=1[F:30])=[N+]=[N-]>[Pd].[Ni]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:5]=1[F:30]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Agent: [Ni]
Agent: [Pd]
Product: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1F

Procedure:
Methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate can be hydrogenated in the presence of appropriate catalyst (such as Pd/C, Pt, Ni) in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.