Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:39]=[CH:38][C:14]([O:15][C:16]3(C=O)[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34]C)[CH:29]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[CH:38][CH:39]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc(C2C=Cc3cc(OC)ccc3C2(C=O)Oc2ccc(OCCN3CCCCC3)cc2)c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(O)c3)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
A solution of 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)-6-methoxynaphthal hydrochloride (0.500 g, 0.96 mmol) in 20 mL of anhydrous methylene chloride under N2 atmosphere was chilled in an acetonitrile-dry ice bath to −20° C. Boron tribromide (1.44 mmol) was added dropwise over 3 minutes by syringe as a 1 M solution (1.44 mL).also in methylene chloride. The resulting mixture was allowed to warm to 0° C. and stirred for 2 hours. The reaction was then poured into a stirring solution of cold saturated sodium bicarbonate (100 mL) and the crude product was extracted with ethyl acetate (4×25 mL). The organic extracts were combined, dried (magnesium sulfate), and concentrated to a oily foam. The crude free base was purified by radial chromatography using 5/95 methanol/methylene chloride. The appropriate fractions were combined and concentrated in vacuo to provide 220 mg (49%) of 1-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(3-hydroxyphenyl)-6-methoxynaphthalene as a white crystalline solid, mp 170-171° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:11])[NH2:10])=[CH:5][CH:4]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[N:11]=1
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To a solution of 4-methylbenzenecarboximidamide hydrochloride (1.70 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1.5 hours. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.05 g (50.0%) of the desired product as a solid.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9](O)=[O:10])[CH2:7][SH:8])=[O:4].[CH:14]1([N:20]=[C:21]=NC2CCCCC2)CCCCC1.Cl.CNC.C(N(CC)CC)C>C(Cl)Cl.CO.C(OC(=O)C)C>[CH3:14][N:20]([CH3:21])[C:9](=[O:10])[C@H:6]([CH2:7][SH:8])[NH:5][C:3](=[O:4])[C:2]([SH:1])([CH3:13])[CH3:12]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CN(C)C(=O)[C@H](CS)NC(=O)C(C)(C)S
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirred solution of N-(2-mercapto-2-methylpropionyl)-L-cysteine (1.0 g) in methylene chloride(4 ml), dicyclohexylcarbodiimide (0.5 g) dissolved in methylene chloride(4 ml) was added dropwise. After the addition, the reaction mixture was stirred for 30 minutes under ice cooling and for 1 hour at room temperature. Dimethylamine hydrochloride(0.2 g) and triethylamine(0.4 ml) dissolved in a mixture of methylene chloride (2 ml) and methanol(1 ml) was added dropwise under ice-cooling. The reaction mixture was stirred for 15 minutes under ice-cooling and 3 hours at room temperature. To the reaction mixture, ethylacetate was added and filtered. The organic layer was washed with water and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.6 g(50%) of the titled compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.B([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22])(O)O>>[F:9][C:8]([F:11])([F:10])[C:7]([C:5]1[S:6][C:2]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=2)[C:21]([OH:23])=[O:22])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C(c1ccc(Br)s1)C(F)(F)F
Reactant: O=C(O)c1cncc(B(O)O)c1
Product: O=C(O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Yield: 82 %

Procedure:
This compound was synthesized from 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanone and 5-borononicotinic acid as described in example 88 step 3 (470 mg, yield 82%). 1H NMR (300 MHz, DMSO-d6) δ 13.74 (br s, 1H), 9.30-9.29 (s, 1H), 9.11-9.10 (m, 1H), 8.59-8.58 (t, J=2.0 Hz, 1H), 8.20-8.19 (m, 1H), 8.07-8.05 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12]1COCC1.IC.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Br)ccc2s1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CSc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 5-bromo-1,3-benzothiazole-2-thiol (3.0 g, 12.19 mmol), dry THF (44 mL), iodomethane (0.80 mL, 12.80 mmol), KOH (0.68 g, 12.19 mmol), and tetra-n-butylammonium bromide (0.39 g, 1.2 mmol) was stirred at rt overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated, aqueous Na2CO3 (50 mL). The organic layer was dried over MgSO4 and then concentrated. The crude material was purified by ISCO® chromatography using 1-2% EtOAc in hexane to obtain the desired product (2.4 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 8.0 (d, 1H), 7.51 (d, 1H), 2.79 (s, 3H); LC-MS m/z[M+H]+ 260.3 & 262.2, RT 3.82 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[CH3:10][C:11](O)=[O:12].C(OC(=O)C)(=O)C.O>CCO>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:11](=[O:12])[CH3:10])[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1ccccc1N
Solvent: CCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccccc1NC(C)=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
2-Ethylaniline (9.70 g, 80.0 mmol) was added to a mixture of glacial AcOH (30 mL) and acetic anhydride (20 mL), and the resulting mixture was refluxed at 120° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into a boiling mixture of water and EtOH (20 mL each). The mixture was stirred at rt for 1 h and then cooled (0-5° C.) overnight. EtOH was evaporated and the remainder of the mixture was diluted with water (100 mL). The obtained mixture was neutralized with Na2CO3 and extracted with EtOAc. The combined extract was washed with brine, dried with anhydrous MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 5% MeOH in CH2Cl2, to afford 5.50 g (42%) of the title compound as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (broad s, 1H), 7.05-7.40 (m, 4H), 2.55 (q, J=7.6 Hz, 2H), 2.02 (s, 3H), 1.09 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=1>N1C=CC=CC=1.Cl.[Cu]I>[CH3:34][O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[C:11]4[C:24]([F:27])([F:25])[F:26])=[CH:18][CH:19]=2)=[CH:39][CH:38]=1
Reactant: Oc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)cc1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenol (180 mg, 0.5 mmol), cesium carbonate (490 mg, 1.5 mmol), CuI (20 mg, 0.1 mmol) and 4-bromo-benzoic acid methyl ester (215 mg, 1.0 mmol) were dissolved in 3 ml of dry pyridine. The reaction mixture was run in microwave (Emory's Optimizer, Personal Chemistry) at 200° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with 1 M HCl (aq.) and the product extracted three times with CH2Cl2. Combined organic phases were dried and evaporated, and the crude material was purified with preparative HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford 151 mg of analytically pure product.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O[NH:38][C:39](=[NH:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C.O>[C:40]1([C:39]2[N:46]=[C:6]([C:5]3[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=3)[O:8][N:38]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: N=C(NO)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)no2)cc1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
To a suspension of mono-methyl terephthalate (1.50 g, 8.33 mmol) in acetonitrile (16 mL) was added EDC (4.65 g, 25.0 mmol), HOBt (1.12 g, 8.33 mmol), DIPEA (3.24 g, 25.0 mmol) and N-hydroxybenzimidamide (1.36 g, 10.0 mmol). The reaction was heated at 100° C. for 30 mins in a microwave. The reaction was then cooled to rt, diluted with water (60 mL) and isolated the crude white precipitate by vacuum filtration. Dissolved in CH2Cl2 and passed through a plug of silica to afford methyl 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoate as an off-white solid (640 mg, 23%). 1H-nmr (400 MHz, CDCl3) δ 8.33 (d, J=8 Hz, 2H), 8.24 (d, J=8 Hz, 2H), 8.21-8.11 (m, 2H), 7.59-7.51 (m, 3H), 4.00 (s, 3H); MS (ESI) m/z 280.9
Reaction SMILES: C(OC([NH:8][C@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@H:10]1[CH3:21])=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].ClCCl.O1CCCC1>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:8][C@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@H:10]1[CH3:21]
Reactant: C[C@@H]1Oc2ccccc2NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1Oc2ccccc2NC(=O)[C@@H]1N

Procedure:
(2S,3R)-3-amino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetate salt was prepared from (2S,3R)-3-t-butyloxycarbonylamino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (Robi, et al., Bioorg. & Med. Chem. Lett. 1994, 4, 1789-1794) by treatment with a solution of trifluoroacetic acid-dichloromethane-tetrahydrofuran (1:10:10) at room temperature, followed by solvent evaporation and coevaporation with tetrahydrofuran under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
20.2 g (0.129 mol) of 4-fluoro-3-nitroaniline was dissolved in 120 ml of pyridine, and 17.8 g (0.136 mol) of ethanesulfonyl chloride was added dropwise to the solution at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the pyridine was distilled off, the thus-obtained product was dissolved in ethyl acetate and washed with diluted hydrochloric acid twice, then with water, and with saturated saline solution. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 29.7 g of the objective product (yield: 93%) in the form of brown crystals. Melting point: 133° to 136° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(NS(C)(=O)=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol), in anhydrous CH2Cl2 (5 mL) under argon were added methane sulfonyl chloride (0.23 mL, 2.99 mmol) and pyridine (0.30 mL, 3.73 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a white solid. 1H NMR (CDCl3) δ: 1.52 (d, J=6.8 Hz, 3 H), 2.67 (s, 3 H), 4.61–4.72 (m, 2 H), 7.24 (d, J=8.3 Hz, 2 H), 7.51 (d, J=8.3 Hz, 2 H). ESIMS (MNa+): 279.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[C:9]([N:11]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13]
Reactant: CON=Cc1cc(N)c(Cl)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: CON=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Reaction time: 15 h

Procedure:
18 g (82 mmol) of 5-amino-2,4-dichlorobenzaldehyde (O-methyl)oxime were added to a solution of 12.5 g (82 mmol) of 3,4,5,6-tetrahydrophthalic anhydride in 300 ml of acetic acid, whereupon the mixture was stirred for 15 hours at reflux temperature. The reaction mixture was subsequently poured into 1 l water. The product was then extracted with 300 ml of methyl tert-butyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The residue was purified by means of silica gel chromatography (eluent: hexane/ethyl acetate=4:1). Yield: 20.9 g; m.p.: 122-124° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][NH2:19])=[O:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:20](O)(=O)C.C(N)=N.O>CN(C)C=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:20]=[N:19][NH:18][C:16]2=[O:17])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(NC(=O)NN)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-n2cn[nH]c2=O)cc1

Procedure:
N-(4-octylphenyl)-N′-aminourea, Formamidine acetate (12.76 g) and N-carbazoyl-4-octylaniline (6.458 g) in N,N-dimethylformamide (19.4 ml) were stirred at 150° C. for 6 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and washed with water to give 4-(4-Octylphenyl)-2,3-dihydro-4H-1,2,4-triazol-3-one (4.27 g).
Reaction SMILES: Cl.C(N=C=N)C.[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1.N1C=CC=CC=1.[CH2:32]1C[O:35][CH2:34][CH2:33]1.CN(C=O)C>>[ClH:25].[Cl:25][C:21]1[CH:20]=[C:19]([NH:18][C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([NH:7][C:34](=[O:35])[CH:33]=[CH2:32])[CH:9]=3)[N:14]=[CH:13][N:12]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Agent: CCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Temperature: 0 °C
Yield: 48 %

Procedure:
1-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1902 mg, 1 mmol) was added to a solution of 6-amino-4[(3-chlorophenyl)amino]quinazoline (136 mg, 0.5 mmol) acrylic acid (74 mg, 1.0 mmol) and pyridine (201 mg, 2.5 mmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 20 minutes the reaction mixture was stirred at 25° C. for 3 hours, and then poured onto water (12.5 mL), and extracted with EtOAc (2×10 mL). The combined extracts were treated with dilute hydrochloric acid (0.5 M, 10 mL), and the precipitate was collected by Buchner filtration, rinsed with water (10 mL), ether (2×10 mL), and air dried to give N-[4-[(3-chlorophenyl)amino]quinazolin-6-yl]acrylamide hydrochloride (93 mg, 48%) as a dull yellow solid, mp 223-227° C. Calculated for C18H13ClN4O.HCl.1.5 H2O: C, 52.59; H, 4.41;N, 14.43%. Found: C, 52.43, H, 4.37; N, 14.27%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[C:20]1[O:24][N:23]=[C:22]([C:25](OCC)=[O:26])[CH:21]=1.[BH4-].[Li+].Cl>CO.ClCCl.CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])[CH:5]=[CH:4][C:3]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][OH:26])[CH:21]=1
Reactant: CCOC(=O)c1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)on1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2cc(CO)no2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
Ethyl 5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}isoxazole-3-carboxylate (Example 2, 0.4 g, 1.1 mmol) was suspended in methanol/dichloromethane/dimethylsulfoxide (9 ml:3 ml:1 ml). Lithium borohydride (0.12 g, 5.5 mmol) was added portionwise. The reaction mixture was stirred under nitrogen at room temperature for 1 hour. The pH was adjusted to pH 3–4 using 1N hydrogen chloride, the mixture was cooled to 0° C., and the resulting white precipitate was collected by suction filtration. The white solid was dried in vacuo, giving 0.28 g of the desired product.
Reaction SMILES: CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.[F:20][C:21]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:22]=1[C:23]([C:25]1[CH:26]=[C:27]([C:30]([OH:32])=O)[NH:28][CH:29]=1)=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:63][C:64]1[S:68][C:67]([CH2:69][NH2:70])=[N:66][N:65]=1.C(N(C(C)C)CC)(C)C>>[CH3:63][C:64]1[S:68][C:67]([CH2:69][NH:70][C:30]([C:27]2[NH:28][CH:29]=[C:25]([C:23](=[O:24])[C:22]3[C:33]([F:38])=[CH:34][C:35]([F:37])=[CH:36][C:21]=3[F:20])[CH:26]=2)=[O:32])=[N:66][N:65]=1
Reactant: Cc1nnc(CN)s1
Reactant: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(CNC(=O)c2cc(C(=O)c3c(F)cc(F)cc3F)c[nH]2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a DMF 3 mL solution of 4-(2,4,6-trifluorobenzoyl)-1-H-pyrrole-2-carboxylic acid (Intermediate 1) (30 mg, 0.11 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (22 mg, 0.15 mmol) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide-hydrochloride (EDC-hydrochloride)(28 mg, 0.15 mmol). The reaction was stirred for 45 min before 1-(5-methyl-1,3,4-thiadiazol-2-yl)methanamine hydrochloride (19 mg, 0.17 mmol) and diisopropylethylamine (0.1 mL, 0.55 mmol) were added. The reaction mixture was stirred at rt overnight, concentrated and chromatographed on silica gel eluting with AcOEt to give the title compound 29 mg.
Reaction SMILES: N1CCC([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)CC1.ClC1C=C(C=O)C(OC)=CC=1NC(=O)C=C.C(O)(=O)C>CC1CCCO1>[C:11]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:8](=[O:7])[OH:22]
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Agent: C=CC(=O)Nc1cc(OC)c(C=O)cc1Cl
Solvent: CC(=O)O
Solvent: CC1CCCO1
Product: O=C(O)Nc1ccccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Biphenyl-2-ylcarbamic acid piperidin-4-yl ester (which may be prepared according to preparation 8 in WO 2004/074246A) (63.0 kg, 212.57 mol) was added to a stirred suspension of N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamide (which may be prepared according to Step C (Preparation 1) or C (Preparation 2)) (50.0 kg, 208.62 mol) and acetic acid (12.6 kg, 209.83 mol) in 2-methyltetrahydrofuran (430 kg) at 25° C. The mixture was then heated to 50° C. over 60 mins and held at this temperature for 2 hours. The resulting suspension was cooled to 20° C. over 90 mins and held at this temperature for 4 hours. The suspension was filtered under vacuum and the filter cake was washed with IMS (3×78.9 kg). The solid was dried in a vacuum oven at 50° C. for 10 hours to give biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-formyl-5-methoxyphenyl-carbamoylethyl]piperidin-4-yl ester as a white solid (90.7 kg, 80.6% th).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[CH2:21]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH3:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:31])[C@@H:25]([NH:26][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:22]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
6 ml (0.042 mol) of TEA was added to a mixture of 4.2 g (0.14 mol) of (3R)-4-(Toluene-4-sulfonyl)-thiomorpholine-3-carboxylic acid, 3.0 g (0.017 mol) of L-leucine ethyl ester hydrochloride, 3.2 g (0.014 mol) of DCC, and 1.7 g (0.014 mol) of DMAP in 200 ml of CH2Cl2, and the mixture was reacted at room temperature for 24 h. After the reaction, the solid was removed by sucking filtration, the solvent was removed by evaporation, the residue was dissolved with an appropriate amount of ethyl acetate, filtered to remove the insoluble matter, diluted with ethyl acetate, successively washed with 10% of NaHCO3 solution and saturated NaCl solution, dried with Na2SO4. The drying agent was removed, ethyl acetate was removed by evaporation, the residue was separated by flash chromatographic column (eluent: CH2Cl2:CH3Cl=1:1), to obtain 4.0 g of oily matter. 1H-NMR (400 MHz, CDCl3): δ 7.77237-7.74077 (m, 2H), 7.36382 (d, 2H, J=7.988 Hz), 6.74090 (d, 1H, J=9.244 Hz), 4.80098-4.77466 (m, 1H), 4.68244-4.58898 (m, 1H), 4.28174-4.15708 (m, 3H), 3.53789-3.28674 (m, 1H), 3.13092 (d, 1H, J=13.676), 2.56954-2.42247 (m, 5H), 2.24620-2.20545 (m, 1H), 1.66352-1.53450 (m, 3H), 1.30702-1.26745 (m, 3H), 0.96159-0.91891 (m, 6H); MS (EI) m/z: 443.1, 397.1, 369.1, 287.1, 256.0, 213.1, 155.0, 139.0, 112.0, 91.0, 65.0.