Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[CH:11]=[C:10]2[CH3:18]>N>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([Cl:3])[CH:11]=[C:10]2[CH3:18]
Reactant: Cc1cc(=O)[nH]c2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Cc1cc(Cl)nc2ccc(Br)cc12

Procedure:
25 mL of phosphorus oxychloride is added to 2.7 g (11.34 mmol) of 6-bromo-4-methyl-1H-quinolin-2-one (Example 1b) and the reaction mixture is refluxed for 2 hours. After cooling, the mixture is added batchwise to 250 mL of 10% NH3 solution, the precipitate formed is filtered off, washed with water, and dried in the circulating air dryer at 30° C. Yield: 2.7 g (93% of theoretical); C10H7BrClN (M=256.526); calc.: molpeak (M+H)+: 256/258/260 (BrCl); found: molpeak (M+H)+: 256/258/260 (BrCl); Rf value: 0.95 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: P(=O)(O)(O)O.[I-:6].[K+].[F:8][C:9]([F:16])([F:15])[CH:10]([CH3:14])[CH2:11][CH2:12]O>>[F:8][C:9]([F:16])([F:15])[CH:10]([CH3:14])[CH2:11][CH2:12][I:6]
Reactant: CC(CCO)C(F)(F)F
Reactant: [I-]
Agent: O=P(O)(O)O
Agent: [K+]
Product: CC(CCI)C(F)(F)F
Temperature: 0 °C

Procedure:
To a mixture of 19 g phosphoric acid (98%) and 19 g potassium iodide are added at 40° under stirring 4.75 g (33.4 mMol) of 4,4,4-trifluoro-3-methyl-butan-1-ol over a period of 10 minutes. The mixture is then heated at 120° for 16 hours, a cooling poured into ice-water and extracted with diethylether. The etheric extracts are washed with 10% sodium thiosulphate and brine acid dried over sodium sulphate. After filtration, the solvent is removed through a 15 cm Vigreux-column at atmospheric pressure, followed by fractionation giving 4,4,4-trifluoro-3-methyl-1-iodo-butane, b.p. 76°-77° at 140 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[CH:5]=[C:6]([Cl:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[C:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=1>[Pt].C(O)C>[Cl:26][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])=[C:11]([CH:23]([CH3:24])[CH3:25])[CH:10]=1)[NH2:27]
Reactant: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Pt]
Solvent: CCO
Product: CC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
3,5-Dichloro-4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)-nitrobenzene and 1.15 g of 10% platinum on carbon in 200 ml of ethanol is hydrogenated on a Parr shaker. Catalyst is removed by tinting through Celite and the filtrate stripped to afford 3,5-dichloro4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)-aniline. This is dissolved with 3.08 ml of ethyl bromoacetate and 3.43 g of diisopropylethylamine in 50 ml dimethylformamide and heated at 140° for 18 hours. Solvent is removed with high vacuum and the residue taken up in ethyl acetate and extracted twice with water. The ethyl acetate is dried, filtered and stripped to give crude product. Chromatography on silica gel with 85:15 to 80:20 hexane:ethyl acetate as eluent affords ethyl N-[3,5-dichloro-4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)phenyl]aminoacetate. NMR (CDCl3): δ0.2 (6H,s), 1.0 (9H,s), 1.2 (6H,d), 1.3 (3H,t), 3.3 (1H,m), 3.9 (2H,d), 4.3 (2H,q), 4.4 (1H,t), 6.4 (1H,d of d), 6.6 (2H,s), 6.6 (1H,d), 6.9 (1H,d).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26](=[CH:28][OH:29])[CH2:25][C:24]=4[CH:32]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)c1cccc(Nc2nc(Nc3ccc4c(c3)CC(=CO)O4)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine, N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine reacted with DIBALH to give N4-(3-tert-butylphenyl)-5-fluoro-N2-[2-(hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamine. LCMS: retn, time: 23.15 min.; purity: 99%; MS (m/e): 407 (MH+); 1 (DMSO-d6): δ 9.34 (1H, s), 9.22 (1H, s), 8.18 (1H, d, J=3.9 Hz), 8.04 (1H, s), 8.00 (1H, d, J=8.7 Hz), 7.60 (1H, t, J=2.1 Hz), 7.47 (2H, m), 7.34 (1H, t, J=7.8 Hz), 7.21 (1H, d, J=8.7 Hz), 6.69 (1H, s), 5.54 (1H, t, J=5.8 Hz), 4.63 (2H, d, J=5.8 Hz), 1.35 (9H, s).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH2:28][CH2:27][C:26]([C:38]([OH:40])=O)=[CH:25][C:24]=3[CH:41]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH2:28][CH2:27][C:26]([C:38]([NH:29][C:23]4[CH:24]=[CH:41][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:40])=[CH:25][C:24]=3[CH:41]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2F)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2F)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (146 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (108 mg) and triethylamine (496 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8) to give 7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 66) (139 mg) as yellow amorphous.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23]>CN(C)C=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:15][C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)=[C:21]([CH:24]=1)[CH:22]=[O:23]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Under N2 in a 1 L round-bottomed flask fitted with a reflux condenser and magnetic stirrer were placed 51.1 g (370 mmol) of K2CO3 and 20.1 g (123 mmol) of 3,4-dichlorophenol (Aldrich Chem. Co., Milwaukee, Wis.) in 500 mL of anhydrous N,N-dimethylformamide (DMF). After stirring the mixture for 30 min., 25 g (123 mmol) of 5-bromo-2-fluoro-benzaldehyde (Aldrich) in 150 mL of DMF was added and the mixture was heated to 90-100° C. overnight. After allowing the reaction to cool to room temperature, the mixture was concentrated at reduced pressure on a rotary evaporator and the resulting oily residue was then diluted with water and EtOAc. The aqueous layer was then extracted with additional EtOAc and the organic layers were combined, washed with H2O and saturated NaCl and dried over Na2SO4. Removal of the solvent in vacuo gave a light yellow oil which was further dried under vacuum overnight to give the title product as a pale yellow solid, 40.2 g; m.p. 129-132° C.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2)(=[O:14])=[O:13])[C:9]#[N:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C@H:8]([C:9]#[N:10])[CH2:7][C:6]([OH:38])=[O:5])(=[O:14])=[O:13])=[C:16]([O:25][CH2:26][CH2:27][C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][CH:32]=[N:33]3)[CH:17]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N[C@H](C#N)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@H](C#N)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Yield: 25.9 %

Procedure:
A solution of (S)-3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid tert-butyl ester (0.20 g, 0.40 mmol) in TFA (2 mL) and CH2Cl2 (20 mL) was stirred for 9 h. After the solvent was removed under vacuum, the residue was subjected to preparative reverse-phase HPLC (VYDAC, C18) using a linear gradient of (A) water containing 0.1% TFA and (3) acetonitrile containing 0.1% TFA (0-40% B, in 120 min) at a flow rate of 15 mL/min. Fractions containing the major peak were pooled and lyophilized to yield 50 mg (26%) of (S)-3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid. MS (APCI) m/z 483.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 126-128° C.; 1H NMR (300 MHz, CDCl3): δ 6.99 (s, 1 H), 6.74 (s, 2 H), 5.00-4.90 (m, 1 H), 4.35 (t, J=8.0 Hz, 2 H), 3.78 (s, 3H), 3.67 (dd, J=10.6, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.35 (s, 3 H), 3.09 (t, J=7.7 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C18H22N3O3Cl2 (M+H)+: 398.1038; Found m/z 398.1064.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O

Procedure:
A slurry of methyl 4-chloro-α-methoxy-5-nitro-o-toluate (7.0 g.) in dilute sodium hydroxide (35 ml of IN) is stirred about 30 hours. The yellow slurry is then diluted with 50 ml. of water resulting in a clear yellow solution. The solution is extracted with ether, then the aqueous layer is separated and acidified to give 5.7 g. of an off-white solid. A sample recrystallized from benzene has a mp 155°-157°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[CH3:11])([O-])=O.NC1NN=C(C2C=CC(OC3C=CC=CC=3)=CC=2)C=1C#N.NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C#N)=C3N=CC=2)C=CC=1.ClCCC(NC1C=C(C2[N:82]3[N:83]=[C:84]([C:89]4[CH:94]=[CH:93][C:92]([O:95][C:96]5[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=5)=[CH:91][CH:90]=4)[C:85]([C:86]([NH2:88])=[O:87])=[C:81]3[NH:80][CH2:79]C2)C=CC=1)=O>>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:82]2[N:83]=[C:84]([C:89]3[CH:94]=[CH:93][C:92]([O:95][C:96]4[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=4)=[CH:91][CH:90]=3)[C:85]([C:86]([NH2:88])=[O:87])=[C:81]2[NH:80][CH2:79][CH2:11]1
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N

Procedure:
The desired product was prepared from 1-(2-nitrophenyl)ethanone and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to the procedures similar to those for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (step 4 to step 5), compound 2 (step 1 and 2) and compound 68 (step 8) under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (DMSO-d6) δ 7.48-7.44 (m, 2H), 7.40-7.33 (m, 2H), 7.15-7.09 (m, 1H), 7.05-6.97 (m, 4H), 6.92 (td, J=8.0, 1.2 Hz, 1H), 6.75 (br s, 1H), 6.64 (dd, J=8.0, 1.2 Hz, 1H), 6.46 (td, J=7.6, 1.2 Hz, 1H), 6.23 (dd, J=7.6, 1.2 Hz, 1H), 5.57-5.52 (m, 1H), 5.19 (br s, 2H), 3.27-3.17 (m, 1H), 2.93 (td, J=2.8, 12.0 Hz, 1H), 2.21-2.11 (m, 1H), 2.10-2.05 (m, 1H). MS (ESI) m/e [M+1]+ 426.0.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[C:15]1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16]>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:20]1[CH:21]=[CH:22][C:15]([OH:16])=[CH:17][C:18]=1[OH:19])=[O:14]
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)CCCCCBr
Agent: Cl[Sn](Cl)(Cl)Cl
Product: O=C(CCCCCBr)c1ccc(O)cc1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Tin chloride (8.18 g) and 6-bromohexanoic acid were stirred at 120° C. Thereto was added resorcinol (5.50 g), and the resulting mixture was stirred for 20 min. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate ester. The organic layer was washed with brine and dried, followed by evaporation of the solvent under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=30:1) to give 3.70 g of 6-bromo-1-(2,4-dihydroxyphenyl)-1-hexanone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pt](=O)=O>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1
Reactant: NCCc1ccc(O)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: NCCC1CCC(O)CC1
Yield: 125.7 %

Procedure:
2-(4-Hydroxyphenyl)ethylamine (1.37 g, 10.0 mmol, 1.0 eq ) was dissolved in acetic acid (10 ml), and platinum dioxide catalyst (137 mg) was added. The mixture was stirred at 3 kgf/cm2 in a stream of hydrogen at 70° C. for 5 hours. The reaction mixture was filtered through Celite and the catalyst was washed with toluene. The filtrate was concentrated under reduced pressure to give 2-(4-hydroxycylohexyl)ethylamine (1.8 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([NH2:15])([CH3:14])[CH2:12][NH2:13]>CO>[NH2:15][C:11]([CH3:14])([CH3:10])[CH2:12][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CC(C)(N)CN
Reactant: N#Cc1ccc(F)cc1
Solvent: CO
Product: CC(C)(N)CNc1ccc(C#N)cc1
Yield: 87.3 %

Procedure:
4-Fluorobenzonitrile (7.0 g, 58 mmol) and 2-methylpropane-1,2-diamine (14 g, 160 mmol) were heated in a sealed vial in a microwave reactor (Biotage) at 180° C. for 25 minutes in two batches. Each batch was dissolved in methanol (50 mL) and then concentrated with silica to dryness. Flash chromatography on silica of each batch with neat acetonitrile and 2% triethylamine in acetonitrile as eluents gave 4-(2-amino-2-methylpropylamino)benzonitrile (9.58 g, 88% combined yield) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH:7]([N:9]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[N:10]1)[CH3:8])(C)(C)C.Cl>O1CCOCC1>[CH3:17][O:16][C:14]([C:12]1[N:11]=[N:10][N:9]([CH:7]([CH3:8])[C:6]([OH:18])=[O:5])[CH:13]=1)=[O:15]
Reactant: COC(=O)c1cn(C(C)C(=O)OC(C)(C)C)nn1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cn(C(C)C(=O)O)nn1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a stirred solution of 0.55 g (2.2 mmol) of methyl 1-(2-tert-butoxy-1-methyl-2-oxoethyl)-1H-1,2,3-triazole-4-carboxylate from step A in 3 mL of anhydrous 1,4-dioxane was added 2.7 mL (11 mmol) of a 4.0 M hydrogen chloride solution in 1,4-dioxane. The resulting mixture was stirred for 1 h and then evaporated to dryness to afford the title compound as an off-white solid (0.40 g, 93%). 1HNMR (500 MHz, CD3OD) δ: 8.67 (s, 1H), 5.60 (q, J=7.3 Hz, 1H), 3.90 (s, 3H), 1.88 (d, J=7.3 Hz, 3H). LC-MS: m/z (ES) 200 (MH)+.
Reaction SMILES: Cl[CH2:2][CH:3]1[N:8]([C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[O:10])[CH2:7][CH:6]([CH3:23])[CH2:5][O:4]1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)=[N:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:35]=[N:34][N:33]([CH2:2][C@H:3]3[N:8]([C:9]([C:11]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=4[N:18]4[N:22]=[CH:21][CH:20]=[N:19]4)=[O:10])[CH2:7][C@@H:6]([CH3:23])[CH2:5][O:4]3)[CH:32]=2)=[N:29][CH:30]=1
Reactant: Fc1ccc(-c2cn[nH]c2)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC(C)COC2CCl)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@@H](C)CO[C@H]2Cn2cc(-c3ccc(F)cn3)cn2)c1

Procedure:
By using (2RS,5SR)-[2-(chloromethyl)-5-methyl-1,3-oxazinan-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone obtained in Reference Example 35 (0.52 g, 1.5 mmol) and 5-fluoro-2-(1H-pyrazol-4-yl)pyridine obtained in Reference Example 11 (0.23 g, 1.4 mmol), the same procedure as in Example 48 was carried out to obtain the title compound (0.44 g). The obtained racemic mixture (0.070 g) was divided using a semi-preparative column based on the racemic compound analysis condition described earlier (condition 13, Rt1=6.6 min, Rt2=12.4 min) to obtain the title compound (0.030 g) having a short relative retention time (Rt1=6.6 min) (colorless oil).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7]C)=[O:6].N([O-])=[O:14].[Na+]>O.OS(O)(=O)=O>[Br:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:14])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)cc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromobenzoate (5.2 g, 23 mmol) in water (80 mL) and H2SO4 (60 mL) was added dropwise a solution of NaNO2 (1.9 g, 28 mmol) in water (10 mL) at 0° C. The reaction mixture was added to a mixture of water (180 mL) and H2SO4 (240 mL). The mixture was heated at reflux for 30 minutes before being cooled to room temperature. The resulting mixture was poured into crushed ice and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford 3-bromo-5-hydroxybenzoic acid (3.8 g, 78% yield), which was directly used in next step. 1H NMR (400 MHz, d-DMSO) δ 10.27 (s, 1H), 7.43 (t, J=1.6 Hz, 1H), 7.28 (dd, J=1.2, 2.0 Hz, 1H), 7.15 (t, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O.Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(Cl)cc1Cl
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](c3ccc(Cl)cc3Cl)C2)o[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2S,4R)-Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (340 mg, 0.92 mmol) (from example 51, step 3) was diluted with hydrogen bromide (33% in AcOH, 4812 μl, 27.48 mmol) and stirred at ambient temperature for 24 h. Evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(2,4-dichlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one ( ). 1H NMR (600 MHz, dmso) δ 1.22 (q, 1H), 1.47 (dq, 1H), 1.84-1.90 (m, 1H), 1.96-2.03 (m, 1H), 2.74 (dt, 1H), 2.87 (tt, 1H), 3.07-3.15 (m, 1H), 3.96 (dd, 1H), 5.73 (s, 1H), 7.40 (dd, 1H), 7.54 (d, 1H), 7.64 (d, 1H). HRMS Calculated for [C14H14Cl2N2O2+H]+: 313.0511. Found: 313.0490
Reaction SMILES: [OH-].[Na+].C(O)C.[C:6]([NH:14][C:15]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(OCC)(=O)C>[C:6]([NH:14][C:15]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:16]=1[C:17]([OH:19])=[O:18])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(Sc2ccccc2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Sc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
0.4 mL of 10% aqueous sodium hydroxide was added to 6 ml of ethanol suspension containing 0.30 g of methyl 2-(benzamido)-4-(phenylthio)benzoate at room temperature, and the resulting mixture was heated to reflux for 1 hour. After one reaction mixture was cooled to room temperature, 1.0 mol/b hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue and a solid substance was separated, by filtration to obtain 0.28 g of 2-(benzamido)-4-(phenylthio)benzoic acid as white solid.