Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[C:19]1([C:25]2[S:26][CH:27]=[CH:28][C:29]=2B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[C:19]1([C:25]2[S:26][CH:27]=[CH:28][C:29]=2[C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:3]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
Reactant: OB(O)c1ccsc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccsc1-c1ccccc1
Temperature: 80 °C
Yield: 22.6 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (137 mg, 0.428 mmol), (2-phenylthiophen-3-yl)boronic acid (87.4 mg, 0.428 mmol), Na2CO3 (136 mg, 1.28 mmol) and Pd(PPh3)4 (24.7 mg, 0.021 mmol) in DME (1.6 mL) and water (0.49 mL) was heated to 80° C. for 18 h under Ar atmosphere. The mixture was diluted with water, extracted with AcOEt, washed with NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=80/20 to 0/100) and recrystallized with AcOEt/heptane to yield the title compound (38.6 mg, 23% yield) as a white solid: mp 167-168° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.62 (1H, d, J=8.0 Hz), 7.30-7.41 (5H, m), 7.47 (1H, brs), 7.51 (1H, d, J=5.2 Hz), 7.55-7.72 (4H, m), 8.91 (1H, d, J=8.0 Hz). Anal. Calcd for C21H13F3N2OS: C, 63.31; H, 3.29; N, 7.03. Found: C, 63.08; H, 3.37; N, 7.01.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.C(O)(=O)C(O)=O.[CH2:27]1[C:30]2([CH2:33][NH:32][CH2:31]2)[CH2:29][O:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:32]3[CH2:33][C:30]4([CH2:27][O:28][CH2:29]4)[CH2:31]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1NCC12COC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC2(COC2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-oxa-6-azaspiro[3.3]heptane oxalate (CAN 1159599-99-1) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=366.4 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10](=[CH:16][N:17](C)C)[C:11]([O:13]CC)=O.[CH2:20]([NH:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35]N)=[N:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:11]([OH:13])=[C:10]([C:3]3[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=3[Cl:1])[CH:16]=[N:17]2)=[N:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1Cl
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)c(Cl)c1

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(2-chloro-4-cyanophenyl)-3-(dimethylamino)acrylate and N-benzyl-6-hydrazinylnicotinamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.44 (d, J=5.8 Hz, 2H) 7.13-7.22 (m, 2H) 7.27 (d, J=4.3 Hz, 5H) 7.75 (d, J=8.3 Hz, 1H) 8.00 (s, 1H) 8.30-8.47 (m, 2H) 8.90 (s, 1H) 9.20 (t, J=5.3 Hz, 1H). MS m/z [M+H]+ 430.3.
Reaction SMILES: N1C=[CH:4][CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10]CC[CH2:7]1>>[CH3:10][N:6]([CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH2:3][CH3:4])[CH3:7]
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Reactant: c1cn[nH]c1
Product: CC[C@H](CN(C)C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N,N-dimethyl-1,2-butanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:39])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29](=[O:38])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=2)[CH2:25][CH2:26][CH2:27]Cl)=[CH:20][CH:19]=1)(C)(C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.Cl.CO.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:29](=[O:38])[CH:24]([C:21]2[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[C:15](=[O:39])[NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[NH2:7])=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCCCl)C(=O)Nc2ccc(Br)cc2)cc1
Reactant: C1COCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCCN2CCOCC2)C(=O)Nc2ccc(Br)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of (E)-[2-(3-{4-[1-(4-bromo-phenylcarbamoyl)-4-chloro-butyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (187.5 mg, 0.3 mmol) in DMF (3 mL), morpholine (261 mg, 3 mmol) was added. Then the solution was stirred at 80 degrees Celsius overnight. A solution of 1.25 M HCl/MeOH (4 mL) was added to the residue, the solution was stirred for 4 h at ambient temperature. After reaction, the solution was neutralized with solid NaHCO3. The final product was obtained by preparative HPLC. MS: calc'd 577 (MH+), exp 577 (MH+). 1H NMR (d6-DMSO, 400 MHz), 10.33 (s, 1H), 9.57 (broad s, 2H), 7.61 (d, 1H, J=15.6 Hz), 7.59-7.54 (m, 4H), 7.49-7.46 (m, 4H), 7.36 (d, 1H, J=7.6 Hz), 6.99 (t, 1H, J=7.6 Hz), 6.91-6.84 (m, 2H), 6.71 (broad s, 1H), 3.96 (d, 2H, J=12.0 Hz,), 3.75 (t, 1H, J=7.2 Hz,), 3.62 (t, 2H, J=12.0 Hz), 3.40 (broad s, 2H), 3.14 (t, 2H, J=7.6 Hz), 3.03 (broad s, 2H), 2.09-2.04 (m, 1H), 1.78-1.71 (m, 1H), 1.67-1.57 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[C:13](OC=C)(=[O:15])[CH3:14]>C(O)(C)(C)C>[C:13]([O:12][CH2:11][C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6])(=[O:15])[CH3:14]
Reactant: C=COC(C)=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC(C)(C)O
Product: CC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Reaction time: 20 h
Yield: 96.9 %

Procedure:
Four grams of the immobilized Lipase PS prepared by the same procedure as in Example 2 was added to 40 ml of a dry t-butanol solution containing 4 g of ascorbic acid and 3 g of vinyl acetate. The reaction was continued for 20 hours at 50° C. The reaction mixture was filtered and concentrated to yield 4.8 g of a crude ascorbic acid-6-acetate. Recrystallization from acetone-benzene gave a crystal with purity of 93%. The water content of the reaction system was 650 ppm.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:24](=[O:25])[C:23]5=[C:29]([Cl:32])[CH:30]=[CH:31][C:21]([Cl:20])=[C:22]5[C:27]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Solvent: ClCCl
Product: O=C1c2c(Cl)ccc(Cl)c2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.44 gm, 9.24 mmoles) and 3,6-dichlorophthalic anhydride (2.01 gm; 9.27 mmoles) in dichloromethane (DCM, 50 ml) was stirred at room temperature for hr. White precipitates formed and the TLC of the reaction mixture showed that there was no starting amine remaining. The solvent was stripped down and the white solids which were poorly soluble in DCM were loaded onto a flash chromatography column, (SiO2 ; 30 gm) and the column was eluted with a solution of 1% CH3OH in DCM. The desired product thus obtained weighed 2.29 gm (54%). Recrystallization from hot ethanol yielded 2.15 gm of white crystals, m.p.=163°-164° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]([OH:30])=O)=[CH:23][CH:22]=2)=[O:18].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.Cl.CN(C)CCCN=C=NCC>O.O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=2)(=[O:33])=[O:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:30])=[CH:23][CH:22]=2)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3cc(C(=O)O)ccc32)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3cc(C(=O)N4CCOCC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazole-4-carbonyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carboxylic acid (113 mg) was dissolved in water (5 ml) and tetrahydrofuran (THF) (10 ml), and then morpholine (53.5 μl) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC-HCl) (43 mg) were added thereto. The mixture was stirred at room temperature for 24 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol/dichloromethane=0/100 to 17/100) to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[5-(morpholine-4-carbonyl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (59 mg).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:16])[C:13](O)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([NH2:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:1]([C:5]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:12](=[O:16])[C:13]([NH:25][CH2:23][CH3:24])=[O:14])[CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN
Reactant: CC(C)(C)c1cc(F)ccc1OC1CN(C(=O)C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCNC(=O)C(=O)N1CC(Oc2ccc(F)cc2C(C)(C)C)C1
Yield: 46.7 %

Procedure:
To a stirred solution of [3-(2-tert-butyl-4-fluorophenoxy)azetidin-1-yl](oxo)acetic acid (0.27 g, 0.93 mmol) and ethylamine hydrochloride (89 mg, 1.1 mmol) in acetonitrile (20.0 mL) were added EDCI (0.21 g, 1.1 mmol) and HOBt (0.17 g, 1.1 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure, the resulting residue was partitioned between ethyl acetate and water and separated. The organic layer was washed with 10% sodium bicarbonate, saturated sodium chloride, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 66:34 to 34:66 hexane/ethyl acetate) to provide 2-[3-(2-tert-butyl-4-fluorophenoxy)azetidin-1-yl]-N-ethyl-2-oxoacetamide (0.14 g, 48%) as a white powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:12][C:11]2[C@@H:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[C@H:9]([OH:20])[C:8]([CH3:22])([CH3:21])[O:7][C:6]=2[CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:23]([O:20][C@@H:9]1[C:8]([CH3:22])([CH3:21])[O:7][C:6]2[CH:5]=[C:4]([Br:3])[S:12][C:11]=2[C@H:10]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)Oc2cc(Br)sc2[C@@H](N2CCCCC2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2cc(Br)sc2[C@@H](N2CCCCC2=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.47 g, 11.7 mmol) was added to a solution of trans-2-bromo-5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno-[3,2-b]pyran (4.0 g, 11.1 mmol) in DMF (50 mL) at 0° C. and stirred at rt for 30 min. Benzylbromide (1.45 mL, 12.2 mmol) was added to the resultant solution and stirred at rt for 2 h. The solution was poured into water (200 mL) and extracted into dichloromethane. The organic phase was washed several times with water and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography using 2% methanol in dichloromethane as the eluant. The product was recrystallized from dichloromethane/hexane to give a colorless solid, 3.87 g (77%); mp 146°-147° C.; IR(KBr): 1634 and 1570 cm-1 ; MS: m/z 450 (MH+); 1H NMR(CDCl 3): 1.32 (s, 3H), 1.50 (s, 3H), 1.53-1.77 (m, 4H), 2.37-2.45 (m, 2H), 2.87 (m, 1H), 3.08 (m, 1H), 3.69 (d, J=8.6 Hz, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.73 (d, J=11.8 Hz, 1H), 5.90 (bs, 1H), 6.54 (s, 1H) and 7.26-7.37 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:37]=[C:36]([F:38])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:21]([O:31][CH2:32][CH2:33][S:34][CH3:35])=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:39])[CH:5]=1)[CH3:2].ClC1C=CC=CC=1C(OO)=[O:48].ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:39])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[C:21]([O:31][CH2:32][CH2:33][S:34]([CH3:35])=[O:48])=[CH:20][N:19]=3)=[N:10]2)=[C:36]([F:38])[CH:37]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCSC)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reactant: O=C(OO)c1ccccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1.24 g 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-[2-(methylsulfanyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (4-16, 2.26 mmol, 1. eq.) in 2.15 ml of dry chloroform, was added slowly at 0° C. a solution of 557 mg 2-chlorobenzenecarboperoxoic acid (77%, 2.49 mmol, 1.1 eq.) in 2.15 ml chloroform. After 30 min dichloromethane and sodium thiosulfate-solution (10%) were added. The slurry was stirred for 5 min. After separating the solid (product) the aqueous layer was washed with dichloromethane twice. The organic layers were dried with sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography and combined the former isolated solid to yield 1.22 g (2.05 mmol, 91%) of the analytically pure target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17](CC)[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3N=CO[N:29]=3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][CH2:36][O:37][C:38]([CH2:40]Br)=[O:39]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:40][C:38]([O:37][CH2:36][CH3:35])=[O:39])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCn1ccc(-c2nc(-c3ccc(-c4ncon4)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc(-c2nc(-c3ccc(C#N)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a mixture of Step 2 product of Example 140 (100 mg, 0.255 mmol) in THF (2 ml) at 0° C. was added NaH (20.4 mg, 0.510 mmol). After stirred at 0° C. for 1 hr, ethyl bromo acetate (0.034 ml, 0.306 mmol) was added and then stirred at 0° C. for one hour. Reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated, separated by prep. TLC (Hex:EtOAc=2:1) to give ethyl (3-{5-[(4-chlorophenyl)sulfanyl]-4-(4-cyanophenyl)-1-methyl-1H-imidazol-2-yl}-1H-pyrazol-1-yl)acetate (70 mg) desired compound. LCMS: [M+1]+=478.0.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:29](O)(=[O:32])[C:30]#[CH:31]>CN(C)C1C=CN=CC=1.CCOCC>[C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:32])[C:30]#[CH:31]
Reactant: OCCCCCCc1ccccc1
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C#CC(=O)OCCCCCCc1ccccc1
Temperature: 25 °C
Yield: 61 %

Procedure:
Under a nitrogen atmosphere at -20° C., a mixture of 1.3 g of dicyclohexylcarbodiimide, 0.051 g of 4-dimethylaminopyridine in 15 ml of dried ether is added dropwise, with stirring, to a mixture of 1 g of 6-phenylhexanol and 0.43 g of propiolic acid in 15 ml of dried ether. After the addition was over, the reaction solution was warmed to the room temperature and stirred at the room temperature for ten hours. After the reaction was completed, the reaction solution was filtered. The filtrate was washed twice with cold 1N hydrochloric acid and twice with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 0.788 g of 6-phenylhexyl propiolate (compound 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].OS(O)(=O)=O.C1C(=O)N([Br:24])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:24][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:8]
Reactant: Cc1cccc(F)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a solution of 1-fluoro-3-methyl-2-nitro-benzene (5 g, 32.24 mmol, 1.0 eq) in TFA (25 mL) and conc.H2SO4 (10 mL) at 0° C. was added NBS (6.31 g, 35.46 mmol, 1.1 eq) in portions. After addition, the mixture was stirred at room temperature for 2 h. The resulting mixture was poured onto ice and the precipitate that formed collected by filtration, washed with water and dried in vacuo to give the title compound as a yellow solid (5 g, 67%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:21]N(C)C=O.[H-].[Na+].CI>O>[CH3:21][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A 12.5 g portion of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide was added to 500 ml of dimethylformamide under argon. A 2.47 g portion of sodium hydride (50% in oil) was added, this mixture was stirred one hour, then 3.2 ml of methyl iodide was added. This mixture was stirred for 2.5 days, then poured into 1.5 liters of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and concentrated in vacuo. The residue was chromatographed as described in Example 1. Fractions 8-15 were combined, concentrated and the solid recrystallized from dichloromethane-hexane, giving 8.5 g of the desired product, mp 200°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C@:15]3([CH3:31])[CH2:20][C:19](=O)[N:18]([CH3:22])[C:17](=[N:23]C(=O)OC(C)(C)C)[NH:16]3)[CH:12]=[CH:13][CH:14]=2)[C:5]([OH:8])=[CH:6][CH:7]=1.[C:32](O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C@@:15]3([CH2:31][CH3:32])[NH:16][C:17](=[NH:23])[N:18]([CH3:22])[CH2:19][CH2:20]3)[CH:12]=[CH:13][CH:14]=2)[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(-c3cc(Cl)ccc3O)c2)NC1=NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@]1(c2cccc(-c3cc(Cl)ccc3O)c2)CCN(C)C(=N)N1
Yield: 60 %

Procedure:
(S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH2Cl2 at RT for 30 min. The volatiles were removed in vacuo. The residue was redissolved in acetonitrile (5 mL) and evaporated again to afford 17 mg of the crude product as a yellow solid. The crude product was purified via reverse phase HPLC to provide 10 mg (60%) of (S)-6-(3-(3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1″-one (CF4; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): 611.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m, 3H), 3.68 (brs, 1H), 5.18 (brs, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s, 3H), 2.95(d, J=15.8 Hz, 1H), 1.74 (s, 3H). MS (ESI): MH+=344.1. HPLC (A) Rt=5.07 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[F:14])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: Fc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccccc1F)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2-fluorobenzyl chloride (1.2 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 291 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.Br.[C:7]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:24]CCCCCCCCCCCCCCCOCCCCCCCCCCCCCCC(O)=O>C(O)(=O)C>[Br:24][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:22])=[O:23]
Reactant: O=C1CCCCCCCCCCCCCCO1
Reactant: O=C(O)CCCCCCCCCCCCCCOCCCCCCCCCCCCCCCBr
Agent: Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCBr

Procedure:
The present reaction can be carried out in the presence of acetic acid and can be performed by using acetic acid as a solvent. As described in the above Non-patent Document 11, when concentrated sulfuric acid-hydrogen bromide acid is used and 15-pentadecanolide is reacted, for example, 15-(15-bromopentadecyloxy)pentadecanoic acid, which is difficult to get separated from the target compound 15-bromopentadecanoic acid, is produced as a byproduct. As a result, it becomes difficult to obtain highly pure 15-bromopentadecanoic acid.