Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C@@H:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][N:4]1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=1>C(OCC)(=O)C.[Pd]>[F:9][C:6]1([F:8])[CH2:5][N:4]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:19]([F:20])([F:21])[F:22])[CH:11]=2)[C@H:3]([CH3:2])[CH2:7]1
Reactant: O=[N+]([O-])c1ccc(N2CC(F)(F)C[C@H]2CBr)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1CC(F)(F)CN1c1ccc(N)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
(S)-2-(bromomethyl)-4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (230 mg, 0.59 mmol) was dissolved in ethyl acetate (5 mL) and TEA (90 mg, 124 μL, 0.89 mmol) and the flask was flushed with nitrogen. 10% Pd/C (58 mg, 0.05 mmol) catalyst was added and the reaction mixture was stirred overnight under an atmosphere of hydrogen. The reaction mixture was filtered, treated with 50% saturated NaHCO3, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to provide (R)-4-(4,4-difluoro-2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)aniline as a purple oil (164 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 6.81 (s, 2H), 6.58 (s, 1H), 4.92 (s, 2H), 4.07-4.01 (m, 1H), 3.74-3.63 (m, 1H), 3.60-3.50 (m, 1H), 2.75-2.60 (m, 1H), 2.22-2.11 (m, 1H), 1.10 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:44][CH2:43][C:40]1[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=1)=[O:24]
Reactant: NCc1ccncc1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccncc2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 4-picolylamine.
Reaction SMILES: [N:1]([C:4]12[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]2=1)=[C:2]=[O:3].[CH3:18][OH:19]>>[CH3:18][O:19][C:2](=[O:3])[NH:1][C:4]12[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]2=1
Reactant: CO
Reactant: O=C=NC12CCCCC1COc1ccccc12
Product: COC(=O)NC12CCCCC1COc1ccccc12

Procedure:
A solution of the product from Example 71 (0.66 g, 2.88 mmol) in 20 ml methanol was refluxed 18 hours. Evaporation and chromatography gave the title compound (0.75 g).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:18][O:19][CH2:20][CH2:21][CH:22](CC)[CH2:23][CH2:24][CH3:25])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[ClH:28].OC(COC1C=CC([Cl:53])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.O[C@H](COC1C=CC=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:53].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:21]([Cl:1])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:28])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: CCCC(CC)CCOC[C@@H](O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccccc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2c(Cl)cccc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M-15,1), 279 (11), 279 (9), 277 (64), 275 (100), 163 (11), 163 (5), 161 (6), 121 (33), 114 (12).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CCN(C(C)C)C(C)C.[C:16]1([C:22]2[N:26]3[C:27]4[C:32]([CH:33]=[CH:34][C:25]3=[N:24][N:23]=2)=[CH:31][C:30]([SH:35])=[CH:29][CH:28]=4)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]1([C:22]2[N:26]3[C:27]4[C:32]([CH:33]=[CH:34][C:25]3=[N:24][N:23]=2)=[CH:31][C:30]([S:35][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:29][CH:28]=4)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Sc1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2nnc3ccc4cc(Sc5nccs5)ccc4n23)cc1
Temperature: 80 °C

Procedure:
To 2-Bromothiazole (0.27 mL, 3.0 mmol) in 1,4-dioxane (20 mL) was added iPr2NEt (0.96 mL, 5.5 mmol), and the reaction was degassed with N2 for 10 minutes. 10e (765 mg, 2.8 mmol) was added, followed by Pd2dba3 (63 mg, 0.07 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (81 mg, 0.14 mmol). The reaction was sealed and heated overnight at 80° C., and then cooled to room temperature and concentrated. The residue was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the desired product, 10f.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35](O)=[O:36])=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:71]1([CH2:76][CH2:77][NH2:78])[CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([NH:78][CH2:77][CH2:76][N:71]2[CH2:75][CH2:74][CH2:73][CH2:72]2)=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid (Example 36h) (5 g, 9.85 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added HATU (5.62 g, 14.78 mmol) and DIPEA (5.16 mL, 29.6 mmol), the resulting mixture was stirred at r.t. for 30 min. Then 2-(pyrrolidin-1-yl)ethanamine (1.861 mL, 14.78 mmol) was added and the resulting mixture was stirred at r.t. overnight. The mixture was concentrated and the residue was purified by normal phase automatic silica column chromatography (Combiflash RF) eluting with MeOH/DCM (0-20%). The product was further purified by reverse phase automatic chromatography (Combinflash RF), using a 150 g golden C18 column and eluting with acetonitrile/Water (0%-100%) to afford 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (3.8 g, 6.29 mmol, 63.9% yield) as pale yellow solid. LCMS: (M+H)+: 604.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12]>>[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH:12][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Br)c1
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(Nc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 92.8 %

Procedure:
Following the general procedure using 3-bromotoluene (121 μL, 1.00 mmol) and 2,6-dimethylaniline (148 μL, 1.20 mmol), the reaction was stirred for 19 h at rt. Column chromatography on silica gel (eluting with 30% EtOAc/hexanes) afforded the product as an off-white solid (196 mg, 93%).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)[CH3:2].C[O:12][C:13](=O)[C:14]1[C:19]([I:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:21][C:17]1[CH:16]=[C:15]2[C:14](=[C:19]([I:20])[CH:18]=1)[C:13](=[O:12])[N:8]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[CH2:22]2
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Reactant: CCc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1ccc(CN2Cc3cc(F)cc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
A mixture of 4-ethyl-benzyl amine (1.3 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.374 g, 1.0 mmol), and K2CO3 (0.277 g, 2 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-ethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.184 g, 47%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.20 (t, 3H), 2.65 (q, 2H), 4.16 (s, 2H), 4.74 (s, 2H), 7.10 (d, 1H), 7.23-7.33 (m, 4H), 7.63 (d, 1H). GC-MS: m/z 395 (M)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[CH3:36][CH:35]([CH3:37])[C:34]([NH:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:2]([NH:1][C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:6][CH:5]=3)=[O:3])[CH2:26][CH2:25]2)[CH:28]=1)=[O:38]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(Oc4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AM using 1-isocyanato-4-phenoxybenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 515.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][CH:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=O)[CH:24]=3)=[CH:19][CH:18]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:66]([NH2:74])[CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>CN(C=O)C>[CH3:32][C:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:74][CH2:66][CH2:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[O:31])[CH:24]=3)=[CH:21][CH:22]=2)[C:9](=[O:10])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(N(Cc2ccc(-c3cccc(C(=O)O)c3)cc2)C(=O)OC(C)(C)C)CC1
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(N(Cc2ccc(-c3cccc(C(=O)NCCc4ccccc4)c3)cc2)C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 4′-[((4,4-dimethylcyclohexyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-methyl]-3-biphenylcarboxylic acid (0.100 g; 0.23 mmol) in DMF (2 mL) was added DIEA (0.035 mL; 0.25 mmol), and HATU (0.095 g; 0.25 mmol). The solution was aged 5 min at room temperature and phenethylamine (0.031 mL; 0.25 mmol) was added. After 45 min the mixture was partitioned between EtOAc and half-satd Na2CO3, layers were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum. LC/MS (method E) tR 1.19 min; m/z 541 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].S(=O)(=O)(O)[OH:29]>>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([NH2:20])=[O:29])[C:3]=1[S:21]([C:24]([F:26])([F:25])[F:27])(=[O:23])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Product: NC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Temperature: 100 °C
Yield: 83 %

Procedure:
A stirred mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfonyl-1 H-pyrazole-3-carbonitrile (1.06 g, 2.21 mmol) and concentrated sulfuric acid (1 ml) was heated to 100° C. for 3 hours. The cooled mixture was added to ice water and the precipitate filtered off, washed with water and air-dried. Purification by flash chomatography (silica, chloroform) gave the title compound (0.869 g, yield 83%) as off-white crystals, mp 217° C., 1H NMR (DMSO-d6): 7.39 (bs, 2H, NH2), 7.57 and 7.78 (bs, 2H, C(O)NH2), and 8.25 (s, 2H, Ar—H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:9]=1[CH:10]=O>O>[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:9]=1[CH:10]=[CH:3][C:4](=[O:5])[CH3:6]
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In water (500 ml) was dissolved sodium hydroxide (4.0 g), and to the mixture was added acetone (100 ml), and then 2,5-dichlorobenzaldehyde (15.9 g). The mixture was stirred at room temperature for 1 hour, and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(2,5-dichlorophenyl)-3-buten-2-one (19.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][NH2:13].C(O[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])C>CO>[NH2:22][C:21]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[N:13]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: CS(=O)(=O)c1ccc(NN)c(F)c1
Reactant: CCOC=C(C#N)C#N
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2N)c(F)c1
Temperature: -6 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 2-fluoro-4-methylsulfonylphenyl hydrazine (1) (4.0336 Kg; 1 eq) (commercially available from, e.g., Peakdale Molecular, Ltd.) in methanol (12.7723 Kg) was added a suspension of ethoxymethylene malononitrile (2.6564 Kg, 1.101 equivalents) in methanol (11.212 Kg) at a rate sufficiently slow to maintain the reaction mixture at −10° to 0° C. with reactor jacket cooling. After the addition had been completed, the reaction mixture was stirred for 1 hour at −6° C. and then heated to reflux for 5 hours, at which time the reaction mixture gave a pyrazole (3): hydrazine (1) HPLC peak area ratio of 105:1. Solvent (20.5153 Kg) was then distilled off the reaction mixture at atmospheric pressure, leaving a residue having less than 20% of the original volume. The resulting mixture was used directly in the next step.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.I[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C1(C)C=CC=CC=1.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>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]
Reactant: Nc1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2nccs2)c1
Temperature: 115 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
The mixture of 2-tributylstannylthiazole (1.57 mL, 5.00 mmol), 3-iodoaniline (0.50 mL, 4.16 mmol) and Pd(Ph3P)4 (465 mg, 0.4 mmol) in 50 mL toluene was degassed using Ar. The mixture was then stirred under Ar at 115° C. for 3 h. The mixture was concentrated and subjected to flash column (0 to 4.5% MeOH in DCM) to isolate 3-(thiazol-2-yl)aniline (709 mg, 95% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: CCc1ccc(CBr)cc1
Product: CCc1ccc(Cn2ccc(-c3nc(C)c(C(=O)NCc4cccnc4)s3)n2)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-ethyl-benzene as described in Example 49 and isolated as a white solid (0.056 g, 42 (% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.52-8.58 (m, 1H), 7.72 (d, J=8 Hz, 1H), 7.06-7.48 (m, 6H), 6.80-6.84 (m, 1H), 6.08-6.15 (m, 1H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H), 2.61-2.70 (m, 2H), 1.13-1.26 (m, 3H); MS (M+H)+=418.2; Rt=1.38 min; HRMS (M+H)+=418.17.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:11][N:10]=1.[F:22][C:23]([F:41])([F:40])[O:24][C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>O>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][C:12]1[CH:13]=[CH:14][C:9]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][O:29][C:28]3[CH:38]=[CH:39][C:25]([O:24][C:23]([F:22])([F:40])[F:41])=[CH:26][CH:27]=3)[CH2:33][CH2:34]2)=[N:10][CH:11]=1
Reactant: Brc1ccc(OC2CCCCO2)cn1
Reactant: FC(F)(F)Oc1ccc(OCCC2CCNCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(OCCC2CCN(c3ccc(OC4CCCCO4)cn3)CC2)cc1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
Toluene (15 ml) was added to a mixture of 2-bromo-5-(tetrahydropyran-2-yloxy)pyridine (2.58 g, 10 mmol), 4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperidine (3.18 g, 11 mmol) and sodium tert-butoxide (1.35 g, 14 mmol), and then the atmosphere was replaced with nitrogen. Bis(dibenzylideneacetone)palladium (Pd2(dba)3 complex) (0.23 g, 0.25 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthine (xantphos) (0.36 g, 0.63 mmol) were added to the mixture, and the reaction mixture was heated at 100° C. for 3 hours under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The result was purified by silica gel column chromatography (ethyl acetate:hexane=10:90→25:75) to afford the title compound as a pale brown powder (4.45 g, 95%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1.[OH-].[NH4+].[CH:22](O)=[O:23]>>[CH2:18]([O:17][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][CH:22]=[O:23])[N:8]=2)=[CH:10][CH:11]=1)=[O:16])[CH3:19]
Reactant: O=CO
Reactant: CCOC(=O)c1ccc(-c2cccc(CN)n2)cc1
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(-c2cccc(CNC=O)n2)cc1

Procedure:
A solution of 0.76 g 6-aminomethyl-2-(p-ethoxycarbonylphenyl)pyridine in 10 ml of formic acid is heated at 90° for 15 h. The reaction mixture is cooled to 0°, made basic with excess saturated ammonium hydroxide solution and extracted with chloroform. The organic extracts are dried and evaporated to yield the title compound (c) which is recrystallized from toluene, m.p. 119.5°-120.5°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:21]=[CH:20][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([CH2:18][OH:19])([CH3:17])[CH2:13][CH2:12]3)=[C:8]([CH3:22])[CH:7]=2)[CH2:2]1.[C:23]1([C:29]2[O:33][C:32]([C:34](OCC)=[O:35])=[N:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C-]#N.[Na+]>CO>[OH:19][CH2:18][C:14]1([CH3:17])[CH2:15][CH2:16][N:11]([CH2:10][C:9]2[CH:20]=[CH:21][C:6]([O:5][CH:3]3[CH2:4][N:1]([C:34]([C:32]4[O:33][C:29]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)=[N:30][N:31]=4)=[O:35])[CH2:2]3)=[CH:7][C:8]=2[CH3:22])[CH2:12][CH2:13]1
Reactant: Cc1cc(OC2CNC2)ccc1CN1CCC(C)(CO)CC1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN1CCC(C)(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 69C (1.65 g, 5.42 mmol) in methanol (25 mL) was added commercially available ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (1.30 g, 5.96 mmol) followed by sodium cyanide (53 mg, 1.10 mmol). The reaction mixture was stirred at RT overnight. The solvent was removed by evaporation and the residue was dissolved in DCM. The solution was washed with NaHCO3, filtered through a phase separator and then evaporated to near dryness. Ether was added and the formed solid was filtered off and washed with ether. The product was dried in vacuo to afford 1.85 g (72%) of 69 as a crystalline solid, m. p. 167° C. 1H NMR (500 MHz, CDCl3): δ 0.96 (s, 3H), 1.31 (m, 2H), 1.52 (m, 2H) 2.28 (m, 2H), 2.34 (s, 3H), 2.51 (m, 2H), 3.38 (s, 2H), 3.40 (s, 2H), 4.31 (dd, 1H), 4.62 (dd, 1H), 4.73 (dd, 1H), 5.05 (m, 1H), 5.13 (m, 1H), 6.54 (dd, 1H), 6.60 (d, 1H), 7.18 (d, 1H), 7.53 (t, 2H), 7.59 (t, 1H), 8.17 (d, 2H), MS (APCI+) m/z 477 [M+H]+, LC purity: 99%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26].O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:25]([NH:24][CH3:23])=[O:26]
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: CN=C=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine (0.5 g, 1.8 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.5 mL, 3.5 mmol), followed by methyl isocyanate (0.121 g, 2.2 mmol), and the reaction was stirred at room temperature under N2 for 30 minutes. The mixture was worked-up with CH2Cl2 and H2O, and the residue was purified by silica gel chromatography to give the title compound.