Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11]O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.I[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]1([S:7]([CH:10]=[CH:11][C:38]2[C:39]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:35]=[CH:36][CH:37]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Ic1cccc2ccccc12
Reactant: O=S(=O)(CCO)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S(=O)(C=Cc1cccc2ccccc12)c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To 0.186 g (1.0 mmol) of 2-(phenylsulfonyl)ethanol, 3 ml of acetonitrile was added, followed by 0.19 g (1.1 mmol) of methanesulfonic anhydride and 0.56 ml (4.0 mmol) of triethylamine, and the mixture was stirred for 5 hours at an internal temperature of 50° C. Subsequently, 0.22 ml (1.5 mmol) of 1-iodonaphthalene, 0.11 g (0.05 mmol) of palladium acetate, and 0.067 g (0.22 mmol) of tri(o-tolyl)phosphine were added thereto, and the mixture was then refluxed for 17 hours. After cooled to room temperature, the reaction mixture was concentrated and purified by column chromatography (hexane/ethyl acetate=80/20) to obtain 0.194 g of [2-(phenylsulfonyl)ethenyl]naphthalene. Yield: 66%.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:2]1[C:3](OC)=O.OCCN.[Cl-].ClCC1CCCC[NH2+]1.[CH3:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]=[S:36]>>[CH3:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]1[N:1]2[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:3][S:36]1
Reactant: COC(=O)C1CCCCN1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: ClCC1CCCC[NH2+]1
Agent: [Cl-]
Solvent: NCCO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2CCCCN12

Procedure:
2-Piperidenemethanol was made from methyl pipecolinate as described in Method B1b. The 2-hydroxyethylamine was converted to 2-chloromethylpiperidinium chloride according to Method B7a. 2-Methyl4-nitrophenyl isothiocyanate was reacted with 2-chloromethylpiperidinium chloride according according to Method C1a to give 9-(2-methyl-4-nitrophenylimino)-1-aza-8-thiabicyclo[4.3.0]nonane.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2>>[ClH:1].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[CH:20][CH:19]=1)[C:26]([CH3:31])=[CH:25]2
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Product: Cc1cc2cc(F)ccc2n1C(=O)c1ccc(OCCCN2CCCCC2)cc1

Procedure:
The title compound (E6) was prepared from 4-(3-piperidin-1-ylpropoxy)benzoic acid hydrochloride (D2) and 5-fluoro-2-methyl-indole using the method described in Example 5 (E5).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29](OCC)=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:37]1[N:42]([CH2:43][CH2:44][NH2:45])[CH2:41][CH2:40][O:39][CH2:38]1>>[F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29]([NH:45][CH2:44][CH2:43][N:42]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NCCN1CCOCC1
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCN3CCOCC3)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(4-morpholino)ethylamine employing methods similar to those described in Example 5 and was obtained as a white solid; 1H NMR (CDCl3) δ 13.49 (1H, br), 10.45 (1H, t, J=6 Hz), 8.57 (1H, s), 7.84 (2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz), 7.04 (1H, s), 7.00 (4H, m), 5.43 (2H, br), 4.31 (2H, m), 4.08 (2H, m), 4.02 (2H, s), 3.99 (2H, m), 3.58 (2H, m), 3.29 (2H, m), 3.03 (3H, s), 2.97 (2H, m); ES+ MS: 595 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:15]([O-])(=O)(=O)=O.[Na+].II.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[I:15])[CH2:2][CH2:3][CH2:4]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(C2CCC2)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCC2)c(I)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-cyclobutylbenzoate (compound 9.1, 2.00 g, 10.5 mmol) in acetic acid (30 mL) was carefully added sodium periodate (1.00 g, 4.68 mmol), iodine (3.00 g, 11.8 mmol) and sulfuric acid (0.15 g). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction was then carefully quenched with saturated aqueous Na2S2O3 (30 mL) and the resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield of the title compound as a yellow oil (1.50 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]([NH2:17])=S)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[K+].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]#[N:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: NC(=S)Nc1ccc(F)cc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1ccc(F)cc1-c1ccccc1

Procedure:
A suspension of N-(5-fluoro-2-biphenylyl)thiourea (8 g) in water (40 ml) was reacted with a solution of potassium hydroxide (18.2 g) in water (40 ml), and a solution of lead acetate trihydrate (12.3 g) in water (70 ml). The reaction mixture heated at 90°-95° C. for 1 hour to give 5-fluoro-2-biphenylylcyanamide as a yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]1)=[O:5].C[Si]([C:22]#[CH:23])(C)C.[NH4+].[Cl-]>C1COCC1>[C:4]([C:6]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:7][CH2:8]1)(=[O:5])[C:22]#[CH:23]
Reactant: C#C[Si](C)(C)C
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 5 h

Procedure:
To a stirred solution of tert-butyl 1-(methoxy(methyl)carbamoyl)cyclopropylcarbamate (5.0 g, 20.49 mmol, 1.0 eq) in THF at −78° C. was added (trimethylsilyl)acetylene (6.36 g, 61.15 mmol, 3.0 eq), and the stirring continued at the same temperature for 5 hr. Product formation was confirmed by LCMS. Saturated NH4Cl solution was added to the reaction mixture, which was then extracted with EtOAC. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using silica gel (60-120). The desired compound was eluted with 15% EtOAC in Pet ether. Yield: 1.5 g (35.70%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[CH2:8][NH:9][CH2:10][C:3]=12.[Cl:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:15][NH:16][C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=[C:19](S(C)=O)[N:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:15][NH:16][C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=[C:19]([N:9]2[CH2:8][C:4]3[C:3](=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:10]2)[N:18]=1
Reactant: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(Cl)c1
Reactant: c1cnc2c(c1)CNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnc(N2Cc3cccnc3C2)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride salt (1.86 g, 12 mmol) was added into the solution of ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-methanesulfinyl-5-pyrimidine carboxylate in DCM. The mixture was cooled in an ice bath, and triethylamine was added dropwisely (2.5 mL, 17.9 mmol). The reaction mixture was stirred at ambient temperature overnight. LC-MS was used to monitor the reaction. After the completion of the reaction, water (30 mL) was added for precipitation. The solid was filtrated and dried to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(5H-pyrrolo[3,4-b]pyridine-6(7H)yl)-5-pyrimidine carboxylate (3.0 g, 65.6% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.Cl.FC1CNC1.C([N:36]([CH:40]([CH3:42])C)[CH:37]([CH3:39])C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:36]2[CH2:37][CH2:39][CH2:42][CH2:40]2)=[O:27])[CH:4]=[N:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: FC1CNC1
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 88.6 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), 3-fluoroazetidine hydrochloride (202 ul, 2.42 mmole), N-ethyldiisopropylamine (282 ul, 1.62 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for 22 h at 70° C. The solvent is removed under reduced pressure and the residue (772 mg) is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording 1-methyl-N-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (152 mg, 88.7%) as a white solid. mp.: 210-2° C. MS: m/z=429.4 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[N:21]([C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1)=[C:22]=[S:23]>>[CH2:31]([O:30][P:29]([CH2:28][C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:19][CH3:20])=[S:23])=[CH:38][CH:37]=1)(=[O:36])[O:33][CH2:34][CH3:35])[CH3:32]
Reactant: CCOP(=O)(Cc1ccc(N=C=S)cc1)OCC
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Product: CCOP(=O)(Cc1ccc(NC(=S)Nc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1)OCC

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.137 g, 0.5 mmol) was reacted with the product from Example 23, Step A (0.156 g, 0.54 mmol) according to the procedure for Example 23, Step B to give the product (0.172 g), mp 180-182° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[S:18][C:19]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=2[O:30][CH3:31])=[C:20]([CH3:22])[N:21]=1>ClCCl.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:19]3[S:18][C:17]([CH3:16])=[N:21][C:20]=3[CH3:22])=[C:24]([O:30][CH3:31])[CH:25]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1sc(C)nc1C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1sc(C)nc1C
Yield: 94.6 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (130 mg, 0.59 mmol) and 4-(2,4-dimethyl-thiazol-5-yl)-3-methoxy-phenylamine (139 mg, 0.49 mmol) using in analogous manner the procedure described in example 206c). Column chromatography (20 g silica, dichloromethane/ethyl acetate 1/1 v/v) afforded the title compound (193 mg, 78%) as a light yellow waxy solid. MS ISP (m/e): 417.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.78 (d, 1H), 7.29 (m, 5H), 7.17 (d, 1H), 7.14 (s, 1H), 6.99 (dd, 1H), 6.48 (s, 1H), 3.97 (s, 2H), 3.78 (s, 3H), 2.67 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:16]O)[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[S:7])(C)(C)C.[ClH:18]>>[ClH:18].[ClH:18].[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:9]2[CH2:16][S:7][C:6]([NH2:5])=[N:8]2)[N:12]=[CH:13]1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cscn1
Agent: Cl
Product: NC1=N[C@H](Cc2cscn2)CS1

Procedure:
A solution of 1.75 g of N-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]thiourea in 20 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 110° C. for 20 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 60° C., taken up in 5 cm3 of ethanol and then concentrated under the same conditions as above. The residue is taken up in 5 cm3 of ethanol and the product is then filtered off and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. 0.54 g of (+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-2-thiazolylamine dihydrochloride is obtained in the form of a cream-coloured solid melting at 195° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 3.67 (mt: 2H); 3.41 (dd, J=11.5 and 5.5 Hz: 1H); 3.68 (dd, J=11.5 and 8 Hz: 1H); 4.63 (mt: 1H); 7.59 (d, J=2 Hz: 1H); 9.14 (d, J=2 Hz: 1H); 9.18 (unresolved complex: 1H); 9.66 (unresolved complex: 1H); 10.04 (broad s: 1H); (αD20=+24.2+/−0.8 at a concentration of 0.5% in methanol)].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:20])=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[CH:9]=1.[Br:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27](O)=[O:28].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.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.CN(C=O)C>[Br:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:20])=[C:8]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[CH:9]=1)=[O:28]
Reactant: O=C(O)c1[nH]cnc1Br
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2cc(CNC(=O)c3[nH]cnc3Br)ccc2Cl)c1
Reaction time: 0.08 h
Yield: 16 %

Procedure:
DMF (5 mL) was added to a mixture of 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile hydrochloride (0.115 g, 0.349 mmol), 4-bromo-1H-imidazole-5-carboxylic acid (0.070 g, 0.366 mmol) and HATU (0.159 g, 0.419 mmol). The mixture was stirred for 5 min then DIPEA (0.122 ml, 0.698 mmol) was added and the yellow solution was stirred at RT under an atmosphere of nitrogen for 2 h. Saturated aqueous NaHCO3 solution (30 mL) and ethyl acetate (75 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (2×50 mL), water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by Reverse Phase HPLC (MeCN/water+0.1% TFA) to give the title compound (0.026 g, 16%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.74 (br. s., 1H), 7.49-7.56 (m, 2H), 7.30 (d, 1H), 7.16-7.24 (m, 3H), 4.57 (br. s., 2H). LCMS m/z 467.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17][CH2:18]C)=[O:16])=[CH:4][CH:3]=1.[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][N:10]2[CH:14]=[C:13]([C:23](=[O:24])[C:22]([Cl:27])([Cl:26])[Cl:21])[CH:12]=[C:11]2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccn1CC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)cn1CC(=O)c1ccc(Cl)cc1
Yield: 42.5 %

Procedure:
To a solution of ethyl 1-[2-(4-Chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (150 mg, 0.54 mmol) in CH2Cl2 (10 ml) was added trichloroacetyl chloride (120 μL, 1.1 mmol) and aluminium chloride (290 mg, 2.2 mmol). After 16 h the reaction was quenched by the addition of a saturated aqueous solution of NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to give a residue that was purified using flash chromatography (2× Biotage SP4, 12 g cartridge, 20-100% EtOAc gradient in n-hexanes) to give methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(trichloroacetyl)-1H-pyrrole-2-carboxylate (97 mg, yield 42%) as a brown solid. 1H NMR (400 MHz, d6-acetone): δ 3.75 (s, 3H), 6.12 (s, 2H), 7.56 (d, 1H, J 2.0 Hz), 7.64-7.68 (m, 2H), 8.10-8.14 (m, 2H), 8.15 (d, 1H, J 2.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[CH:11]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[O:14][C:13]([CH3:21])([CH3:20])[C:12]1=[O:22].Br[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][N:25]=1.[Na].[Na].[Na].S(C1C=C(P(C2C=CC=C(S(O)(=O)=O)C=2)C2C=CC=C(S(O)(=O)=O)C=2)C=CC=1)(O)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[Cl:30][C:29]1[C:24]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH:11]3[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[O:14][C:13]([CH3:21])([CH3:20])[C:12]3=[O:22])[CH:4]=2)=[N:25][CH:26]=[C:27]([Cl:31])[CH:28]=1
Reactant: Cc1ccc(B(O)O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Clc1cnc(Br)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2ncc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.3 %

Procedure:
To a microwave vial is added 4-methyl-3-(2,2,6,6-tetramethyl-3,5-dioxo-tetrahydropyran-4-yl)phenylboronic acid (200 mg, 0.657 mmol), 2-bromo-3,5-dichloropyridine (149 mg, 0.657 mmol), palladium acetate (3.7 mg, 0.0164 mmol), tris(3-sulfophenyl)phosphine trisodium salt (22 mg, 0.0394 mmol) and potassium phosphate (697 mg, 3.28 mol), followed by a degassed solvent mixture of water/acetonitrile (1.6 ml, 2:1 ratio). The mixture is flushed with nitrogen then stirred at ambient temperature for 5 minutes before heating at 160° C. under microwave irradiation for 15 minutes. After cooling to room temperature the reaction is partitioned between 2M aqueous hydrochloric acid and dichloromethane, and the organic phase is separated. The aqueous phase is further extracted with dichloromethane and all organic fractions are combined then evaporated. The residue is purified by preparative reverse phase HPLC to give 4-[5-(3,5-dichloropyridin-2-yl)-2-methylphenyl]-2,2,6,6-tetramethylpyran-3,5-dione (113 mg).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([F:14])[CH:8]=1)C.[OH-].[Na+]>CO>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:15])=[O:3])=[CH:8][C:9]=1[F:14]
Reactant: CCOC(=O)C=Cc1ccc(Br)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1ccc(Br)c(F)c1
Yield: 84.6 %

Procedure:
10.5 g (38.6 mmol) of 3-(4-bromo-3-fluoro-phenyl)-acrylic acid ethyl ester were dissolved in 100 mL of methanol and stirred overnight with 97 mL of aqueous 1 M sodium hydroxide solution. After removal of the methanol in vacuo the residue was acidified with concentrated hydrochloric acid. The precipitate was isolated by suction and dried in vacuo at 50° C. furnishing 8.0 g of 3-(4-bromo-3-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH:10]([OH:12])[CH3:11])=[N:6][C:7]=1Br.[CH2:13]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[F:32])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:1][C:2]1[C:7]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([NH:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:22])=[C:24]([F:32])[CH:25]=2)=[N:6][C:5]([CH2:9][CH:10]([OH:12])[CH3:11])=[CH:4][N:3]=1
Reactant: CC(O)Cc1cnc(N)c(Br)n1
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(O)Cc1cnc(N)c(-c2ccc(C(=O)NCc3ccccc3)c(F)c2)n1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+/−)-1-(5-amino-6-bromopyrazin-2-yl)propan-2-ol (30 mg, 0.129 mmol) in DME (970 μL) was added 4-(benzylcarbamoyl)-3-fluorophenylboronic acid (31.8 mg, 0.116 mmol), PdCl2(dppf)CH2Cl2 adduct (10.56 mg, 0.013 mmol), 2M Na2CO3 (323 μL). The reaction mixture was stirred at 120° C. for 10 min in microwave. The reaction mixture was partitioned between EtOAc and water. the organic was dried and concentrated. the crude product was purified by Prep HPLC. The pure fraction was combined and desalt to yield (+/−)-4-(3-amino-6-(2-hydroxypropyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide. LCMS (m/z): 381.2 (MH+), 0.67 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.95-7.81 (m, 2H), 7.66 (dd, J=1.6, 8.2 Hz, 1H), 7.58 (dd, J=1.6, 11.7 Hz, 1H), 7.43-7.31 (m, 4H), 7.31-7.19 (m, 1H), 4.62 (s, 2H), 4.16-4.04 (m, 1H), 2.79 (d, J=6.3 Hz, 2H), 1.23 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[O:21]=[C:22]1[CH2:27][CH2:26][C:25]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.CCCC(C)C.CCO>>[CH3:1][C@H:2]([C:6]1[CH:7]=[C:8]([C:16]([F:17])([F:19])[F:18])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[C:3]([NH:34][C:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:22](=[O:21])[CH2:27][CH2:26]1)=[O:4]
Reactant: C[C@@H](C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Solvent: CCCC(C)C
Solvent: CCO
Product: C[C@@H](C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (R)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 41) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 18) according to the method of Example 50. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H, m), 5.71 (1H, s), 3.70 (1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60 (1H, m), and 1.52 (3H, d, J 7.0 Hz). e.e. [Determined by chiral HPLC (Chiralcel OD-H 250×4.6 mm i.d.; isohexane/EtOH (96:4); 1 mL/min; 210 nm]>99%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[O:7][C:6]([CH:8]=[C:9]2[S:13]C(=S)N[C:10]2=[O:15])=[CH:5][CH:4]=1.[OH-:18].[Na+]>O>[SH:13][C:9](=[CH:8][C:6]1[O:7][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=1)[C:10]([OH:18])=[O:15]
Reactant: O=C1NC(=S)SC1=Cc1ccc(C(F)(F)F)o1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(S)=Cc1ccc(C(F)(F)F)o1
Temperature: 25 °C
Yield: 60 %

Procedure:
1.58 g of the above 5-(5-trifluoromethyl-2-furylmethylene)rhodanine, 23 ml of 1 N sodium hydroxide solution and 25 ml of water are stirred under nitrogen at room temperature for 10 hours. After cooling with an ice bath and acidification with concentrated hydrochloric acid to pH 1.5, the resulting slurry is filtered to yield a slightly brown precipitate which is washed with 50 ml of water by stirring at room temperature under nitrogen and filtered to yield 0.8 g of slightly brown crystals (yield 60%) of α-mercapto-β-(5-trifluoromethyl-2-furyl)acrylic acid. M.P. 158° C.