Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1C=CC=CC=1>[OH-].[Na+]>[Cl:1][C:2]1[C:7]([CH:8]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C=O)c(Cl)nc1C
Reactant: O=C(O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1cc(C=CC(=O)O)c(Cl)nc1C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g) piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and evaported to an oil. This oil was dissolved in sodium hydroxide solution and was extracted with chloroform (discarded). The aqueous phase was acidified with hydrochloric acid and was extracted with chloroform. The chloroform extracts were washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%) m.p. 150°-158°. This acid was esterified using ethanol and sulphuric acid to give the ethyl ester m.p. 85°-88°.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9](=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[CH:13][CH:12]=1)[CH2:2]2.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(#N)C>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][N:3]([C:9](=[O:22])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]4[CH:21]=[N:20][N:19]=[N:18]4)=[CH:15][CH:16]=2)[CH2:4]3)=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2CCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (100 mg, 0.335 mmol) was combined with 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.34 mmol) and Hunig's base (43.3 mg, 0.335 mmol) in acetonitrile (1 mL) and stirred at 60° C. for 5 h. Purification by mass-directed HPLC afforded the title compound. LC/MS: [(M+1)]+=448.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[CH2:25]O)[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:30])=O.[Na+].[Cl-]>ClCCl.CN(C=O)C>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[CH2:25][Cl:30])[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cc2cc(C(F)(F)F)ccc2CO)c2cccnc21
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(Cc2cc(C(F)(F)F)ccc2CCl)c2cccnc21
Reaction time: 3 h
Yield: 73.9 %

Procedure:
To a solution of 15 (3.5 g, 10.4 mmol) in dichloromethane (20 mL) was charged DMF (0.04 mL, 0.5 mmol). This solution was cooled under an ice bath. Thionyl chloride (0.85 mL, 11.5 mmol) was then added under 5° C., and the resulting reaction was aged for 3 h at this temperature. Once the reaction was complete, 5% aqueous NaCl (16.5 mL) was added. The organic layer was separated and washed with 5% aqueous NaCl (16.5 mL). The solvent was removed via rotovap, and the crude was purified by silica gel column chromatography (0 to 10% AcOEt/hexane) to give the desired compound 16 as an oil (3.05 g, 74%). 1H NMR (CDCl3, 500 MHz): δ 8.20 (dd, J=5.1, 1.7 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.1, 1.1 Hz, 1H), 7.18 (s, 1H), 7.12 (dd, J=6.3, 2.7 Hz, 1H), 6.88 (dd, J=7.3, 5.1 Hz, 1H), 4.77 (ABq, J=12.9 Hz, 2H), 3.72 (m, 1H), 3.46 (dd, J=14.2, 4.4, 1H), 3.18 (dd, J=14.2, 8.7 Hz, 1H), 1.67 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 177.6, 159.1, 146.5, 143.3, 136.6, 131.0, 129.7 (m, 2C), 124.0, 123.0, 123.9 (q, J=271 Hz), 117.4, 126.6, 62.4, 58.8, 46.1, 32.9, 28.6.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[F:27])(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: O=S(=O)(c1ccccc1F)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccccc5F)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-[4-(2-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 282. NMR (CDCl3/MeOD): 2.53-2.56 (4H, m), 3.15-3.20 (4H, m), 3.75 (2H, s), 3.75-3.81 (4H, m), 3.89-3.93 (4H, m), 7.15 (1H, s), 7.14-7.25 (2H, m), 7.51-7.58 (1H, m), 7.71-7.77 (1H, m), 9.08 (2H, s). MS (ESI+): MH+ 571.22 (80%)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1.C(OC(=O)C)(=O)C>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccncn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C=Cc2ccncn2)cc1
Temperature: 120 °C
Yield: 77 %

Procedure:
The starting compound is prepared as follows. p-Nitrobenzaldehyde (24.2 g), 4-methyl-pyrimidine (15.5 g) and acetic anhydride (16.7 g) are mixed at room temperature, and the mixture is heated at 120° C. for 5 hours. After cooling, the mixture is poured into water (500 ml), and the aqueous mixture is extracted several times with chloroform. The combined chloroform extracts are dried over magnesium sulfate and concentrated until crystals separated. Addition of ether gives 4-[2-(p-nitrophenyl)ethenyl]pyrimidine (28 g), m.p. 213°-215° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.[NH2:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH3:22]>>[CH3:22][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][CH2:14][C:13]1[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=1[NH:11][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: CCOC(=O)c1ccoc1
Reactant: CN1CCCCC1CCc1ccccc1N
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccoc1

Procedure:
Reaction of ethyl furan-3-carboxylate prepared by the method of Boyd et al, Synthesis, 545, (Oct. 1971) with 2-(2-amino-phenethyl)-1-methylpiperidine according to the procedure of Example 115 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]-3-furancarboxanilide, m.p. 114.5° - 115.5° C. (corr.), from isopropyl ether and then ethyl acetate.
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:32](OC(C)(C)C)=[O:33])[C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:18][CH:17]=3)=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.C[Si](I)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([NH:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[CH2:14][C:10]3[N:9]4[C:5](=[CH:6][N:7]=[C:8]4[CH:13]=[CH:12][CH:11]=3)[C:32]2=[O:33])=[CH:21][CH:20]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12)c1ccc(CCNS(=O)(=O)C(F)(F)F)cc1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1c2cnc3cccc(n23)CN1c1ccc(CCNS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a solution of 644 mg (1.00 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl]aminomethyl]imidazo[1,2-a]pyridine in 5 ml of chloroform was added dropwise 0.29 ml (2.00 mmol) of trimethylsilyl iodide at room temperature. The reaction mixture was stirred for 30 minutes at room temperature, and poured into ice-water. The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. To the mixture was added 50 ml of chloroform for extraction of the desired compound. The organic layer was washed with 50 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=20:1) to afford 195.7 mg of the desired compound (46.1%, a pale yellow solid).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:8][C:7]([CH3:24])([CH3:23])[C:6]1[CH2:25][CH2:26][CH2:27][C:28](=[O:29])[C:5]2=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:8][C:7]([CH3:23])([CH3:24])[C:6]1[CH2:25][CH2:26][CH2:27][C:28](=[O:29])[C:5]2=1)(=[O:32])[CH3:31]
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1=C(CCCC1=O)C(C)(C)N2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(cc1C(C)CCCc1ccccc1)NC(C)(C)C1=C2C(=O)CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridine (2.2 ml.) is added to a suspension of 5,6,7,8,9,10-hexahydro-2-hydroxy-3-(1-methyl-4-phenylbutyl)-6,6-dimethyl-10-oxobenzo[c]quinoline (250 mg., 0.642 mmole) in 2.2 ml. of acetic anhydride under a nitrogen atmosphere. The mixture is stirred for 1.5 hours at room temperature and then poured onto ice (50 ml.). The mixture is extracted with ether, the extracts washed with water (4×50 ml.) and brine (1×60 ml.), dried (MgSO4) and evaporated under reduced pressure.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:29][N:30](C)[C:31](C1CN(C)C(=O)C=1O)=O>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:29][N:30]([CH3:31])[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccccc1F)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccccc1F)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 58 %

Procedure:
3-[(2-Fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 50-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (58% yield); mp 147° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.1 (3H, s, NCH3), 3.76 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.97 (2H, s, NCH2), 7.06–7.39 (4H, m, aromatics). Anal. calcd for C14H15FN2O4: C, 57.14; H, 5.14; N, 9.52. Found: C, 57.00; H, 5.29; N, 9.33.
Reaction SMILES: C([BH3-])#N.[Na+].C1(N2[C:15]([CH2:16][O:17]C)=[C:14]([C:19]3ON=[C:21]([C:24]4C=CC(C=O)=CC=4)[N:20]=3)C=N2)CCCCC1.C(O)(=[O:34])C>CO>[NH:20]1[CH2:19][CH2:14][CH:15]([C:16]([OH:17])=[O:34])[CH2:24][CH2:21]1
Reactant: CC(=O)O
Reactant: COCc1c(-c2nc(-c3ccc(C=O)cc3)no2)cnn1C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1CCNCC1

Procedure:
Sodium cyanoborohydride (32.5 mg; 0.517 mmol) was added to a solution of 4-(5-(1-cyclohexyl-5-(methoxymethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained from step 1, (172 mg; 0.47 mmol) and isonipecotic acid (121.4 mg; 0.94 mmol) in a mixture of methanol (3 mL) and acetic acid (80.7 μl; 0.141 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC to give Example 64 as a white solid. 1H NMR (DMSO-d6) δ 8.23 (1 H, s), 8.04 (2 H, d, J=8.1 Hz), 7.54 (2 H, d, J=8.0 Hz), 5.02 (2 H, s), 4.44-4.34 (1 H, m), 3.56 (2 H, s), 3.34 (3 H, s), 2.78 (2 H, d, J=11.0 Hz), 2.26-2.17 (1 H, m), 2.06 (2 H, t, J=11.2 Hz), 1.96-1.76 (8 H, m), 1.71 (1 H, d, J=12.8 Hz), 1.66-1.52 (2 H, m), 1.53-1.37 (2 H, m), 1.25 (1 H, t, J=13.0 Hz). LC/MS: 480 (M+H)+. HPLC (Method G) Rt=2.39 min (Purity: 96.7%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH2:12][CH3:13].Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[C:12]2[CH3:13]
Reactant: CCC(=O)c1cccnc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride is synthesized based on the method described in U.S. Pat. No. 3,468,894. (4-Chloro-phenyl)-hydrazine hydrochloride (3.0 g, 16.8 mmol) and 3-propionylpyridine (2.4 g, 17.6 mmol) in ethanol (45 mL) is heated to reflux for 6 h. The mixture is then cooled to room temperature and added to HCl (4M in 1,4-dioxane, 17.6 mL). The resulting mixture is heated to reflux for 24 h. The mixture is then cooled to room temperature and the yellow precipitate is filtered and washed with methanol (10 mL) three times to give 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as a yellow solid. MS (ESI) m/z 243.0 and 244.9 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]2[CH:12]=[C:13]([CH2:15]O)[O:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[O:1]([C:8]1[CH:18]=[CH:17][C:11]2[CH:12]=[C:13]([CH2:15][N:23]3[C:19](=[O:29])[C:20]4[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:22]3=[O:24])[O:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc2ccc(Oc3ccccc3)cc2o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(Oc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a tetrahydrofuran (4 mL) solution of (6-phenoxy-benzofuran-2-yl)-methanol (177 mg, 737 μmol) described in Production Example 49-1-2 were added phthalimide (119 mg, 811 μmol), triphenylphosphine (232 mg, 884 μmol) and diethylazodicarboxylate (403 μL, 884 mmol) at 0° C., which was stirred at room temperature for 4 hours and 30 minutes. Water was added to the reaction solution followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (209 mg, 77%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([N:32]1[C:36]([CH3:38])([CH3:37])[CH2:35][NH:34][C:33]1=[O:39])(=O)C1C=CC=CC=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:34]4[CH2:35][C:36]([CH3:38])([CH3:37])[NH:32][C:33]4=[O:39])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1(C)CNC(=O)N1C(=O)c1ccccc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)NC4=O)nc3)CC2)c(C)c1
Yield: 36.7 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 1-benzoyl-5,5-dimethylimidazolidin-2-one (105 mg) described in Preparation Example 58 and by the reaction and treatment in the same manner as in Example 509 to give the title compound (60 mg) produced by debenzoylation that simultaneously proceeded during the reaction.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:16])([F:15])[F:14].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH:12][C:23]([C:22]3[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=3)=[O:24])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:14])([F:15])[F:16]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: Cn1c(C(F)(F)F)cc2cc(CN)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc2cc(CNC(=O)c3ccc(C(F)(F)F)nc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
[(1-Methyl-2-trifluoromethylindol-5-yl)methyl]amine (Intermediate 11, 150 mg, 0.657 mmol) was dissolved in DCM (10 mL) and 6-(trifluoromethyl)nicotinoyl chloride (ABCR; 165 mg, 0.789 mmol) was added. Et3N (0.183 mL, 1.315 mmol) was added and the reaction mixture was left to stir at room temperature for 2 hrs. The reaction mixture was quenched with methanol (10 mL) and evaporated to dryness. The resulting residues were partitioned between ethyl acetate and a 1M solution of citric acid. The organic layer was collected, dried (MgSO4), filtered and the solvent removed. The resulting residues were then purified by MDAP and evaporated to dryness to give the title compound (100 mg);
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(C2=CCOCC2)c(C(=O)O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C2CCOCC2)c(C(=O)O)c1

Procedure:
To 0.07 mmol 2-(3,6-Dihydro-2H-pyran-4-yl)-5-methanesulfonyl-benzoic acid (CAS: 847547-05-1) in 0.5 ml methanol under argon was added 20 mg Pd/C, followed by 0.07 mmol ammonium formate. The reaction mixture was refluxed for 30 minutes, filtered and evaporated. Water was added and the solution was acidified with 2N HCl to pH 1. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and evaporated to yield the title compound as a colorless oil. MS (m/e): 283.2([M−H], 100%).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][CH:35]=1)[CH2:15][S:16][CH2:17][C:18]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1)(O)[C:19]([F:22])([F:21])[F:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CN=C1.C(=O)(O)[O-].[Na+]>C(#N)C>[O:5]([C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][CH:35]=1)[CH2:15][S:16][CH2:17][C:18]([Cl:3])([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1)[C:19]([F:22])([F:21])[F:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(O)(CSCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CCOc1ccc(C(Cl)(CSCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Thionyl chloride (0.2 g) was added to a cooled solution of 1,1,1-trifluoro-2-(4-ethoxyphenyl)-2-hydroxyprop-3-yl 3-phenoxybenzyl sulphide (0.165 g) and imidazole (0.123 g) in acetonitrile (5 cm3), the temperature of the mixture being maintained at 0° C. The reaction mixture was then allowed to warm to the ambient temperature (21° C.) and stirred for 30 minutes, before being added to a saturated aqueous solution of sodium bicarbonate (7 cm3). The product was extracted into diethyl ether (3×15 cm3), and the combined organic layers were dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel support, eluting with petroleum ether containing 10% by volume diethy ether, to give 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)prop-3-yl 3-phenoxybenzyl sulphide (0.12 g) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-:21].[Na+]>Cl>[CH3:1][N:2]([CH3:20])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:19])=[O:21])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CN(C)c1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Yield: 52.1 %

Procedure:
A solution of 3-[4-(dimethylamino)phenyl]-1H-indazole-5-carbonitrile (125 mg, 0.476 mmol) in 5.00 mL of concentrated aq. HCl was heated at 47° C. for 1 h, and then added dropwise with stirring to 20 mL of 6.0 N aq. NaOH that was cooled in a water bath. The mixture was extracted with 2×EtOAc, and the combined organics were dried (Na2SO4). Purification by silica gel chromatography using EtOAc as eluent afforded the title compound (69.3 mg, 52.1% yield): 1H NMR (DMSO-d6) δ 13.19 (s, 1H), 8.58 (s, 1H), 8.10 (br s, 1H), 7.9S–7.82 (m, 3H), 7.56 (d, 1H), 7.30 (br s, 1H), 6.84 (d, 2H), 2.98 (s, 6H); ES-MS (m/z) 281 [M+1]+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=O)=[CH:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH2:20][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:12]1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1NCc1c[nH]c2ncccc12
Temperature: 25 °C

Procedure:
A mixture of anthranilic acid (1.37 g, 1.0 mmol), 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.46 g, 1.0 mmol), and p-toluenesulfonic acid mohohydrate (0.025 g, 0.13 mmol) in 30 mL of anhydrous toluene was stirred at reflux for 1 h. After being cooled to RT, NaBH4 (0.9 g) was added, and the mixture was stirred at RT for 30 min. The reaction was quenched with MeOH, and the volatiles were removed under reduced pressure. The residue was taken up in water, AcOH was added to bring pH to 4, and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, and condensed. The residue was purified by flash column chromatography to give the titled compound. MS (ES+): 268.1 (M+H)+. Calc'd for C15H13N3O2-267.10.
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][C:7]1([OH:29])[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]1)=[N+:4]=[N-:5].[CH3:30]I.O>CN(C=O)C>[N:3]([CH2:6][C:7]1([O:29][CH3:30])[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:8]1)=[N+:4]=[N-:5]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)(CN=[N+]=[N-])C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(CN=[N+]=[N-])CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
Under ice-cooling, sodium hydride (60% oil, 8 mg) was added to a solution of tert-butyl (6RS,7SR)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (120 mg) in DMF (5 mL). The mixture was stirred at room temperature for 20 min, methyl iodide (122 mg) was added, and the mixture was stirred at the same temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (115 mg).