Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH:26]=O)[CH3:21].[NH2:35][C:36]([NH2:38])=[O:37].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:26]([C:25]3[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]([OH:31])=[C:23]([O:22][CH2:20][CH3:21])[CH:24]=3)[NH:35][C:36](=[O:37])[NH:38][C:12]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1OC
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(OC)c(OC)c2)cc([N+](=O)[O-])c1O
Yield: 9.9 %

Procedure:
To a solution of 2-(3,4-dimethoxyphenyl)-1-phenylethanone (Intermediate 7) (130 mg, 0.5 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (106 mg, 0.5 mmol) and urea (69 mg, 1.5 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, then the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by thin layer chromatography (PE:EtOAc=1:2) to give Compound 24 (24.3 mg, yield 9.8%). 1H NMR (CD3OD 400 MHz): δ 7.62 (d, J=1.6 Hz, 1H), 7.30 (s, 5H), 7.17 (s, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.51 (dd, J=2.0 Hz, 8.0 Hz, 1H), 6.38 (d, J=2.0 Hz, 1H), 5.30 (s, 1H), 4.09-4.06 (m, 2H), 3.71 (s, 3H), 3.41 (s, 3H), 1.40 (t, J=7.2 Hz, 3H); MS (ESI): m/z 492.3 [M+1]+.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.[CH2:10](N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:41]([C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51](=[O:58])[CH2:52][CH:53](O)[C:54]([OH:56])=[O:55])=[C:46]([O:59][CH3:60])[CH:45]=1)[CH:42]=[CH2:43]>ClCCl>[CH3:10][O:56][C:54](=[O:55])[CH:53]([O:8][C:7]([C:3]1[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=1)=[O:9])[CH2:52][C:51]([O:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:41][CH:42]=[CH2:43])=[CH:45][C:46]=1[O:59][CH3:60])=[O:58]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCc1ccc(OC(=O)CC(O)C(=O)O)c(OC)c1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C=CCc1ccc(OC(=O)CC(OC(=O)c2cccnc2)C(=O)OC)c(OC)c1
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a suspension of niacin (90 mg, 0.7 mmol) in dichloromethane (10.0 mL) were added N-ethyldiisopropyl amine (0.58 mL, 3.0 mmol), EDCI.HCl (380 mg, 2.0 mmol), HOBt (50 mg, 0.3 mmol) at 0° C. and stirred for 15 min. Then 2-Hydroxy-succinic acid 4-(4-allyl-2-methoxy-phenyl)ester (200 mg, 0.6 mmol) was added at the same temperature and the reaction mixture was stirred at room temperature (25° C.) over a period of 5 h. The reaction mixture was diluted with DCM (150 mL), washed with water (4×50 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of volatiles was purified by column chromatography to obtain pale yellow viscous oil (140 mg, 51%).
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][C@@H:6]([C:11]#[CH:12])[NH:7][C:8](=[O:10])[CH3:9])C.[OH-].[Na+]>CCO>[C:8]([NH:7][C@H:6]([C:11]#[CH:12])[CH2:5][C:4]([OH:13])=[O:3])(=[O:10])[CH3:9]
Reactant: C#C[C@H](CC(=O)OCC)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#C[C@H](CC(=O)O)NC(C)=O
Reaction time: 1 h

Procedure:
To a solution of 13-12 (108 mg, 0.24 mmol) in EtOH (2 mL) was added 1N NaOH (0.270 ml, 0.264 mmol). After stirring for 1 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 to 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 13-13 as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH:18]=1)[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].O.C(=O)(O)[O-]>C(O)C.C(OCC)(=O)C>[NH2:19][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][C:6]=1[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccccc1Oc1cc(Cl)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
A mixture of compound 50 (4.40 g, 14.30 mmol) and 5 nCl2.2H2O (16.13 g, 71.5 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 h. Water and saturated bicarbonate solution (˜250 ml) was added (very effervescent). The reaction mixture was diluted with ethyl acetate and then Celite® was added and the mixture was stirred for 15 min then filtered. The filtrate was extracted with ethyl acetate twice, and the organic extract was dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography, dry loaded with THF onto 80 g SiO2 and eluted with 0% to 50% ethyl acetate in hexanes to afford title compound 51 (2.10 g, 51%) as a beige solid. LRMS (ESI): (calc) 277.05. (found) 278.2 (MH)+. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.46 (ddd, J=7.9, 7.4, 1.8 Hz, 1H), 7.17 (td, J=7.6, 1.2 Hz, 1H), 6.97 (dd, J=8.3, 0.9 Hz, 1H), 6.94 (dd, J=8.4, 2.3 Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.05 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:9][CH2:10][N:11]([CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].[NH:40]([C:44]1[S:45][CH:46]=[C:47]([CH2:49][S:50][CH2:51][CH2:52][NH2:53])[N:48]=1)[C:41]([NH2:43])=[NH:42]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:28]([NH:53][CH2:52][CH2:51][S:50][CH2:49][C:47]2[N:48]=[C:44]([NH:40][C:41]([NH2:43])=[NH:42])[S:45][CH:46]=2)=[O:29])[CH3:21])=[CH:4][CH:3]=1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CN(CCCCCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCCCCCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.6 g (1.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,8-octanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.4 g (1.7 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: chloroform/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method, DMSO/MNBA): m/z (rel. int.[%])=645 ([M+H]+,<1), 234 (100); IR (KBr): 1638 cm-1 (C=O). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 135°-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>O>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(C=O)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a 500-mL round bottom flask with stirbar was added 4-amino-benzaldehyde (2.0 g, 0.0165 mol) and diluted hydrochloric acid (4 N, 150 mL). The mixture was cooled in ice-water bath to keep the temperature around 0° C. Sodium nitrite (2.28 g, 0.033 mol) solution in water (20 mL) was added to the above mixture at 0° C. and stirred for 0.5 h, and then sodium azide (2.15 g, 0.033 mol) solution in water (20 mL) was added to the above mixture dropwise to keep the temperature at 0° C. (a lot of foam were formed in this process). The reaction was warmed gradually to room temperature over 1 h, and then permitted to react at room temperature overnight. TLC showed that there was only one main product in the reaction mixture so the reaction was stopped. The crude product was extracted with EtOAc (50 mL×5) and the combined organic layers were dried with anhydrous MgSO4. After removing the solvent, a light yellow liquid was obtained as the pure final product (2.30 g, 95% yield), IR (neat): 3062, 2114, 1693, 1597, 1578, 1503, 1282, 1166, 1126, 852 cm−1. 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 7.91 (dt, J=8.8, 2.0 Hz, 2H), 7.19 (dt, J=8.8, 2.0 Hz, 2H); 1H NMR (400 MHz, MeOD): δ 7.45 (dt, J=8.8, 2.0 Hz, 2H), 7.08 (dt, J=8.8, 2.0 Hz, 2H), 5.38 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 190.7, 146.4, 133.2, 131.6, 119.5.
Reaction SMILES: [CH:1]1([C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])(C)[C:5]([OH:7])=O)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:38])[C@@H:25]([NH2:37])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1.[CH3:39]N1CCOCC1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:22][O:23][C:24](=[O:38])[CH:25]([NH:37][C:5](=[O:7])[CH:4]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12])[CH2:1][CH:3]1[CH2:2][CH2:39]1)[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1
Reactant: CC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])(C(=O)O)C1CC1
Reactant: CN1CCOCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2ccccc2c1)NC(=O)C(CC1CC1)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 85.1 %

Procedure:
To a solution of cyclopropyl-2-(2-nitro-benzenesulfonylamino)-propionic acid (7.74 mmol) in DMF (10 mL) are added 2-(S)-amino-3-naphthalen-2-yl-propionic acid methyl ester (3.1 g, 11.7 mmol), N-methylmorpholine (4.67 g, 46.27 mmol), 1-hydroxybenzotriazole (17.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.93 g, 10.07 mmol) consecutively. The resulting mixture is stirred for 4 hours, quenched with aqueous NH4Cl and extracted with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified over silica gel (hexanes/ethyl acetate, 1:1) to afford 3.46 g (85% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.04 (dd, J=7.7, 1.4 Hz, 1H), 7.42–7.68 (m, 9H), 7.24 (dd, J=8.4, 1.5 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.20 (d, J=6.9 Hz, 1H), 4.84–4.96 (m, 1H), 3.98–4.07 (m, 1H), 3.71 (s, 3H), 3.29 (dd, J=14.0, 5.6 Hz, 1H), 3.14 (dd, J=14.0, 7.4 Hz, 1H), 1.62–1.72 (m, 1H), 1.23–1.42 (m, 1H), 0.02–0.40 (m, 3H), −0.14–0.02(, 2H); 13C NMR (75 MHz, CDCl3) δ 171.74, 170.45, 147.91, 134.02, 133.73, 133.61, 133.18, 132.70, 131.07, 128.55, 128.32, 127.89, 127.41, 126.54, 126.12, 125.76, 58.59, 53.56, 52.74, 38.34, 37.55, 6.86, 4.38; MS (ESMS) m/z 526.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:21][OH:22].CN([CH:26]=[O:27])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:11]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:21]([O:27][CH3:26])=[O:22])[N:3]=[C:4]2[CH:10]=[CH:9]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CO
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
CO was bubbled into an orange solution of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (50.0 g, 142 mmol) in DMF (2.50 L) within a 5 L round bottom flask for about 2 min. Bis(triphenylphosphine)-palladium(II) dichloride (9.96 g, 14.2 mmol), TEA (59 mL, 423 mmol) and MeOH (173.0 mL, 4259 mmol) were added and the flask was fitted with a balloon of CO. The mixture was heated at about 95° C. under an atmosphere of CO (1 atmosphere). After stirring overnight, the reaction mixture was cooled to ambient temperature overnight and poured into ice water (3.2 L). The mixture was stirred for about 10 min and the precipitate was collected by filtration, while washing with water, and dried for 1 h. The crude material was dissolved in DCM, separated from residual water, dried over anhydrous MgSO4, filtered, added silica gel, and concd under reduced pressure to prepare for chromatography. The crude material was purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to yield methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate with 5 mol % DCM as an excipient (40.7 g, 86%, 93% purity): LC/MS (Table 1, Method a) Rt=2.35 min; MS m/z 332 (M+H)+.
Reaction SMILES: [Br:1]Br.CO[C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9](OC)[C:10]=1OC.C1(C2SC=C(C(C3C=C(OC)C(OC)=C(OC)C=3)=O)N=2)C=CC=CC=1.O>C(O)C>[Br:1][CH2:16][C:15]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=1)=[O:17]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: BrBr
Agent: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Solvent: O
Solvent: CCO
Product: O=C(CBr)c1ccccc1
Yield: 70 %

Procedure:
Bromine (160 mg, 1 mmol) was added dropwise to a stirred solution of an 1-(3,4,5-trimethoxyphenyl)ethanone (210 mg, 1 mmol) in ethanol (30 mL) and the solution was stirred at 0° C. for 1h and then poured into water to form a precipitate. This was recrystallized from ethanol to give bromoacetophenone (70%) and used directly for next step. A mixture of bromoacetophenone (288 mg, 1 mmol) and benzothioamide (137 mg, 1 mmol) in ethanol was refluxed for 1h. The reaction mixture was concentrated in vacuo and purified with flash column to give 2i (167 mg, 51.1%). 1H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.48-7.44 (m, 3H), 7.41 (s, 1H), 7.22 (s, 2H), 3.97 (s, 6H), 3.89 (s, 3H). MS (ESI) m/z 350.1 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][N:14]=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][C:39]([N:45]1[CH2:50][CH2:49][CH:48]([NH:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:67])[F:66])=[CH:61][CH:60]=3)=[CH:55][CH:54]=2)[CH2:47][CH2:46]1)([CH3:44])[C:40]([O:42][CH3:43])=[O:41]>CC(N(C)C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:51]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:60]=[CH:61][C:62]([C:65]([F:67])([F:68])[F:66])=[CH:63][CH:64]=3)=[CH:55][CH:54]=2)[CH:48]2[CH2:49][CH2:50][N:45]([C:39]([CH3:38])([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH2:46][CH2:47]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][N:14]=2
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)cc(=O)c2cccnc21
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)cc(=O)c3cccnc32)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]acetic acid (Int. C2) (100 mg, 1 equiv), carbonyldiimidazole (50 mg, 1.05 equiv) and dimethyl-acetamide (4 ml) was stirred at 60° C. for 30 min then methyl 2-methyl-2-[4-({[4′-(trifluoro-methyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B1) (132 mg, 1.05 equiv) was added and the temperature raised to 80° C. for 2 h. A further portion of carbonyldiimidazole (0.5 equiv) was added and stirring continued at 80° C. for 15 h. After cooling the crude mixture was applied to reverse phase HPLC (Preparative Method A) to obtain methyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]-acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methyl-propanoate (99 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][C:7]2([CH3:15])[CH3:14].Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>CS(C)=O>[CH3:14][C:7]1([CH3:15])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=3)[CH:5]=2)[C:9](=[O:13])[CH2:8]1
Reactant: CC1(C)CC(=O)c2ccc(O)cc21
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2ccc(Oc3ccc(C#N)cn3)cc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Add NaH (60%/oil, 196 mg, 4.91 mmol) to a mixture of 5-hydroxy-3,3-dimethyl-1-indanone (787 mg, 4.46 mmol) and DMSO (00 ml) sting at ambient temperature under nitrogen. After ten minutes, add 6-chloronicotinonitrile (619 mg, 4.46 mmol) dissolved in DMSO (10 ml) and stir the resulting mixture at 60° C. overnight. Quench the reaction with saturated aqueous NH4Cl and extract with EtOAc (2×). Wash extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to a brown, oily solid. Purify on silica gel (10% EtOAc/DCM) to give 877 mg of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)-nicotinonitrile as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(O)c(N)c1
Yield: 106 %

Procedure:
A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl(2-ethylbenzoxazol-5-yl)carboxylate, mp 35°-37° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](O)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)=[O:9].N1C=CC=CC=1C.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(C(=O)c2ccccc2Cl)c(O)n1
Solvent: Cc1ccccn1
Product: CSc1ncc(C(=O)c2ccccc2Cl)c(Cl)n1
Temperature: 80 °C

Procedure:
To a cooled (ice bath) mixture of (2-chlorophenyl)-(4-hydroxy-2-methylsulfanylpyrimidin-5-yl)methanone (18.72 g, 66 mmol) and picoline (3.95 mL, 39.6 mmol) was added dropwise phosphoryl chloride (37.3 mL, 396 mmol) via an addition funnel. The resulting mixture was removed from the ice bath and heated to 80° C. for 2 hours. The reaction was cooled to ambient temperature and poured onto ice (250 mL). Ethyl acetate was added and the layers were partitioned and separated. The organic layer was further washed with two consecutive solutions of saturated sodium bicarbonate (150 mL) followed by brine (150 mL). The aqueous layers were back extracted with ethyl acetate (2×150 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to give the product as a yellow solid (17.36 g, (M+H)+=299.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[CH3:20][N:21]([CH:23]=O)[CH3:22].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O>O.CCOCC>[CH2:9]([C:10]1[N:11]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:14]=[CH:15][C:2]([F:1])=[C:3]([C:16]([F:17])([F:18])[F:19])[CH:4]=3)=[CH:13][CH:12]=2)[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:6][CH:5]3[CH2:14][CH2:22][N:21]([CH3:20])[CH2:23][CH2:4]3)=[CH:31][CH:30]=2)[N:11]=1)[CH2:8][CH2:7][CH3:13]
Reactant: CN(C)C=O
Reactant: Nc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCc1nc(-c2ccc(OC3CCN(C)CC3)cc2)cn1-c1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the alpha-bromoacetophenone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in Et2O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography on silica gel (elution with 5–20% EtOAc/Hexane).
Reaction SMILES: Br[C:2]1[C:3]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([Cl:8])[S:5][C:6]=1[Cl:7].CC[O:26][CH2:27]C.C1C[O:32]CC1>>[Cl:7][C:6]1[S:5][C:4]([Cl:8])=[C:3]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:2]=1[C:27]([OH:26])=[O:32]
Reactant: Clc1cccc(C(OC2CCCCO2)c2c(Cl)sc(Cl)c2Br)c1
Reactant: C1CCOC1
Reactant: CCOCC
Product: O=C(O)c1c(Cl)sc(Cl)c1C(OC1CCCCO1)c1cccc(Cl)c1

Procedure:
2-[(4-Bromo-2,5-dichloro-3-thienyl)(3-chlorophenyl)methoxy]tetrahydro-2H-pyran from Example 8, Step 2 (334 mg, 0.731 mmol) was reacted under conditions similar to Example 1, Step 6 (Et2O was used as a solvent instead of THF; reaction was quenched with 25% aq. NH4OAc instead of 1N HCl). The crude was purified by chromatography on silica gel (50:50 EtOAc/hexane containing 0.25% AcOH) to afford the desired product as a white foam.
Reaction SMILES: Br[CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:27]([Cl:28])=[C:26]([O:29]C(=O)C)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:33]C(=O)C)=[CH:13][CH:12]=1)[C:3](OCCCC)=[O:4].[NH2:37][C:38](N)=[S:39].S1(CCCC1)(=O)=[O:42].Cl.O=O>O.COCCO>[Cl:28][C:27]1[C:26](=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:33])[C:18]=1[O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:2]2[S:39][C:38](=[O:42])[NH:37][C:3]2=[O:4])=[CH:12][CH:13]=1
Reactant: O=S1(=O)CCCC1
Reactant: CCCCOC(=O)C(Br)Cc1ccc(Oc2c(Cl)c(OC(C)=O)c3ccccc3c2OC(C)=O)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: O=O
Solvent: COCCO
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OC3=C(Cl)C(=O)c4ccccc4C3=O)cc2)S1
Temperature: 120 °C

Procedure:
A mixture of 5.8 g of butyl 2-bromo-3-[4-(1,4-diacetoxy-3-chloro-2-naphthyloxy)phenyl]propiona te (prepared as described in Preparation 18), 1 g of thiourea and 10 ml of sulfolane was heated at 120° C. for 5 hours under an atmosphere of nitrogen. At the end of this time, 20 ml of ethylene glycol monomethyl ether and 10 ml of 2N aqueous hydrochloric acid were added to the mixture in the presence of atmospheric oxygen, and the resulting mixture was heated at 100° C. for 6 hours. The reaction mixture was then poured into water, after which it was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed from the extract by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of benzene and ethyl acetate as the eluent. About 2.4 g of the title compound were obtained by recrystallization from a mixture of tetrahydrofuran and hexane as crystals, melting at 250°-252° C.