Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[C:2]=[O:3].[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)C(O)=O.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>O.CC(C)=O>[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([N:1]=[C:2]=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=C=O
Reactant: C[Si](C)(C)c1c(F)cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[Si](C)(C)c1c(F)cccc1N=C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of the intermediate isocyanate was carried out via a Curtius rearrangement. See Capson, T. L. et al., Tetrahedron Lett., 25, 3515 (1984) and references herein. To a solution of the compound prepared in (2) (3.03 g, 14.3 mmol) in CH2C12 (20 mL) was added oxalylchloride (1.30 mL, 15.0 mmol) and the resulting mixture was stirred 3 h at room temperature. The residue obtained after evaporation of the solvent was diluted with THF (10 mL) and injected with vigorous stirring to a ice-cooled solution of NaN3 (3.70 g, 57 mmol) in H2O (20 mL) and acetone (50 mL). After 15 min at 0° C. and 1 min at room temperature, the solution was extracted with Et2O (4×50 mL) and dried (Na2SO4). The residue obtained after evaporation of solvents was refluxed in toluene for 1 h 30 to provide, upon solvent removal, 2.85 g (79%) of a slightly yellow oil: IR (neat, cm−1) 2269, 1598, 1433, 1252, 1228, 846, 788; 1H NMR (300 MHz, CDCl3) δ0.38 (d, J=1.9 Hz, 9H), 6.82 (br t, J=8.3 Hz, 1H), 6.90 (br d, J=8.2 Hz, 1H), 7.25 (ddd, J1=J28.1 Hz, J36.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ0.4, 112.6 (d, JCF=26Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, JCF241 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:16][CH2:15][C:14]([F:21])([F:13])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Temperature: 75 °C
Reaction time: 108 h

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.05 ml), anhydrous potassium carbonate (3.29 g) and imethylphosphoric acid triamide (2.07 g) was heated at 70-80° C. with stirring for 4.5 days. Then, the insoluble matter was filtered off and the filtrate was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract layer was dried over magnesium sulfate, then the solvent was distilled off, and the residue was applied to a silica gel column (50 g). Elution with chloroform-methanol (10:1) and recrystallization from ethyl acetate-hexane gave 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles. Melting point 148-149° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:19]([OH:21])=O)[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:62]=[CH:61][N:60]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[N:59]=1>CN(C=O)C.O>[CH3:14][C@H:13]([O:15][C:16]1[CH:17]=[C:18]([C:19]([NH:57][C:58]2[CH:62]=[CH:61][N:60]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[N:59]=2)=[O:21])[CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[CH2:12][O:11][CH3:10]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
DIPEA (28.5 mL, 164 mmol) was added to a suspension of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (20.7 g, 65.6 mmol), HATU (31.2 g, 82.0 mmol) and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (15.0 g, 82.0 mmol) in DMF (30 mL) and the reaction mixture stirred for 16 hours at RT. Water (250 mL) was added and the reaction mixture extracted with diethyl ether (3×150 mL). The organic layer was washed with saturated brine solution and dried (MgSO4). The filtrate was concentrated in vacuo and the residue crystallised on standing. The crystals were washed with isohexane to give to give the desired material as yellow crystals (23.4 g; 73%). m/z 482 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:19](=[O:21])[CH3:20])[N:10]=2)[CH:7]=1
Reactant: Nc1nc2ccc(Br)cn2n1
Reactant: CC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2ccc(Br)cn2n1
Temperature: 20 °C

Procedure:
To a solution of 6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3) (7.10 g, 33.3 mmol) in dry acetonitrile (150 mL) at 5° C. was added triethylamine (11.6 mL, 83.3 mmol) followed by acetyl chloride (2.35 mL 83.3 mmol). The reaction mixture was then allowed to warm to room temperature (20° C.) and stirred until all starting material was consumed (if required, further triethylamine (4.64 mL, 33.3 mmol) and acetyl chloride (33.3 mmol) were added to ensure complete reaction). After this time the solvent was removed in vacuo and to the resultant residue was added 7 N (Methanolic ammonia solution (50 mL)). The reaction mixture was stirred at room temperature (20° C.) to hydrolyze any bis-acylated material. After 16 h evaporation in vacuo and trituration from diethyl ether (50 mL) afforded the title compound which was collected by filtration, washed with water (2×50 mL), acetone (50 mL) and diethyl ether (50 mL) and then dried in vacuo.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[N:38][C:39]([NH:42][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH3:21])[C:7](=[O:22])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: COCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Product: COCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 29.8 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-6-methoxymethyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.5 g, 7.78 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.99 g, 10.73 mmol) were heated to reflux in toluene (25 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-[6-(8-cyclopentyl-6-methoxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1.24 g, 30.5%). 1H NMR δ (400 MHz, CDCl3) 8.59 (s, 1H), 8.26 (d, J=9.3 Hz, 1H), 7.97 (d, J=2.7 Hz, 1H), 7.6 (t, J=1.5 Hz, 1H), 7.38 (dd, J=2.7, 9.0 Hz, 1H), 5.89 (m, 1H), 4.55 (d, J=1.2 Hz, 1H), 3.66 (q, J=7.1 Hz, 2H), 3.60 (m, 4H), 3.11 (m, 4H), 2.34 (m, 2H), 2.07 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.30 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>ClCCl>[CH:16]1([C:22]([C:13]2[S:12][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:10])[F:9])[O:5][N:4]=3)=[CH:15][CH:14]=2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(=O)C3CCCCC3)s2)noc1C(F)(F)F
Yield: 35 %

Procedure:
A solution of 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole (Preparative Example 21, 468 mg, 2.0 mmol) in dichloromethane (20 mL) was treated with FeCl3 (324 mg, 2.0 mmol) followed by cyclohexylcarbonyl chloride (268 μL, 05. mmol). The reaction was heated at reflux for 20 hours followed by evaporation and partitioning between EtOAc (25 mL) and an aqueous 1N hydrochloric acid solution (25 mL). The organic portion was then washed with a second portion of 1N hydrochloric acid solution and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford crude product. The crude product was then chromatographed on silica gel with EtOAc/hexanes (3%) as eluant to afford product as a colorless solid (240 mg, 35%). 1H NMR (CDCl3) 1.24-1.76 (m, 6H), 1.84-1.94 (m, 4H), 2.37 (d, J=1.3, 3H), 3.05-3.15 (m, 1H), 7.54 (d, J=4.0, 1H), 7.74 (d, J=4.0, 1H). 13C NMR 7.9, 25.9, 26.0, 29.7, 47.8, 114.8, 118.7 (q, J=271), 129.1, 131.6, 135.5, 146.0, 155.4 (q, J=41), 158.0, 196.8. 19F NMR −63.1. LC/MS 7.92 min, [M+1]+ 344.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5]C(C)=[CH:7][CH:8]=1.[O-][Mn](=O)(=O)=O.[K+].CC[O:21][C:22]([CH3:24])=[O:23]>O.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:24]([C:22]([OH:21])=[O:23])=[N:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C(=O)O)nc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-methoxy-6-methyl-2-nitropyridine (7 g, 0.041 mol) in water (140.0 mL) was added KMnO4 (32.88 g, 0.208 mol, S.d.fine chemicals, India) at 80° C. The reaction mixture was stirred for 16 h at 100° C. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was filtered and the solids were washed with water. The filtrate was acidified and extracted with EtOAc (500 mL×2). The organic layers were then dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as an off white solid. 1H-NMR (400 MHz, DMSO-d6): δ 13.6 (br. s., 1H), 8.39 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 4.06 (s, 3H). MS (ESI, positive ion) m/z: 199 (M+H).
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25]1(=[O:39])[N:29]([CH2:30][CH2:31][C:32]#[CH:33])[C:28](=[O:34])[C:27]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]12>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]1(=[O:34])[N:29]([CH2:30][CH2:31][C:32]#[C:33][C:2]2[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=2)[C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:25](=[O:39])[C:26]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:27]12
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 78.8 %

Procedure:
5-Iodo-2'-deoxyuridine (354 mg, 1 mmol) was dissolved in 10 mL of dimethylformamide. Cuprous iodide (76 mg, 0.4 mmol), tetrakis (triphenylphosphine) palladium (0) (230 mg, 0.2 mmol), and triethylamine (200 mg, 2.0 mmol) were added. 4-Phthalimidobut-1-yn (300 mg, 1.5 mmol) was added all at once and the reaction kept at 60° C. for three hours. The clear yellow reaction was then evaporated and methylene chloride was added. Scratching of the flask induced crystallization of nearly all of the product which was filtered and recrystallized from 95% ethanol to give 335 mg (78%) of title compound as fine, feathery needles.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.I[CH2:13][C:14]([CH2:55][O:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:13][C:14]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:55][O:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CI)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Reactant: COc1cc(O)ccc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=O)c(OC)c1
Temperature: 130 °C
Reaction time: 72 h
Yield: 96.3 %

Procedure:
4-Hydroxy-2-methoxybenzaldehyde (136 mg, 894 μmol) was dissolved in DMF (10 ml), 1-[3-iodo-2,2-bis(octadecyloxymethyl)propoxy]octadecane (600 mg, 598 μmol) and potassium carbonate (165 mg, 1.19 mmol) were added, and the mixture was stirred at 130° C. for 3 days. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (10 ml) and chloroform (10 ml) were added, and the mixture was stirred. The aqueous layer was removed, and the organic layer was further washed twice with purified water (10 ml). The organic layer was evaporated under reduced pressure, and the residue was precipitated with methanol to give crude crystals of 2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldehyde (592 mg, 96%). The obtained crude crystals were purified by silica gel column chromatography (chloroform-hexane=2:1-chloroform→hexane-ethyl acetate=10:1).
Reaction SMILES: C([N:3](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:25]=[C:26]1[N:34]([C@@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[CH2:33][C@@:32]2(C(O)=O)[C@H:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2>C1(C)C=CC=CC=1>[NH2:3][C@:32]12[CH2:33][N:34]([C@@H:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH3:36])[C:26](=[O:25])[C@@H:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)O)CC=CC[C@H]2C1=O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@]2(N)CC=CC[C@H]2C1=O
Yield: 83.7 %

Procedure:
Triethylamine (1.61 mL, 11.5 mmol) and diphenylphosphoryl azide (1.62 mL, 7.52 mmol) were added to a solution of [(1S,6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-en-1-yl]carboxylic acid (1.65 g, 5.78 mmol) in toluene (28.9 mL) in a nitrogen atmosphere with stirring under ice-cooling, and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and triethylamine was azeotropically distilled with toluene (×3). 1,4-Dioxane (14.4 mL) and 4 mol/L hydrochloric acid (14.4 mL) were added to the resulting residue, and the mixture was stirred at 50° C. for six hours. The reaction solution was diluted with water (30.0 mL) and washed with ethyl acetate (50 mL×2). A 1 mol/L sodium hydroxide solution (55.0 mL) was added to the aqueous layer, followed by extraction with chloroform (100 mL×1, 80 mL×1). The organic layer was washed with brine (150 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 1.24 g of the title compound as an amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2oc(=O)ccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccc2cc(CBr)ccc2o1

Procedure:
To a solution of 500 g (31.25 mmoles) of 6-methylcoumarin in 200 ml CCl4 is added 5.56 g (31.25 mmoles) of NBS. This solution is subjected to a sunlamp at reflux for 41/2 hours. After cooling, the reaction mixture is filtered and the filtrate concentrated in vacuo to yield a solid which upon trituration with ethyl acetate affords 6-bromomethylcoumarin which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[S:13])[N:11]([CH3:14])[N:10]=[C:9]2[C:15]([F:18])([F:17])[F:16])=[C:4]([Cl:19])[CH:3]=1.[C:20](#N)[CH3:21].C(=O)(O)[O-].[Na+].I[CH2:29][CH3:30]>O>[Cl:19][C:4]1[CH:3]=[C:2]([N:1]([CH2:20][CH3:21])[CH2:29][CH3:30])[CH:7]=[CH:6][C:5]=1[N:8]1[C:12](=[S:13])[N:11]([CH3:14])[N:10]=[C:9]1[C:15]([F:16])([F:18])[F:17]
Reactant: CC#N
Reactant: Cn1nc(C(F)(F)F)n(-c2ccc(N)cc2Cl)c1=S
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(-n2c(C(F)(F)F)nn(C)c2=S)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 3.5 g (0.011 mole) of 4-(4-amino-2-chlorophenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione in a 100 ml of acetonitrile were added in succession 2.9 g (0.034 mole) of sodium bicarbonate and 3.7 g (0.024 mole) of iodoethane. The reaction mixture was heated at reflux for approximately 18 hours. An additional 1.8 g (0.011 mole) of iodoethane was added, and the reaction was stirred at room temperature for two days. The mixture was cooled, and the solvent was evaporated under reduced pressure, leaving a residue. Water was added to the residue, and the mixture was extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was purified by column chromatography to produce two fractions. The first fraction yielded 0.5 g of 4-(2-chloro-4-diethylaminophenyl) -3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione as a solid, mp 108°-110° C., Compound 98 of Table 1. The second fraction yielded 1.5 g of 4-(2-chloro-4-ethylaminophenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione as a solid, mp 87°-90° C., Compound 96 of Table 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=3[CH3:27])[C:32]([OH:34])=[O:33])[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 150 °C
Yield: 99.5 %

Procedure:
To the solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (191 mg, 0.50 mmol) in dioxane (15 mL) and water (5 mL) were added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (197 mg, 0.75 mmol), K2CO3 (415 mg, 3.0 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.025 mmol). The reaction mixture was heated to 150° C. for about 15 minutes with microwave. The reaction mixture was concentrated to dry then was added DMSO (2 mL), water (0.5 mL) and HOAc (1 drop). The solution was filtered and applied to the reverse phase HPLC to afford the titled compound 0.24 g (quantitative). LC-MS m/z 483 (M+H)+; 1H-NMR (CD3OD) 2.36 (s, 3 H), 2.76 (s, 6H), 3.16 (s, 2 H), 3.56 (s, 2 H), 4.13 (s, 2 H), 7.21 (m, 1 H), 7.53 (m, 2 H), 7.95 (s, 1 H), 8.09 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:21][C:22]([OH:24])=[O:23])[C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)CBr
Reactant: Cc1ccc([C@@H]2CCC(C)(C)C(=O)N2)cc1F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc([C@@H]2CCC(C)(C)C(=O)N2CC(=O)O)cc1F
Reaction time: 0.25 h

Procedure:
To a stirred solution of (S)-6-(3-fluoro-4-methylphenyl)-3,3-dimethylpiperidin-2-one from Step A (80 mg, 0.340 mmol) in DMF (3 mL) at ambient temperature was added NaH (19 mg of a 60% dispersion in oil, 0.476 mmol). After 15 min, methyl bromoacetate (0.051 mL, 0.544 mmol) was added and the mixture was stirred for 16 h. Sodium hydroxide (0.061 mL of a 10 M solution, 0.612 mmol) was added and the mixture stirred for 2 h. The crude product was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The compound was further purified by SFC, utilizing a ChiralPak AD column and eluting with CO2:MeOH-91:9, to give the title compound. MS: m/z=294 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:4][CH2:3]1.O1CCCC1.O.[OH-].[K+]>CO>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(N[C@H]2CC[C@H](O)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(N[C@H]2CC[C@H](O)CC2)c1

Procedure:
To a solution of methyl 3-[(trans-4-hydroxycyclohexyl)amino]benzoate (0.25 g, 1.00 mmol) in a mixture of methanol (20 mL), terahydrofuran (10 mL) and water (10 mL) was added a 4M aqueous solution of potassium hydroxide (0.5 mL, 2.00 mmol), and the reaction mixture was heated to reflux for five minutes. The organic portion of the solvent was evaporated, and the pH of the aqueous solution was adjusted to 2 by the addition of 2M aqueous hydrochloric acid. The aqueous mixture was partitioned with ethyl acetate, the organic layer was separated and washed with brine, dried over sodium sulfate, filtered, and the solution was concentrated to give 3-[(trans-4-hydroxycyclohexyl)amino]benzoic acid (40 mg, 17%). MS (EI) for C13H17NO3: 234 (M−H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C=C[S:42]C=3CCC2C)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[CH:18]=[CH:17][S:42][C:14]=3[CH2:15][CH2:16][CH:12]2[CH3:13])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2c3ccsc3CCC2C)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.08, 6.87, 6.80, 5.55, 5.08, 4.45, 4.40, 2.91–2.78, 2.58, 2.22, 2.05–1.98, 1.79, 1.28, 1.10, 1.00.