Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.C(N(CC)CC)C.Cl.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24]>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:24][CH2:23][C:22]([F:26])([F:25])[F:21])=[O:4]
Reactant: NCC(F)(F)F
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccccc1C(=O)NCC(F)(F)F
Reaction time: 16 h
Yield: 52.3 %

Procedure:
A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol), 15 mL water, and triethylamine (4.69 mL, 0.033 mol). (2,2,2-trifluoroethyl)amine hydrochloride (4.98 g, 0.036 mol) was added slowly to the reaction mixture. After 16 h, the reaction mixture was concentrated to dryness. The crude product was purified silica gel column (EtOAc/Hexanes) to afford the title compound as a white solid (3.42 g, 51%): Mass (M+H)+=120, 219.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[CH2:8][CH2:9][N:10]3[CH:21]=[CH:20][CH:19]=[C:11]3[C:12](=[CH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]2[CH2:8][CH2:9][N:10]3[CH:21]=[CH:20][CH:19]=[C:11]3[C:12](=[CH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=2[CH:5]=1
Reactant: CN(C)CCC=C1c2cc([N+](=O)[O-])ccc2CCn2cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCC=C1c2cc(N)ccc2CCn2cccc21

Procedure:
A mixture of 9-nitro-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine (2.0 g.), 0.2 g. of 10% Pd/C and 350 ml. of methanol is hydrogenated until the theoretical amount of hydrogen is absorbed. The mixture is filtered and the filtrate is evaporated to dryness to yield 9-amino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][F:35])=[CH:27][CH:26]=2)[C:21]([OH:23])=O)=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:36][CH:37]1[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@H:20]([NH:19][C:17]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:10])=[O:9])=[O:18])[C:21](=[O:23])[NH:36][CH:37]2[CH2:38][C:39]([CH3:46])([CH3:45])[NH:40][C:41]([CH3:44])([CH3:43])[CH2:42]2)=[CH:26][CH:27]=1
Reactant: O=C(O)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC1(C)CC(NC(=O)[C@H](Cc2ccc(OCCCF)cc2)NC(=O)C2CCCCN2S(=O)(=O)c2cccc(F)c2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
(S)-2-{[(S)-1-(3-Fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-[4-(3-fluoro-propoxy)-phenyl]-propionic acid (80 mg, 0.16 mmol), 4-amino-2,2,6,6-tetramethylpiperidine (25 mg, 0.16 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol) were mixed in dichloromethane (2 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution, and the organic fraction dried over magnesium sulfate. After filtration and subsequent concentration, the resulting oil was chromatographed (dichloromethane/methanol, 9/1) on silica gel to produce 27 mg (27%) of the title compound. MS: m/e 649.33 (M+H). 1H NMR (300 MHz, d6-DMSO): δ0.70-2.20 (m, 27H), 2.80 (m, 2H), 3.20 (m, 1H), 3.65 (d, 1H, J=12 Hz), 4.00 (m, 3H), 4.30 (q, 1H, J=6 Hz), 4.50 (m, 2H), 4.65 (t, 1H, J=6 Hz), 6.90 (d, 2H, J=9 Hz), 7.15 (d, 2H, J=9 Hz), 7.50 (m, 4H), 8.00 (m, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1.I[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[F:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:15][CH2:16][CH3:17])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(F)cc2o1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)oc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To 670 mg (16.74 mmol) of hexanes washed sodium hydride in 20 ml DMF was added a solution of 2.33 g (15.22 mmol) 6-fluoro-1,3-benzoxazolin-2(3H)-one in 40 ml DMF. The reaction was stirred for 10 minutes before 3.11 g (18.3 mmol) 1-iodopropane was added and then stirred for 3 hr at room temperature. After quenching onto 50 ml of ice/water, the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic layers were washed with water (1×100 ml), dried over Na2SO4 and evaporated to dryness in vacuo to give 2.2 g (75% yield) of the alkylated product as a brown solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[CH:53][C:54]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[CH:53][C:54]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3[nH]ccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
DIEA (0.014 mL, 0.073 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.066 mmol) and HATU (0.030 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-Indol-5-yl)-phenylamine (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.017 g of product in 61% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: O=[CH:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH2:19][C:20]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:8]([O:7][C:6]([NH:5][CH2:4][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][NH:19][C:20]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCC(C=O)c1ccccc1
Reactant: COC(=O)C1(N)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1(NCC(CNC(=O)OC(C)(C)C)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a solution of tert-butyl (3-oxo-2-phenylpropyl)carbamate from Step B (0.5 g, 2 mmol) in dry chloroform (20 mL) was added methyl 1-amino-1-cyclopentanecarboxylate (0.431 g, 3.01 mmol). After 15 minutes, sodium triacetoxyborohydride (0.893 g, 4.21 mmol) was added. After 4 hours of stirring at ambient temperature, the reaction mixture was diluted with DCM and 5% sodium bicarbonate. The layers were separated and the aqueous layer was extracted once with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a residue, which was subjected to a normal phase chromatography, eluting with a gradient of 1-6% methanol in DCM. Concentration of the fractions containing the product provided the title compound. MS: m/z=377 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:9]2[S:8][C:6]3=[N:7][C:2]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(-c3cccnc3)nc2s1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
A mixture of 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (204 mmol, 100 mg), pyridine-3-boronic acid (0.306 mmol, 37 mg), potassium phosphate, tribasic (0.408, 87 mg), (0.05 eq, 9 mg), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.1 eq, 9 mg) was stirred at 100° C. for 30 min. Evaporated to dryness and purified by chromatography (0-100% ethyl acetate in CH2Cl2) and HPLC to yield N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(pyridin-3-yl)thieno[2,3-b]pyrazine-6-carboxamide 96j (3 mg, 2%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.29 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.62 (m, 3H), 7.76 (d, J=7.8 Hz, 1H), 7.90 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.59 (s, 1H), 8.64 (m, 1H), 8.75 (m, 1H), 9.45 (s, 1H), 9.58 (s, 1H), 10.38 (s, 1H), 10.54 (s, 1H). (m/z)=534 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:10](O[C:13](=[O:14])[C:5]=12)=[O:11].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[N:4]1[C:5]2[C:13](=[O:14])[NH:2][NH:3][C:10](=[O:11])[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2ncccc12
Yield: 76.2 %

Procedure:
Hydrazine hydrate (13.09 g, 0.261 mol) was added to a stirred solution of pyridine-2,3-dicarboxylic anhydride (30.0 g, 0.201 mol) and sodium acetate (21.45 g, 0.261 mol) in 40% acetic acid/water (400 ml). The reaction was heated at reflux for 3 days under nitrogen. The yellow precipitate was filtered off and washed successively with water (4×200 ml), hexane (3×150 ml) and diethyl ether (3×150 ml) to give the title-compound (25.0 g, 76%), 1H NMR (250 MHz, d6-DMSO) δ 7.90 (1H, q, J=4.5Hz, Ar—H), 8.51 (1H, d, J=4.5Hz, Ar—H), 9.13 (1H, d, J=4.6Hz, Ar—H), 11.65 (2H, br s, 2 of NH); MS (ES+) m/e 164 [MH]+.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([O:18]C)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Methyl (2S,4S)-1-Boc-4-azidopyrrolidine-2-carboxylate (10 g, 37 mmol) obtained in Step D of Preparation 1 was dissolved in MeOH (100 mL) and water (100 mL). LiOH (2.5 g, 111 mmol) was added thereto. The reaction solution was stirred for 3 hours at room temperature, concentrated in vacuo and acidify with 1N HCl. The solution was extracted with EtOAc. The extracted organic solution was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (9.5 g, 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:28])([F:27])[C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:17]1[CH2:18][C@H:13]([C:12]([F:28])([F:27])[F:11])[CH2:14][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:16]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 4-chloro-3-nitropyridine (580 mg, 3.6 mmol), tert-butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (800 mg, 3 mmol), isopropyl alcohol (5.0 mL) and DIPEA (1.0 mL, 6.0 mmol) was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using CombiFlash® apparatus eluting with 50-100% EtOAc/hexanes. The purification gave 1.0 g (80% yield) of the sub-title compound as a yellow solid. LCMS calc. for C16H22F3N4O4(M+H)+: m/z=: 391.2. found: 391.1.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)([CH3:10])[C:7]([OH:9])=[O:8].[CH:24]1C=CC=C[CH:25]=1>C(N(CC)CC)C>[CH3:10][C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:14][CH:13]=1)([CH3:5])[C:7]([O:9][CH2:24][CH3:25])=[O:8]
Reactant: CC(C)(Oc1ccc(C2CCOCC2)cc1)C(=O)O
Reactant: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.2 ml of thionyl chloride were added at 15° C to a mixture of 7 g of 2-methyl-2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoic acid, 70 ml of benzene and 3.5 ml of triethylamine and the mixture was stirred for 2 hours at room temperature and was then filtered. The filtrate was slowly added to 250 ml of 5.4N hydrochloric acid in ethanol and the mixture was stirred for 12 hours at room temperature and was then concentrated to dryness. The residue was added to 100 ml of ether and the solution was washed with a saturated sodium bicarbonate solution and then with water. The solution was dried and evaporated to dryness and the oily residue was distilled under reduced pressure to obtain 6.5 g of ethyl 2-methyl-2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoate with a boiling point of 138°-140° C at 0.1 mm Hg.
Reaction SMILES: S([O-])(O[CH3:5])(=O)=O.[F:7][C:8]([C:11]1[C:12](=[O:25])[C:13]([OH:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]=1[CH3:17])([F:10])[F:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CCOCC>[F:9][C:8]([C:11]1[C:12](=[O:25])[C:13]([O:24][CH3:5])=[N:14][N:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:16]=1[CH3:17])([F:7])[F:10]
Reactant: COS(=O)(=O)[O-]
Reactant: Cc1c(C(F)(F)F)c(=O)c(O)nn1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1nn(-c2ccccc2)c(C)c(C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Tetrabutylammonium bromide (635 mg), 6N soda (13 ml), and methyl sulfate (5.59 ml) are added to a solution of Compound 1 (5.31 grams) in THF. After 1 hour 30 minutes of stirring at 25° C., the solution is evaporated under vacuum, dissolved in water, and extracted with ethyl acetate. After washing with water, drying, filtration and evaporation under vacuum, a residue is obtained which is dissolved in ether and recrystallized from a 60/40 mixture of dioxane and hexane, to provide Compound 2 (3.97 grams; yield 71%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)#[N:4].Br[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14]2)#[N:4]
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Reactant: CCCCC(Br)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(c1ccc(C(F)(F)F)cc1)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 0 %

Procedure:
Sodium hydride (5 moles, 200 mg of 60% in mineral oil) was added to 5-(2-cyanophenyl)indole (4.6 moles, 1.0 g.) in 50 ml DMF and stirred for 45 minutes. 1-Bromo-1-(4-trifluoromethylphenyl)pentane (5 moles, 1.44 g) was added. The reaction was stirred at room temperature overnight, poured into ice water, and extracted into ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The intermediate was chromatographed over silica gel eluted with 10% ethyl acetate in hexane to yield 820 mg of 5-(2-cyanophenyl)-1-[1-(4-trifluoromethylphenyl)-1-pentyl]indole.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:29][CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(OC(F)(F)F)cc3)c(=O)n(C3CCCC3)c12
Yield: 50.9 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(4-trifluoromethoxy-phenyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (24 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-4-trifluoromethoxy-benzene (0.5 mmol) following general procedure C. LCMS: m/z 472 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:16])([F:15])[CH2:12][O:13][CH3:14])=[N:9][N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)#[CH:18]>C1COCC1.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.[Cu]I>[F:15][C:11]([C:8]1[N:6]2[CH:7]=[C:2]([C:18]#[C:17][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([F:16])[CH2:12][O:13][CH3:14]
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COCC(F)(F)c1nnc2ccc(Br)cn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COCC(F)(F)c1nnc2ccc(C#Cc3ccc(C(F)(F)F)cc3)cn12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-bromo-3-(1,1-difluoro-2-methoxyethyl)[1,2,4]triazolo[4,3-a]pyridine (46 mg, 0.16 mmol) in THF (5 mL) was added catalytical amount of dichlorobis(triphenylphosphine)palladium(II) (11 mg) and copper(I) iodide (3 mg), followed by 1-ethynyl-4-(trifluoromethyl)benzene (41 mg, 0.24 mmol). The resulting mixture was flushed with N2 and Et3N (2 mL) was added. The reaction mixture was stirred at 70° C. overnight and purified by prep-TLC (EtOAc:hexanes=2:3) followed by HPLC to give 3-(1,1-difluoro-2-methoxyethyl)-6-((4-(trifluoromethyl)phenyl)ethynyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:34])[C:15](=[O:33])[C:16]2[CH:21]=[C:20]([S:22]CC[Si](C)(C)C)[CH:19]=[C:18]([C:29](F)(F)F)[CH:17]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:34])[C:15](=[O:33])[C:16]2[CH:17]=[C:18]([CH3:29])[CH:19]=[C:20]([SH:22])[CH:21]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C)cc(S)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(trifluoromethyl)-5-(2-(trimethylsilyl)ethylthio)benzamide (0.711 g, 1.32 mmol) in THF (12.6 mL) was added tetrabutylammonium fluoride (1M solution in THF, 6.96 mL, 6.96 mmol) and the clear light yellow solution was stirred at room temperature for 90 minutes. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system eluting with a gradient of CH2Cl2:MeOH (100:0 to 90:10). Colorless solid (0.41 g; 63%). MS (ESI): m/z=437.09 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[C:19]([NH:1][C:2](=[S:12])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:20])[C:18]1[CH:17]=[CH:21][CH:13]=[CH:3][CH:4]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1c(N)sc2c1CC(C)(C)OC2
Product: COC(=O)c1c(NC(=S)NC(=O)c2ccccc2)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a combined mixture of methyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (ChemBridge, CAS 713111-73-0, 31 mg, 0.13 mmol, 1 equiv.) and PhCONCS (0.02 mL, 0.15 mmol, 1.2 equiv.) was added THF (0.7 mL) The resulting solution was stirred at 50° C. for 3 days. The solvent was then removed under reduced pressure and the crude product was triturated with hexanes, filtered, and rinsed with hexanes (4×5 mL). The product was further purified by preparatory HPLC (0-50% EtOAC:hexanes) and isolated as a white solid (38 mg, 72% yield). 1H NMR (400 MHz, CDCl3) δ 14.83 (s, 1H), 9.14 (s, 1H), 7.98 (dd, J=8.4, 1.2 Hz, 2H), 7.72-7.63 (m, 1H), 7.56 (dd, J=10.5, 4.8 Hz, 2H), 4.77 (t, J=1.5 Hz, 2H), 4.04 (s, 3H), 2.85 (s, 2H), 1.35 (s, 6H). LCMS retention time: 3.508 min; LCMS purity at 215 nm=96%. HRMS m/z calculated for C19H21N2O4S2 [M++1]: 405.0937. found 405.0942.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:21])=O>ClCCCl>[Cl:21][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCc2c(sc3ncn(CCO)c(=O)c23)C1
Solvent: ClCCCl
Product: CN1CCc2c(sc3ncn(CCCl)c(=O)c23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
42.0 g (158 mmol) of 3,4,5,6,7,8-hexahydro-3-(2-hydroxy)ethyl-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one in 240 ml of 1,2-dichloroethane was heated to reflux and then 12.7 ml (175 mmol) of thionyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After rafluxing for 2 h, the mixture was allowed to cool and was poured into ice/water. After partitioning between methylene chloride and water at pH=10, the aqueous phase was back-extracted with methylene chloride. The combined organic phases were dried and concentrated. The crude product (40 g) was recrystallized from 400 ml of isopropanol. 30.5 g (68%) of product with melting point 159-161° C. were isolated.