Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([Cl:18])[C:12](Cl)=[C:13](Cl)[C:14]=1[Cl:15])[C:8]([OH:10])=[O:9].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([Cl:18])[C:12]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[C:13]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)[C:14]=1[Cl:15])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(Sc2c(Cl)c(C(=O)O)c(C(O)=NCCO)c(Cl)c2Sc2ccc(C)cc2)cc1

Procedure:
20 g (60.8 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 15.86 g (127.67 millimols) of p-thiocresol, 34.03 g (246.22 millimols) of potassium carbonate and 200 ml of tetrahydrofuran are stirred at 25° C. for 2.5 days. The mixture is acidified and extracted with methylene chloride. After recrystallisation from toluene, 26.42 g (86% of theory) of the title compound are obtained; melting point 211°-2° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[N:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][N:23]=1>>[CH2:28]([C:25]1[CH:24]=[N:23][C:22]([N:15]2[CH2:14][CH2:13][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][C:4]=3[F:20])[CH2:17][CH2:16]2)=[N:27][CH:26]=1)[CH3:29]
Reactant: Fc1cc(Br)ccc1COC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3F)CC2)nc1

Procedure:
This compound was prepared from the product of step A and 2-chloro-5-ethylpyrimidine according to the conditions outlined in intermediate 7 (step B). 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 2H), 7.33-7.31 (m, 2H), 7.26 (d, J 9.0 Hz, 1H), 4.72-4.65 (m, 2H), 4.60 (d, J 12.4 Hz, 1H), 4.52 (d, J 12.4 Hz, 1H), 3.65 (dd, J 10.1 & 6.4 Hz, 1H), 3.47 (t, J 9.6 Hz, 1H), 2.88-2.76 (m, 2H), 2.47 (q, J 7.5 Hz, 1H), 1.95 (d, J 13.0 Hz, 1H), 1.82 (d, J 13.3 Hz, 1H), 1.45-1.35 (m, 2H), 1.21 (t, J 7.5 Hz, 3H), 1.09-1.00 (m, 1H), 0.79-0.69 (m, 2H), 0.09-0.04 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=1.CCN(C(C)C)C(C)C.[SH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:15][O:14][CH2:13][O:12][C:4]1[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=[C:2]([S:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:3]=1
Reactant: COCOc1cc(Br)cn(COC)c1=O
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCOc1cc(SCCC(=O)OC)cn(COC)c1=O
Yield: 84.9 %

Procedure:
A mixture of 5-bromo-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 15) (3.5 g, 12.6 mmol), Pd2(dba)3 (0.46 g, 0.50 mmol), Xantphos (0.58 g, 1.00 mmol) and DIPEA (4.40 ml, 25.2 mmol) in dioxane (60 ml) was degassed and then placed under an atmosphere of nitrogen. To this mixture was added methyl 3-mercaptopropanoate (1.66 g, 13.8 mmol) and the whole was heated under reflux for 3 hours. Upon cooling it was filtered through a pad of celite and ethyl acetate was washed through the pad of celite to recover any remaining compound. The organic filtrate was washed with water and then saturated aqueous sodium chloride solution and the organics were dried (MgSO4), filtered and concentrated under vacuum. The crude residue was purified by column chromatography (SiO2; 0-100% dichloromethane in petrol, then 0-10% methanol in dichloromethane). Product fractions were collected and concentrated in vacuo to give a yellow oil. This oil was purified further by reverse phase column chromatography (SiO2—C18; 5-95% methanol in water with 0.1% formic acid) to give methyl 3-{[5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl]sulfanyl}propanoate (3.4 g, 10.7 mmol, 85%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:37][CH:38]=2)=[CH:30][CH:29]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:37][CH:38]=2)=[CH:32][CH:33]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCC/C=C/CO
Reactant: CCCCCc1ccc(-c2ccc(O)cc2)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(-c2ccc(CCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
Triphenylphosphine (0.53 g) was added in small portions to a solution of (E)-hex-2-en-1-ol (0.20 g), 2-(4-hydroxyphenyl)-5-pentylthiophene (0.50 g), diethylazodicarboxylate (0.35 g) in dry tetrahydrofuran (15 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:1 petroleum (40-60° C.) ether/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.10 g of 2-(4-[(E)-hex-2-enyloxy]phenyl)-5-pentylthiophene, K, 82° C., I.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=O.[F:10][C:11]([F:16])([F:15])[C:12](O)=[O:13]>>[F:10][C:11]([F:16])([F:15])[C:12]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:13]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Temperature: 0 °C
Yield: 75 %

Procedure:
Aspartic acid (100 g: 0.75 mol) is suspended in trifluoroacetic acid (300 ml) and cooled under mechanical agitation in an ice and salt bath; trifluoroacetic acid (300 ml: 2.16 mol) is added drop-wise, adjusting the addition so that the temperature does not rise above 10° C. On completing the addition, the suspension is left for half an hour under vigorous stirring at a temperature below 10° C., after which the temperature is allowed to rise slowly to room temperature. The solution is reacted for 2 hours at 45° C. and for 1 night at room temperature. Extraction is done with acetone (300 ml) and cooling to solubilise the mass which is of very firm consistency and the solution is then concentrated to dryness. The solid obtained is washed twice with 500 cc of n-hexane and then with 1 liter of n-hexane/ethyl ether at a ratio of 4:1, triturating and vacuum filtering. 135 g of product are obtained which can be used as such if the analyses are compliant. The product is crystallised by n-hexane/EtOAc obtaining 119 g of product which is vacuum dried thoroughly at 40° C. Yield 75%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([CH3:33])([CH3:32])[CH2:5][N:6]1[C@H:18]([CH3:19])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C@H:7]1[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=1>CO>[F:3][C:4]([CH3:32])([CH3:33])[CH2:5][N:6]1[C@H:18]([CH3:19])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C@H:7]1[C:20]1[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc(/C=C/C(=O)O)cc2)N1CC(C)(C)F
Temperature: 20 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
7.5M Sodium hydroxide solution (0.983 ml, 7.37 mmol) was added to a solution of (E)-methyl 3-(4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (310 mg, 0.74 mmol) in methanol (5 ml). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX-2 column. Fractions containing the desired product were eluted from the column using 7M NH3/methanol and pure fractions were evaporated to dryness to afford a yellow solid. The crude product was purified by preparative HPLC (Waters SunFire column, 5μ silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and then loaded onto SCX-2 column and eluted with 7N ammonia in methanol to afford the title product (63.0 mg, 21.02%) as a yellow solid. 1H NMR (400 MHz, DMSO, 30° C.) δ 1.06 (3H, d), 1.30 (3H, d), 1.47 (3H, d), 2.53-2.64 (2H, m), 2.79 (2H, s), 3.10 (1H, d), 5.08 (1H, s), 6.47 (1H, d), 6.98 (1H, t), 7.06 (1H, t), 7.19-7.37 (3H, m), 7.44 (1H, d), 7.56 (1H, d), 7.63 (2H, d), 10.81 (1H, s), 12.30 (1H, s). m/z: ES+ [M+H]+ 407.
Reaction SMILES: [C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([OH:24])[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2].[C:30](=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.CO>CC(C)=O.CI>[C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([O:24][CH3:30])[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Temperature: 45 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (25 mg) in a mixture of acetone (1 ml) and methyl iodide (1 ml) was added potassium carbonate (50 mg), and the mixture was stirred for 3 hours at 45° C. The reaction mixture was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (15:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (25 mg).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2Cl)=[N:13][C:12]([Cl:17])=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Cl:17][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[C:15]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Yield: 62.9 %

Procedure:
Following general procedure I, cyclopropyl(4,6-dichloro-1,5-naphthyridin-3-yl)-methanone (267 mg, 1.0 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)-piperidin-3-ylcarbamate (340 mg, 1.2 mmol) to afford the desired product (329 mg, 63%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 10.19 (br s, 1H), 9.03 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.04 (d, J=2.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.31-7.25 (m, 1H), 6.70 (d, J=9.1 Hz, 1H), 4.78 (br s, 1H), 3.83-3.62 (m, 3H), 3.47-3.25 (m, 2H), 2.55-2.47 (m, 1H), 1.97-1.83 (m, 2H), 1.73-1.58 (m, 1H), 1.45 (s, 9H), 1.12-1.04 (m, 2H), 1.00-0.90 (m, 2H); ESI MS m/z 523 [M+H]+
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=O)C1C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:36][C:37]1(C)C(C)(C)OB(C=C)O1.[OH-].[Na+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O.O1CCOCC1>[NH2:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH:36]=[CH2:37])[CH:16]=2
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc2cc(N)c(C(=O)O)nc2c1
Temperature: 80 °C

Procedure:
Ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (1.50 g, 3.49 mmol), K3PO4 (1.48 g, 6.97 mmol), 1,4-dioxane (45 mL), water (7.5 mL) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.80 g, 5.2 mmol) were added to a flask. The reaction mixture was purged with nitrogen for 10 min., then dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.18 g, 0.23 mmol) was added. The flask was then sealed and the reaction mixture was heated at 80° C. for 1 h, then allowed to cool to room temperature. After the reaction mixture was allowed to cool, aq. NaOH (2.5 M; 45 mL) was added, the resulting cloudy mixture was then heated at 95° C. for 3 h, and then allowed to cool. The crude product formed as a precipitate, which was collected by vacuum filtration and used in the next step without further purification. LCMS calc. for C12H11N2O2 (M+H)+: m/z=215.2. Found: 215.0.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].[O:10]=[C:11]1[CH2:16][C:15](=O)[CH2:14][CH2:13][NH:12]1>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH:4][C:15]1[CH2:14][CH2:13][NH:12][C:11](=[O:10])[CH:16]=1
Reactant: Nc1c(Br)cccc1Br
Reactant: O=C1CCNC(=O)C1
Product: O=C1C=C(Nc2c(Br)cccc2Br)CCN1
Yield: 29.7 %

Procedure:
A mixture of 2,6-dibromoaniline (4.4 g) and 2,4-dioxopiperidine (2.0 g) was heated at 120° for 2.5 h. The mixture was then cooled (0°) and triturated with ether 9100 ml) to give a solid which was purified by FCC eluting with System A (100:8:1) to give the title compound (1.8 g), m.p. 240°-243°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27].[S:28]1[CH2:33][CH:32]=[C:31](B(O)O)[CH2:30][CH2:29]1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:28]1[CH2:29][CH:30]=[C:31]([C:6]2[CH:5]=[C:4]([F:16])[C:3]([C:17]3[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=3[F:27])=[C:2]([F:1])[CH:7]=2)[CH2:32][CH2:33]1
Reactant: OB(O)C1=CCSCC1
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OS(=O)(=O)C(F)(F)F)cc2F)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3=CCSCC3)cc2F)n1
Temperature: 90 °C
Yield: 60 %

Procedure:
To a degassed solution of methyl 6-(2,6-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)-5-fluoropicolinate (1.0 equiv.) and 3,6-dihydro-2H-thiopyran-4-ylboronic acid (1.5 equiv.) in DME/2M Na2CO3 (3/1, 0.10 M) was added PdCl2(dppf).CH2Cl2 adduct (0.10 equiv.). The reaction was heated to 90° C. in an oil bath for 15 min. The reaction mixture was partitioned with water and EtOAc; the organics were dried over MgSO4, filtered, and concentrated. The crude was purified via ISCO SiO2 chromatography. Pure fractions were combined and concentrated to yield methyl 6-(4-(3,6-dihydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinate in 60% yield. LC/MS=366.1 (M+H), Rt=1.00 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C1([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([C:49]#[N:50])[CH:40]=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:37](=[O:36])[NH:38][C:39]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([C:49]#[N:50])[CH:40]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3[nH]ccc3c2)C1
Reactant: N#Cc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C#N)cc(C(F)(F)F)c3)c2)C1
Reaction time: 24 h

Procedure:
4-(1H-Indol-5-yloxy)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, Example 31-F (140 mg, 0.38 mmol) is dissolved in THF (5 mL) and NaH (31 mg, 0.76 mmol, 60% in mineral oil) is added followed by (3-cyano-5-trifluoromethyl-phenyl)-carbamic acid phenyl ester (428 mg, 1.15 mmol). After 24 h, the reaction is concentrated and then partitioned between DCM and water. The crude residue is purified via FCC (5-90% EtOAc/heptane) to give the title compound. MS (ESI) m/z 579.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[F:35][C:36]1[CH:37]=[C:38]([CH:43]=[C:44]([F:47])[C:45]=1F)[C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+].C1COCC1>O.CS(C)=O>[C:18]([O:17][C:16]([N:15]([CH2:14][C@@H:9]1[C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:45]2[C:44]([F:47])=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[F:35])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(F)c(F)c(F)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)c(N2CC[C@H](c3ccccc3F)[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 191 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, 118 mg of methyl 3,4,5-trifluorobenzoate, 114 mg of potassium carbonate, and 2.0 mL of THF-2.0 mL of DMSO was stirred at 100° C. overnight. After cooling, to the reaction mixture was added water, followed by extraction with ethyl acetate, and then drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 147 mg of methyl 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]-3,5-difluorobenzoate as a colorless amorphous substance.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][C:9]=1[N:21]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:7])(C)(C)C.[ClH:39].O1CCOCC1>ClCCl>[ClH:39].[CH2:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([N:21]([C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])[C:9]2[CH:10]=[C:11]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:12]=[CH:13][C:8]=2[C:6]([OH:7])=[O:5])[CH2:23][CH2:24]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)N1CCC(N(C(=O)C(F)(F)F)c2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC(N(C(=O)C(F)(F)F)c2cc(N3CCN(C)CC3)ccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
ethyl 4-{[2-(tert-butoxycarbonyl)-5-(4-methylpiperazin-1-yl)phenyl](trifluoroacetyl)amino}piperidine-1-carboxylate (2.15 g, 3.960 mmol) was dissolved in dry dichloromethane (8 mL) under nitrogen atmosphere. A 4 M solution of HCl in dioxane (9.9 mL, 39.6 mmol, 10 eq) was then added dropwise and the mixture was stirred at room temperature. After 5 hours 5 more equivalents of HCl were added and the reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and stripped twice with DCM. It was then taken up with DCM/dioxane 1:3 and slurried for 1 hour. The solid was filtered, washed with ether and dried under vacuum at 50° C. for 1 hour. 1.78 g of title compound were obtained as a beige powder (86% yield).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].Br[C:18]1[C:19]([Cl:30])=[CH:20][N:21]=[C:22]2[C:27]=1[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]2.[Cl-].[Li+].C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:3]([C:18]1[C:19]([Cl:30])=[CH:20][N:21]=[C:22]2[C:27]=1[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]2)[CH:2]=[CH2:1]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(Cl)cnc2ccc(OC)nc12
Temperature: 105 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Allyltributylstannane (7.3 g, 21.9 mmol, 1.2 eq) is added at room temperature to a stirred solution of 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (5.0 g, 18.3 mmol, 1.0 eq) in N,N-dimethylformamide (100 mL), followed by tetrakis(triphenylphosphine)palladium(0) (0.63 g, 0.55 mmol, 0.03 eq) and lithium chloride (2.9 g, 67.6 mmol, 3.7 eq). After 1 hour stirring at 105° C., the reaction mixture is cooled down to room temperature and filtered through decalite. The filtrate is concentrated to give a crude product that is extracted with ethyl acetate (3×100 mL) and a 10% ammonium hydroxide aqueous solution (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 30:1, v/v) to afford 8-allyl-7-chloro-2-methoxy-[1,5]naphthyridine as a colorless oil (2.5 g, 58% yield).
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:20]3[C:15](=[C:16]([C:22]#[N:23])[C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.Cl>C(Cl)Cl>[F:21][C:17]1[CH:18]=[CH:19][C:20]2[CH:12]([CH2:11][N:9]3[CH2:8][CH2:7][NH:6][CH2:5][CH2:10]3)[CH2:13][CH2:14][C:15]=2[C:16]=1[C:22]#[N:23]
Reactant: CC(C)(C)C1CN(CC2CCc3c2ccc(F)c3C#N)CCN1C(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c1CCC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution 1,1-dimethylethyl-4-[(4-cyano-5-fluoro-2,3-dihydro-1H-inden-1-yl)methyl]piperazine-1-carboxylate (0.060 g) in DCM (2 mL) was added 4N HCl (2 mL) at RT. The mixture was allowed to stir at RT for 2 hours. The solvents were removed on a rotary evaporator, and the residue was redissolved in aq NaHCO3 solution. The solution was extracted with IPA-CHCl3 (3:1) twice (50 mL each). The extractions were combined, dried over sodium sulfate, and concentrated to give 5-fluoro-1-(piperazin-1-ylmethyl)-2,3-dihydro-1H-indene-4-carbonitrile. LC-MS (IE, m/z): 260 [M+1]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[CH:15][CH:16]=[N:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[N:17]1[C:18]2[C:13](=[C:12]3[C:21](=[CH:20][CH:19]=2)[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[S:8](=[O:10])(=[O:9])[NH:11]3)[N:14]=[CH:15][CH:16]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2nccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3nccnc23)-c2ccccc21
Yield: 16.4 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-quinoxalin-5-yl-benzenesulfonamide (Intermediate 304) (440 mg, 1.4 mmol), t-butyl nitrite (0.27 ml, 2.19 mmol), AcOH (4.5 ml) and THF (4.5 ml) gave the title compound (65 mg, 16%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.