Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1O.[C:16]1(O)C=CC=CC=1.[Zn](C)C.CC(C[AlH]CC(C)C)C>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]>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:16]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Reactant: Oc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)C[AlH]CC(C)C
Product: CCOC(=O)Cc1ccc(C)c(O)c1

Procedure:
Ethyl 3-hydroxy4-methylphenylacetate (5a) was prepared from ethyl 3-methoxy-4-hydroxy-phenylacetate as shown in Scheme 2. The phenol was converted to the triflate ester 4b which was subjected to displacement with Me2Zn, DIBAL-H and PdCl2(dppf) (E.-i. Negishi in Metal-catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang (eds.), Wiley-VCH, Mannheim 1998, chap. 1; E. Erdik, Tetrahedron 1992 48:9577-9648) to afford the 4c. Boron tribromide demethylation afforded 5a. Ethyl 3-hydroxy-4-ethylphenylacetate 5b was prepared by Friedel-Crafts acylation of 4d which afforded ethyl 4-acetyl-3-methoxyphenylacetate (4e). Reduction of the ketone with triethylsilane and TFA produced the corresponding 4-ethyl substituted derivative 4f which was demethylated with BBr3 to afford 5b. Ethyl 3-hydroxy-4-iso-propylphenylacetate (5c) was prepared by Wittig olefmation of 4e and subsequent catalytic hydrogenation of the 2-propenyl substituent to yield 4h. Demethylation with boron tribromide produced 5c.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:30])[CH:7]=[CH:6]2)#[N:2].CC(=CC)C.O.O.P([O-])(O)(O)=[O:39].[Na+].Cl([O-])(=O)=O.[Na+].O.Cl>C(#N)C.O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:9]=2)=[C:15]([C:23]2[C:24]([C:29]([OH:39])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:16]=1)([O-:22])=[O:21]
Reactant: O=P([O-])(O)O
Reactant: N#Cc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3-c3ccccc3C=O)ccc2c1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3-c3ccccc3C(=O)O)ccc2c1

Procedure:
The compound (4-(6-cyano-2-naphthyloxy)-3-(2-formylphenyl)nitrobenzene) (800 mg) obtained in a previous production example, 2-methyl-2-butene (1.4 ml) and sodium dihydrogen phosphate dihydrate (2 g) were dissolved in acetonitrile:water (2:1, 50 ml) and then sodium chlorate (1 g) was added. After reaction for one hour at room temperature, 1 N hydrochloric acid water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid water and saturated saline and then dried over magnesium sulfate, and the solvent was distilled off to obtain 5′-nitro-2′-(6-cyano-2-naphthyloxy)-1,1′-biphenyl-2-carboxylic acid (800 mg). This was dissolved in toluene without purification and subjected to the same process as in Production Example 1 to obtain t-butyl 2′-(6-cyano-2-naphthyloxy)-5′-nitro-1,1′-biphenyl-2-carboxylate.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6][CH2:5]2.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][N:4]4[C:10](=[N:1][CH:2]=[CH:3]4)[C:9]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: Nc1ccc2c(c1)-c1nccn1CCC2
Reactant: CNC(=O)c1cc(F)ccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(F)ccc1Nc1nc(Nc2ccc3c(c2)-c2nccn2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-fluoro-N-methyl-benzamide was converted to 2-[5-chloro-2-(5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-5-fluoro-N-methyl-benzamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.43 (dd, 1H), 8.19 (s, 1H), 8.12 (d, 1H), 7.76 (d, 1H), 7.69 (dd, 1H), 7.61 (d, 1H), 7.5 (m, 2H), 7.03 (td, 1H), 4.26 (t, 2H), 2.92 (s, 3H), 2.81 (t, 2H), 2.52 (pent, 2H); 19F NMR (282 MHz, CD3OD) δ −77.9, −119.1; MS (m/e) 478 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)[C:11]([N+:24]([O-])=O)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl-].[NH4+].O1CCCC1.CO>O>[NH2:24][C:11]1[C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[CH:13][C:4]([CH2:3][O:2][CH3:1])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCc1cc(-n2ccnc2C2CCOC2)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(-n2ccnc2C2CCOC2)c(N)cc1C(=O)OC
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 86.9 %

Procedure:
To a mixture of 6.65 g of methyl 2-(methoxymethyl)-5-nitro-4-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]benzoate, 980 mg of ammonium chloride, 33.0 mL of tetrahydrofuran, 66.0 mL of methanol, and 33.0 mL of water was added 4.8 g of reduced iron, followed by stirring at 70° C. for 4.5 hours. The insoluble matter was filtered through celite. The filtrate was concentrated, and water and ethyl acetate were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 5.30 g of methyl 5-amino-2-(methoxymethyl)-4-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]benzoate as a brown solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:41][NH2:42].CO>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1
Reactant: C[Si](C)(C)ON
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1)NO
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(3-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 109) (410 mg, 1.04 mmol) in dichloromethane (10 ml) was treated with 1,1′-carbonyidiimidazole (169 mg, 1.04 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (418 μl, 3.12 mmol) was added and the reation mixture was stirred for 18 hours. The reaction mixture was then treated with methanol (5 ml) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (3×30 ml) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 (dichloromethane:methanol) gradually changing to 95:5 (dichloromethane:methanol) to afford a white waxy solid. The solid was recrystallised from ethyl acetate to afford the title compound as a white solid (128 mg).
Reaction SMILES: [C:1](=[N:5][C:6]1[C:11]([CH2:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([N:23]=[C:24]([CH2:26][CH3:27])[CH3:25])=[C:17]([CH2:28][CH3:29])[CH:16]=2)=[CH:8][C:7]=1[CH2:30][CH3:31])([CH2:3][CH3:4])[CH3:2]>[Pt].CC(C)=O>[CH:24]([NH:23][C:18]1[C:17]([CH2:28][CH3:29])=[CH:16][C:15]([CH2:14][C:9]2[CH:8]=[C:7]([CH2:30][CH3:31])[C:6]([NH:5][CH:1]([CH2:3][CH3:4])[CH3:2])=[C:11]([CH2:12][CH3:13])[CH:10]=2)=[CH:20][C:19]=1[CH2:21][CH3:22])([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)=Nc1c(CC)cc(Cc2cc(CC)c(N=C(C)CC)c(CC)c2)cc1CC
Agent: [Pt]
Solvent: CC(C)=O
Product: CCc1cc(Cc2cc(CC)c(NC(C)CC)c(CC)c2)cc(CC)c1NC(C)CC
Reaction time: 6.5 h

Procedure:
N,N′-di-sec-butylidene-4,4′-methylenebis(2,6-diethylbenzeneamine) (22.53 g) and Pt(S)/C (2.65 g) were added to acetone (34.0 g) in an autoclave. The closed autoclave was purged 3 times with 125 psig of H2 (9.63×105 Pa) at 22° C. The mixture was kept at 21° C. and 125 psi (8.62×105 Pa) of H2 for 6.5 hours, forming the corresponding N,N′-di-sec-butyl-4,4′-methylenebis(2,6-diethylbenzeneamine) quantitatively.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:14]=1
Reactant: C#Cc1cccnc1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: c1cncc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 3-ethynylpyridine (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.70 (ddd, J=8.1, 4.9, 0.8 Hz, 1H), 7.96 (s, 1H), 8.37 (ddd, J=8.2, 1.9, 1.7 Hz, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 9.17 (dd, J=2.2, 0.8 Hz, 1H), 9.34 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 225 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CC#N>[O:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)cn1
Reactant: NCC1CCOCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cnc(Nc2cc(NCC3CCOCC3)ncn2)cn1
Yield: 41.1 %

Procedure:
A solution of 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (20 mg, 0.086 mmol), 4-(aminomethyl)tetrahydropyran (18 mg, 0.17 mmol), and triethylamine (0.02 mL, 0.13 mmol) in MeCN (0.2 mL) was heated to 145° C. for 30 minutes by microwave irradiation. The mixture was cooled and solvent was removed by evaporation. The crude material was redissolved in a mixture of dichloromethane (89%), MeOH (10%), 0.88 s.g. NH3 (1%) and adsorbed onto a solvent-conditioned Trikonex silica chromatography column. Elution with the same solvent mixture gave 5-(6-((tetrahydro-2H-pyran-4-yl)methylamino) pyrimidin-4-ylamino)pyrazine-2-carbonitrile as a yellow powder (11 mg, 41%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][CH2:7][C:6](=O)[CH:5]1[C:10]([O:12][CH3:13])=[O:11])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:18]>CO>[NH2:18][C:6]1[CH2:7][CH2:8][CH:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1C(=O)CCC1C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C1=C(N)CCC1C(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A solution of methyl 2-isopropyl-5-oxocyclopentanecarboxylate (5.4 g, 29.31 mmol) in MeOH (145 mL) was treated with ammonium acetate (22.59 g, 293.1 mmol), and the mixture was heated to 50° C. for 2 hours and stirred at room temperature overnight. The solvents were removed under reduced pressure, and the crude residue was taken up in DCM and H2O. The combined organics were washed with brine, dried Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (5 then 15% EtOAc/Hexane) to yield pure methyl 2-amino-5-isopropylcyclopent-1-enecarboxylate (3.27 g, 61%). LCMS (APCI+) m/z 184.0 [M+H]+; Rt=3.51 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[S:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:2].B1([O-])OO1.[OH2:29].[OH2:30].O.O.[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:14]2[N:15]=[C:16]([S:19]([CH3:20])(=[O:30])=[O:29])[N:17]=[CH:18][C:13]=2[S:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:2]
Reactant: CCOc1ccccc1-c1c(C(=O)OC)sc2cnc(SC)nc12
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CCOc1ccccc1-c1c(C(=O)OC)sc2cnc(S(C)(=O)=O)nc12
Temperature: 70 °C
Yield: 82.4 %

Procedure:
A mixture of 330 mg of methyl 7-(2-ethoxyphenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate, prepared by analogy to the method described in example 4, and 634 mg of sodium perborate tetrahydrate in 15 ml of acetic acid is microwave-heated at 70° C. in a sealed tube for 1 h 30. The mixture is diluted with 5 volumes of water and the resulting precipitate is filtered off and washed with water. The solid is taken up with dichloromethane and 100 ml of a solution of sodium thiosulfate. The pH is adjusted to pH 8-9 by adding solid potassium carbonate and the aqueous phase is extracted with dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum. This crude is purified on 40 g of silica, elution being carried out with dichloromethane, so as to obtain 296 mg of methyl 7-(2-ethoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of a yellow solid.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[CH:18](O)=[O:19]>CCCCCC>[CH:18]([NH:11][C:10]1[C:9](=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:17])=[O:16])=[O:19]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=CO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=CNc1ccccc1C(=O)O

Procedure:
A toluene (1100 ml) solution of anthranilic acid (205.5 g) and formic acid (170 ml) was heated under reflux for 4.5 hours. After the solution was allowed to cool, hexane was added to crystals deposited. The crystals were collected by filtration and washed with hexane. The resulting crystals were dried at 110° C. under reduced pressure to obtain N-formyl-anthranilic acid (244.0 g, crude product) as white crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C@H:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.C(N(CC)CC)C.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[C:45]([CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1)[C:46](Cl)=[O:47]>ClCCl.O.CO>[F:41][C:42]([F:57])([F:56])[C:43]1[CH:44]=[C:45]([C:46]([N:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:9]2)=[O:47])[CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCOCC2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCOCC2)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Rac-cis-4-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-morpholine (650 mg, 1.75 mmol) was dissolved in dichloromethane (15 mL) and 1-chloroethyl-chloroformate (0.575 mL, 5.27 mmol) were added at 0° C. The reaction mixture was refluxed overnight. Methanol (15 mL) was added and reflux was continued for 3 h. The solvents were evaporated. The crude intermediate was dissolved in dichloromethane (30 mL) and triethylamine (1.22 mL, 8.75 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (0.35 mL, 1.93 mmol) were added. The reaction mixture was stirred at room temperature overnight and than diluted with 50 mL water. The organic phase was separated and the aqueous layer was extracted twice with 50 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with hexane/ethyl acetate/triethylamine 20:10.1 gave the desired product (820 mg, 90%) as a yellow solid, MS: m/e=521.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](O)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][OH:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccc(Br)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccc(Br)cc2[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
6-Bromo-1H-indole-2-carboxylic acid (2.4 g, 10 mmol) was dissolved in THF (20 mL) and cooled to 0° C. Lithium aluminum hydride (20 mmol, 1 M in THF) was added to the solution via syringe. The mixture was stirred overnight at room temperature. The excess reagent was quenched with the slow addition of aqueous KOH (10 mL, 1 M). The mixture was stirred vigorously for 30 min. The mixture was filtered through Celite. The filtrate was concentrated and chromatographed (0-20% EtOAc in CH2Cl2) to afford the product as a yellow powder (1.87 g, 83%). LC-MS 224.1, 226.1 [M+H]+, RT 1.03 min.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1)=[O:5].N1C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][N:10]([S:35]([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[C:9]=2[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccc2c(n1)NCCC2)c1c(F)cccc1F
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(n1)N(S(=O)(=O)c1ccc(F)cc1)CCC2)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2,6-Difluoro-N-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide (30 mg, 0.10 mmol) was dissolved in dichloromethane (0.3 mL) and pyridine (0.025 mL, 0.31 mmol). 4-Fluorobenzenesulfonyl chloride (23 mg, 0.12 mmol) was then added and the reaction mixture was stirred at room temperature for 12 hours. Next, the reaction mixture was washed with 1M HCl(aq), sat'd NaHCO3(aq), and brine. The resulting organic solution was concentrated, dissolved in DMSO, and purified by HPLC to give 2,6-difluoro-N-(8-(4-fluorobenzenesulfonyl)-5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl]benzamide. 1H NMR 250 MHz CDCl3 δ 8.13 (bs, 1H), 8.03 (dd, J=7.9, 4.3 Hz, 2H), 7.83 (d, J=7.9 Hz, 1H), 7.48 (p, J=6.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 2H), 7.06 (t, J=7.8 Hz, 2H), 4.07 (dd, J=5.8, 4.3 Hz, 2H), 2.76 (t, J=6.5 Hz, 2H), 2.06 (p, J=5.8 Hz, 2H). LCMS (ESI): calc. C21H16F3N3O3S=447; obs. M+H=448.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.O>[CH3:24][S:25]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:3]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN2CC[C@H](O)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1

Procedure:
(S)-3-Hydroxy-1-(4-methoxyphenethyl)pyrrolidine (541 mg, 2.45 mmol) was dissolved in dichloromethane (15 ml). Triethylamine (272 mg, 2.69 mmol) and methanesulfonyl chloride (295 mg, 2.58 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(4-methoxyphenethyl)pyrrolidine in the form of a white solid (734 mg, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:3]=1[O:21][CH3:22].[NH2:23][C:24]1[C:25]([CH3:32])=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.O(C(C)(C)C)[Na]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:30]([C:27]1[N:28]=[CH:29][C:24]([NH:23][C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[C:3]=2[O:21][CH3:22])=[C:25]([CH3:32])[CH:26]=1)#[N:31]
Reactant: Cc1cc(C#N)ncc1N
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(Nc2cnc(C#N)cc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a solution of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (0.3 g, 0.91 mmol) in dioxane (3 mL), were added 5-amino-4-methylpicolinonitrile (0.12 g, 0.91 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.031 g, 0.091 mmol), Pd(OAc)2 (0.10 g, 0.45 mmol), and NaO-t-Bu (0.21 g, 2.2 mmol) at an ambient temperature. The reaction was warmed to 75° C. and stirred for 2 hrs. After cooling to room temperature, the reaction was poured into H2O and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified over SiO2 to afford isopropyl 4-(6-(6-cyano-4-methylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate in 31% (102 mg). 1HNMR (CDCl3, 400 MHz) δ 1.21 (d, J=4.71, 6H), 1.71-1.75 (m, 2H), 1.95-2.01 (m, 2H), 2.31 (s, 3H), 2.62 (s, 3H), 3.32-3.41 (m, 2H), 3.64-3.71 (m, 2H), 4.85-4.90 (m, 1H), 5.35˜5.41 (m, 1H), 7.81 (s, 1H), 8.10 (s, 1H), 8.82 (d, J=4.71 Hz, 1H). Exact mass calculated for C21H26N6O4 426.47. found 427.51 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:19]Br)=[O:4].[CH3:21][O:22][C:23](=[O:36])[CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:19][N:25]([CH2:24][C:23]([O:22][CH3:21])=[O:36])[S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)(=[O:28])=[O:27])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(=O)n(Cc2ccccc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1c(C(=O)OC)ccc(=O)n1Cc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
A mixture of 1-benzyl-2-bromomethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.4 g, 7.14 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (1.74 g, 7.14 mmol), sodium iodide (2.14 g, 14.3 mmol) and potassium carbonate (1.97 g, 14.3 mmol) in DMF (45 mL) was stirred at r.t. for 16 h. Brine (100 mL) and EtOAc (100 mL) were added and the aqueous layer was extracted several times with EtOAc. The organic layers were combined, washed with water, and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-75% EtOAc/hexanes) to give 1.95 g of the title compound as a yellow oil. MS: (+) m/z 499.06 (M+1).