Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16](CC)[CH2:17]C)C.ClC(OCC)=O.C(NCC)C>O1CCCC1>[CH3:14][N:16]([CH3:17])[C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCNCC
Product: CN(C)C(=O)CCNC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 90 %

Procedure:
N-(t-Butyloxycarbonyl)-β-alanine, 3.8 g (20 mmol) was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to 0° C. and stirred. To this mixture, 2.4 g (24 mmol) of triethylamine was added and 2.16 g (20 mmol) of ethyl chloroformate was slowly added. After stirring the reaction mixture for an hour at 0° C., 4 ml of 40% diethylamine aqueous solution was slowly added and stirred vigorously for an hour. The mixture was extracted by adding 100 ml of dichloromethane and 50 ml of water. The organic layer was washed with 1 N HCl aqueous solution and subsequently with saturated sodium bicarbonate aqueous solution. The washed mixture was dried to obtain 3.9 g (90%) of N-(t-butyloxy-carbonyl)-β-alanine dimethylamide.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C=CC(Cl)=CC1=2)=[N+](C)C)C.[NH2:51][C:52]1[C:53]([CH3:67])=[C:54]([CH2:58][CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH:55]=[CH:56][CH:57]=1>CN(C=O)C.N1C=CC=CC=1>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])=[CH:12][CH:11]=2)[C:7]([NH:51][C:52]2[C:53]([CH3:67])=[C:54]([CH2:58][CH2:59][C:60]([O:62][C:63]([CH3:64])([CH3:66])[CH3:65])=[O:61])[CH:55]=[CH:56][CH:57]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(N)cccc1CCC(=O)OC(C)(C)C
Reactant: O=C(O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7.5 g (20.6 mmol) of (+/−)-2-cyclopentyl-2-(4-((1,3-dioxoisoindolin-2-yl)methyl)phenyl)acetic acid were dissolved in a mixture of 170 ml of DMF and 68 ml of pyridine, and 10.2 g (26.8 mmol) of TCTU were added. After 30 min of stirring at room temperature, 4.86 g (20.6 mmol) of tert-butyl 3-(3-amino-2-methylphenyl)propanoate were added. After stirring at room temperature overnight, the reaction mixture was concentrated and the residue pre-purified by flash chromatography on silica gel (mobile phase dichloromethane/methanol 100:1). The product obtained in this manner was triturated successively with ethanol and methanol, and the solid was filtered off with suction and dried under high vacuum. This gave 8.5 g (71% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[C:12]=1[Cl:13].[CH2:15](O)[CH2:16][OH:17].C(OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[S:10][CH2:9][CH2:8][C:7]3([O:17][CH2:16][CH2:15][O:11]3)[C:6]=2[C:12]=1[Cl:13]
Reactant: O=C1CCSc2c(Cl)cc(Br)c(Cl)c21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Solvent: CCOCC
Product: Clc1cc(Br)c(Cl)c2c1SCCC21OCCO1

Procedure:
15 g (0.048 mol) of the title compound of Step C, 150 mL of ethylene glycol, 100 mL of trimethyl orthoformate (purchased from Aldrich Chemical Company), and 0.06 g of p-toluenesulfonic acid monohydrate were stirred together at 80° C. under nitrogen overnight. The mixture was diluted with 250 mL of diethyl ether and washed with a 1:1 mixture of 1N sodium hydroxide:saturated aqueous NaCl (2×300 mL), saturated aqueous NaCl (1×500 mL), dried (Na2SO4), filtered, and evaporated to dryness. The crude product was chromatographed over silica gel eluting with a mixture of ethyl acetate:hexane (0.5:9.5) to yield 8.39 g of the title compound of Step D as a solid melting at 152-153° C. 1H NMR (CDCl3): δ2.3 (m,2H), 3.0 (m,2H), 4.16 (m,2H), 4.37 (m,2H), 7.6 (s,1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3ccc(Br)cc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(CN2CCN(c3ccc(Br)cc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(4-bromophenyl)- 4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(4-bromophenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][S:24]([N:23]([CH3:28])[CH3:22])(=[O:26])=[O:25])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Yield: 37.4 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (200 mg, 0.72 mmol) and dimethylsulfamoyl chloride (122 mg, 0.85 mmol) according to the procedure described for example 27. Obtained the title compound as an off-white foam (104 mg, 37%), MS (ISP) m/e=385.3 [(M−H)+].
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(Cl)cc1
Product: CN(c1ccc(Cl)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (60 mg, 0.302 mmol) and 4-chloro-N-methylaniline (50 mg, 0.332 mmol) by a procedure similar to Example 1b and was isolated as white powder (30 mg, 50%). 1H NMR (CDCl3): 8.66 (d, J=8.4 Hz, 1H), 7.78 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.19 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18]=2[CH3:35])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:104]1[CH2:109][CH2:108][O:107][CH2:106][CH2:105]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:25]1[CH:24]=[C:23]([F:28])[CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])=[N:6][CH:7]=[C:2]([N:104]3[CH2:109][CH2:108][O:107][CH2:106][CH2:105]3)[CH:3]=1)=[C:18]([CH3:35])[C:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[N:20]2
Reactant: COc1ccccc1-c1ncc(Br)cc1Nc1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ncc(N2CCOCC2)cc1Nc1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 100 °C
Reaction time: 23 h

Procedure:
A mixture of N-(5-bromo-2-(2-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (84.1 mg, 0.158 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (16.6 mg, 0.035 mmol), tris(dibenzylideneacetone)dipalladium (0) (15.4 mg, 0.017 mmol), morpholine (0.03 mL, 0.345 mmol), and sodium tert-butoxide (47.8 mg, 0.5 mmol) in dry toluene (5 mL) was degassed by nitrogen. The mixture was heated to 100° C. After 23 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (5-20% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with SFC chromatography to afford 5,7-difluoro-N-(2-(2-methoxyphenyl)-5-morpholinopyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.10 (1H, d, J=2.5 Hz), 7.92 (1H, m), 7.75 (1H, d, J=7.8 Hz), 7.57 (1H, ddd, J=9.7, 2.5, 1.3 Hz), 7.49 (1H, dd, J=7.4, 1.8 Hz), 7.46 (1H, m), 7.34 (1H, ddd, J=7.6, 4.8, 1.3 Hz), 7.13 (1H, td, J=7.4, 1.0 Hz), 7.08 (1H, m), 6.96 (1H, ddd, J=13.4, 8.7, 2.3 Hz), 6.65 (1H, m), 3.95 (3H, s), 3.90 (4H, m), 3.29 (4H, m), 1.94 (3H, br. s.) Mass Spectrum (pos.) m/e: 540.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[S:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:14]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1cc(Sc2cccc(Cl)c2Cl)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1csc(Nc2cc(Sc3cccc(Cl)c3Cl)ccn2)n1
Yield: 75.8 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.196 g, 1.72 mmol), 2-chloro-4-(2,3-dichlorophenylthio)pyridine (0.500 g, 1.72 mmol), potassium phosphate (0.402 g, 1.89 mmol), Pd2(dba)3 (0.079 g, 0.086 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.050 g, 0.086 mmol) were reacted to provide N-(4-(2,3-dichlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (0.480 g, 76% yield). 1H NMR (d6-DMSO) δ 11.10 (s, 1H), 8.15 (d, 1H), 7.82 (d, 1H), 7.66 (d, 1H), 7.49 (t, 1H), 6.71 (s, 1H), 6.69 (d, 1H), 6.54 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2.[OH:26]O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2)=[O:26]
Reactant: O=C1CCc2cc(OCCSc3ccc4ccccc4c3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCS(=O)c3ccc4ccccc4c3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[2-(2-naphthyl-mercapto)-ethoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([NH:9][C@H:10]([CH3:21])[C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[O:8])[CH2:3]1>CO.[Pd]>[OH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([NH:9][C@H:10]([CH3:21])[C:11]([OH:13])=[O:12])=[O:8])[CH2:3]1
Reactant: C[C@@H](NC(=O)[C@@H]1CC[C@H](O)C1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)[C@@H]1CC[C@H](O)C1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 131.6 %

Procedure:
Pd/C (10%, 1 g) was added to a solution of compound (R)-benzyl 2-((1R,3S)-3-hydroxycyclopentanecarboxamido)propanoate (500 mg, 1.7 mmol) in MeOH (20 mL). The suspension was stirred under hydrogen atmosphere at ambient temperature for 2 h. Pd/C was filtered off and washed with MeOH (5 mL). The filtrate and washings were combined and concentrated to dryness to afford (R)-2-((1R,3S)-3-hydroxycyclopentanecarboxamido)propanoic acid (450 mg, quantitative). (R)-2-((1S,3R)-3-hydroxycyclopentanecarboxamido)propanoic acid was obtained in a similar manner.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:13]1[CH:32]=[CH:31][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([Cl:26])[N:23]3[N:27]=[C:28]([CH3:30])[CH:29]=[C:22]3[N:21]=2)=[O:18])=[CH:15][CH:14]=1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].P([O-])([O-])([O-])=O>C1COCC1>[Cl:26][C:24]1[N:23]2[N:27]=[C:28]([CH3:30])[CH:29]=[C:22]2[N:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:31]=[CH:32][C:13]([C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[CH:14][CH:15]=2)[CH:25]=1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc3)cc(Cl)n2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Reaction time: 60 h

Procedure:
4-(1-(tert-Butyldimethylsilyloxy)-2-methylpropan-2-yl)-N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (4F, 3.9 g, 1.0 equivalent) was dissolved in THF (0.13 M) and treated with TBAF (1.0 M in THF, 4.0 equivalents). After 60 hours, pH 7 phosphate buffer was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (SiO2, gradient of 25 to 50% EtOAc/hexanes) to give N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (s, 6H), 2.44 (s, 3H), 3.46 (d, J=5.05 Hz, 2H), 4.76 (t, J=5.31 Hz, 1H), 6.45 (s, 1H), 7.52 (d, J=8.59 Hz, 2H), 7.99 (d, J=8.59 Hz, 2H), 8.06 (s, 1H), 11.30 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27]>CO>[ClH:27].[ClH:27].[C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccccc3)CC2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(C2CCN(CC3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.550 g (9.902 mM) of tert-butyl 4-(4-phenylpiperidinomethyl)piperidine-1-carboxylate in 30 ml of methanol was added 5 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 3 hours. The solvent was then distilled off and the residue was crystallized from ethanol-diethyl ether to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH2:10][CH2:9][CH:8]=2)=[N:4][C:3]=1[C:12]([NH:14][C:15]1[CH:16]=[N:17][N:18]([CH3:29])[C:19]=1[C@@H:20]1[CH2:26][CH2:25][C@@H:24]([NH2:27])[C@@H:23]([F:28])[CH2:22][O:21]1)=[O:13]>CO.[Pd]>[NH2:1][C:2]1[S:6][C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[C:12]([NH:14][C:15]1[CH:16]=[N:17][N:18]([CH3:29])[C:19]=1[C@@H:20]1[CH2:26][CH2:25][C@@H:24]([NH2:27])[C@@H:23]([F:28])[CH2:22][O:21]1)=[O:13]
Reactant: Cn1ncc(NC(=O)c2nc(C3=CCCC3)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1
Agent: [Pd]
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(C3CCCC3)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-N-(5-((2S,5R,6R)-5-amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(cyclopent-1-en-1-yl)thiazole-4-carboxamide (Example 271) in methanol was added 10% palladium on carbon, and the mixture was stirred overnight under an atmosphere of hydrogen. The mixture was then filtered through Celite and concentrated in vacuo. HPLC purification provided 272. 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.77 (s, 1H), 7.05 (s, 2H), 5.17-4.78 (m, 2H), 4.17-3.92 (m, 2H), 3.71 (s, 3H), 3.47-3.34 (m, 1H), 3.27-3.15 (m, 1H), 2.23-2.11 (m, 1H), 2.11-1.95 (m, 2H), 1.94-1.83 (m, 1H), 1.82-1.57 (m, 9H). LCMS (ES+) m/z 423 (M+1).
Reaction SMILES: C([Si]([C:11]#[C:12][C:13]1[CH:18]=[CH:17][N:16]2[CH:19]=[CH:20][N:21]=[C:15]2[CH:14]=1)(C(C)C)C(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:12]([C:13]1[CH:18]=[CH:17][N:16]2[CH:19]=[CH:20][N:21]=[C:15]2[CH:14]=1)#[CH:11]
Reactant: CC(C)[Si](C#Cc1ccn2ccnc2c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.5 %

Procedure:
Combine 7-[(Triisopropylsilanyl)-ethynyl]-imidazo[1,2-a]pyridine (3.23 g, 10.82 mmol) and tetrabutylammonium fluoride (1.19 mL, 1.19 mmol, 1.0 M in THF) in THF (5 mL). Stir the mixture at room temperature for 40 minutes, then concentrate in vacuo to a black oil. Purify by column chromatography (ethyl acetate) to afford product (1.10 g, 71%). MS(ES), m/z 143.1 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9].[CH3:20][Sn](C)(C)C>CN(C=O)C.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[N:3][C:2]=1[CH3:20]
Reactant: C[Sn](C)(C)C
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)nnc1Br
Agent: Cl[Pd+]
Agent: [CH2-]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(-c2cccc(C(F)(F)F)c2)nnc1C
Yield: 63 %

Procedure:
3-Bromo-4-methoxy-6-[3-(trifluoromethyl)phenyl]pyridazine (1.0 g, 0.003 mole, Compound No. 65), tetramethyltin (1.28 g, 0.0072 mole) and trans-benzyl(chloro)bis-(triphenylphosphine)palladium(II) (20 mg) were heated to 100° C. in DMF under N2 for 18 h. The reaction was then cooled and partitioned between aqueous KF solution and ethyl acetate. The KF solution was extracted with additional ethyl acetate. The organic layers were washed with brine, dried (MgSO4), filtered through silica gel and then evaporated in vacuo. The crude oil was then chromatographed on a Prep-500 to give 4-methoxy-3-methyl-6-[3-(trifluoromethyl)phenyl]pyridazine (0.51 g, 63% yield, Compound No. 66) as a light yellow solid.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH2:3]1.C1CCN2C(=NCCC2)CC1.[B-](F)(F)(F)F.CCN([S+](F)F)CC>C(Cl)Cl>[O:19]=[C:5]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:2]=[CH:3][N:4]1[C:20]1[CH2:21][O:22][C:23](=[O:25])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(C1=CC(=O)OC1)CC2O
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC2(C=CN(C3=CC(=O)OC3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxy-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (210 mg, 0.596 mmol) in DCM (6 mL) at 0° C. was added DBU (269 μA, 1.79 mmol), and XtalFluor-E® (409 mg, 1.79 mmol). The reaction mixture was stirred overnight while warming up to rt, then quenched with aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LCMS: [(M+1)]+=335;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([NH2:37])=[CH:35][C:34]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[N:28]1([C:31]2[C:36]([NH:37][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=3[CH3:24])=[CH:35][C:34]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:33][N:32]=2)[CH2:27][CH2:26][O:25][CH2:30][CH2:29]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (70.0 mg, 0.190 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.21 (1H, d, J=7.8 Hz), 7.84 (1H, d, J=11.7.0 Hz), 7.80 (1H, td, J=7.5, 1.4 Hz), 7.70 (1H, td, J=7.7, 1.4 Hz), 7.54 (1H, br. s.), 7.50 (1H, d, J=9.4), 7.41 (1H, d, J=7.4 Hz), 7.06 (1H, ddd, J=13.5, 8.6, 2.5 Hz), 6.52 (1H, br. s.), 3.84-4.03 (4H, m), 3.70-3.83 (4H, m), 3.32-3.56 (2H, m), 2.87-3.19 (9H, m), 1.92 (3H, s). Mass Spectrum (ESI) m/e=596.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:13])=[O:12].[Cl-].[CH3:16]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:12])=[O:13]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: [Cl-]
Product: COC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
A round bottom flask was charged with 4-chloro-3-(chlorosulfonyl)benzoic acid (16.0 g, 63.24 mmol) and methanol (100 mL), and thinoyl chloride (9.3 mL, 126.5 mmol) was added slowly at 0° C. The reaction mixture was then heated to reflux for 1.5 hours. The volatiles were removed under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The solvents were removed under reduced pressure to get the title compound as a solid.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.CCOCC>[C:25]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:13]([CH2:14][NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Nc1ccncc1)c1ccc(OCC(c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(C(COc2ccc(CNc3ccncc3)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 14-6 (0.144 g, 0.365 mmol) in tetrahydrofuran (1 ml) and ether (3 ml) under nitrogen was added lithium aluminum hydride (30 mg, 0.79 mmol). The mixture was stirred at room temperature overnight and then was decomposed with water and sodium hydroxide. The mixture was filtered and concentrated in vacuo to a colorless oil 14-7 which was purified by silica gel chromatography and converted to the HCl salt, mp: 213°-214.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:18]1COCC1>C(O)=O>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([O:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)=[CH:3][C:2]=2[N:1]=[CH:18]1
Reactant: C1CCOC1
Reactant: Nc1ccc(Oc2ccc(CO)cc2)cc1N
Solvent: O=CO
Product: OCc1ccc(Oc2ccc3[nH]cnc3c2)cc1

Procedure:
{4-[(3,4-diaminophenyl)oxy]phenyl}methanol (3.21 g of crude material) was dissolved in 20 ml THF and 10 ml of formic acid. The reaction was heated in a 100 degree Centigrade oil bath for approximately 22 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed 5 times with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in 30 ml of THF and 10 ml of 10% aqueous LiOH and heated at 100 degrees Centigrade for 30 minutes. The reaction was diluted with water and ethyl acetate. The organic layer was washed with brine three times, dried over MgSO4, and concentrated under reduced pressure onto basic alumina. The compound was purified by silica gel column chromatography (100% dichloromethane to 10% (2M NH3 in methanol) in dichloromethane gradient) to give 1.26 g of [4-(1H-benzimidazol-5-yloxy)phenyl]methanol.