Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].[Br:3][C:4]1[N:5]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:6]([S:9][CH2:10][C:11]([OH:13])=[O:12])=[N:7][N:8]=1>C(O)C>[Br:3][C:4]1[N:5]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:6]([S:9][CH2:10][C:11]([O-:13])=[O:12])=[N:7][N:8]=1.[Na+:2]
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
Aqueous sodium hydroxide solution (1M, 2.0 mL, 2.0 mmol) was added dropwise over 5 mins to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in ethanol (10 mL) at 10° C. The mixture was stirred at 10° C. for a further 10 mins. Volatile solvents were removed in vacuo to dryness to provide sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as a solid (850 mg, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1)=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[CH3:17][O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:18].[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]
Reactant: COCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCNCC1=O
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-4-(2-methoxyethyl)-3-oxopiperazine (6.6 g) was dissolved in dichloromethane (100 ml), the resulting solution cooled in an ice-bath, and trifluoroacetic acid (145 ml) added. The mixture was stirred at the same temperature for 2 hours. Solvent was evaporated to yield 1-(2-methoxyethyl)-2-oxopiperazine product as a salt with 4 moles of trifluoroacetic acid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH:16]12[O:9][CH:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:17]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
mCPBA (14.6 g, 63.3 mmol) was added slowly to a stirred solution of benzyl 3,6-dihydropyridine-1(2H)-carboxylate (12.50 g, 57.5 mmol) in DCM (80 mL) which was cooled in an ice bath. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then quenched with aq. Na2CO3 and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound. LCMS calc. for C13H16NO3 (M+H)+: m/z=234.1. Found: 234.0.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[N:14][CH:15]=1)=[O:9].Br[CH2:40][CH:41]1[CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:36][C:33]([F:34])([F:35])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][N:19]([CH2:40][CH:41]3[CH2:43][CH2:42]3)[CH2:20][CH:21]=2)=[N:14][CH:15]=1)=[O:9]
Reactant: BrCC1CC1
Reactant: Cc1ccccc1-c1cc(C2=CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(C2=CCN(CC3CC3)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.3 %

Procedure:
A mixture of 60 mg (0.11 mmol) 4-o-tolyl-1′,2′,3′, 6′-tetrahydro-[2,4′]bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide (Example 42), 0.011 ml (0.11 mmol) (bromomethyl)cyclopropane and 19 mg (0.14 mmol) potassium carbonate in 1.5 ml acetonitrile was stirred at room temperature for 15 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography afforded 28 mg (42%) of the title compound as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][O:39][CH2:40][CH2:41][N:42]([CH2:52][CH2:53][O:54][CH3:55])[C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:42]([CH2:52][CH2:53][O:54][CH3:55])[CH2:41][CH2:40][O:39][CH3:38])=[O:51])[CH2:46][CH2:47]3)=[O:28])[C@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: COCCN(CCOC)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxy-ethyl)-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 16) in an analogous manner as described in example 25. LR-MS: 797.4 [(M+H)+]
Reaction SMILES: C([O:5][C:6](=[O:14])[NH:7][C@@H:8]([CH2:11][O:12][CH3:13])[CH2:9]O)(C)(C)C.O1CCCC1.CC(C)([O-])C.[K+]>O>[CH3:13][O:12][CH2:11][C@H:8]1[CH2:9][O:14][C:6](=[O:5])[NH:7]1
Reactant: COC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl[(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate (synthesized according to the procedure described in Sowinski, J. A.; Toogood, P. L. J. Org. Chem. (1996), 61(22), 7671-7676) (8.3 g, 40.4 mmol) tetrahydrofuran (100 mL), 1M solution of potassium t-butoxide in tetrahydrofuran (80.9 mL, 80.9 mmol) was added dropwise at 0° C. and the mixture was stirred at the room temperature for 2 hours. Water (20 ml) was added to the reaction mixture and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine and dried over Na2SO4. Yield: 5.0 g (94%). 1H NMR (300 MHz, DMSO-d6) δ: 3.3 (s, 3H), 3.3 (m, 2H), 3.9 (m, 1H), 4.0 (dd, 1H), 4.3 (t, 1H), 7.7 (d, 1H). [α]D25=−5.876.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].C(OC(O)C)C>[Pd].[Pt]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Pd]
Agent: [Pt]
Agent: CCOC(C)O
Product: Nc1ccc(-c2nc3cc(N)ccc3o2)cc1

Procedure:
The process of claim 17 wherein the 2-(4-nitrophenyl)-5-nitrobenzoxazole is reduced by hydrogen and palladium or platinum over carbon in the presence of ethoxyethanol under such conditions to form 2-(4-aminophenyl)-5-aminobenzoxazole.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>CC(N(C)C)=O>[OH:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[OH:29])[S:3][C:4]=2[CH:10]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: OCc1ccc2nc(Br)sc2c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: OCc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a suspension of (2-bromobenzo[d]thiazol-6-yl)methanol (400 mg, 1.6 mmol) from Step 2 of Example 2 in DMA (6 mL) were added DIEA (258 mg, 2.0 mmol) and (1R,2R)-2-aminocyclohexanol (226 mg, 2.0 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure to give crude (1R,2R)-2-((6-(hydroxymethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown oil (445 mg, 100%), which was used for the next step without any further purification. LCMS (ESI) m/z 279 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:5][NH:6]2>O1CCCC1.[Li+].[OH-].C(OCC)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][NH:6]2
Reactant: COC(=O)CSc1c[nH]c2cc(F)cc(F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CSc1c[nH]c2cc(F)cc(F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Methyl 2-((4,6-difluoro-1H-indol-3-yl)thio)acetate (253 mg, 0.98 mmol) from Step A was dissolved in a mixture of tetrahydrofuran (8 mL) and 2.0 M aqueous LiOH (2 mL), then stirred vigorously at ambient temperature for 30 minutes. Tetrahydrofuran was removed in vacuo, the aqueous layer neutralized with 1.2 N HCl and extracted with CH2Cl2. The organic layer was dried over magnesium sulfate and removed in vacuo to produce an oily residue. After diluting the residue with diethylether and removing the solvent in vacuo a solid formed which was the desired product (232 mg, 0.95 mmol, 98% yield). LCMS>99% at 254 nm, RT=1.17 min, m/z=244 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29]4)=[CH:24][CH:23]=3)[C:16]2=[CH:15][N:14]=1.C(O)(C(F)(F)F)=O.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl.CO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][N:28]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:29]4)=[CH:24][CH:23]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC5)n[nH]c3n2)c1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(S(C)(=O)=O)CC5)n[nH]c3n2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 7-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (10.0 mg, 0.0191 mmol) in dichloromethane (0.10 mL) was treated with TFA (0.10 mL). The mixture was stirred at r.t. for 1 h. The volatiles were evaporated. The residue was dissolved in acetonitrile (0.5 mL) and N,N-diisopropylethylamine (30.0 μL). To the mixture was added methanesulfonyl chloride (2.0 μL, 0.026 mmol). The mixture was stirred at r.t. for 30 min, and then diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=502.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29]>>[F:29][C:28]([F:31])([F:30])[CH:27]([OH:32])[CH2:26][NH:25][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23]
Reactant: NCC(O)C(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NCC(O)C(F)(F)F)n(C)n1
Yield: 47 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using rac-3-amino-1,1,1-trifluoropropan-2-ol instead of 2-amino-2-methyl-1-propanol, to the title compound (63 mg, 47%) which was obtained as a colorless gum. MS: m/e=443.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:11](/[CH:12]=[CH:13]/[C@@H:14]([OH:24])[CH2:15][C@@H:16]([OH:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:9]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:32]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C@@H:14]([OH:24])[CH2:15][C@@H:16]([OH:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:10]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:9]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:32]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(-c2ccccc2)nn(-c2ccnc(Nc3ccccc3)n2)c1-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C[C@H](O)C[C@H](O)CCc1c(-c2ccccc2)nn(-c2ccnc(Nc3ccccc3)n2)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A flask containing (3R,5S,E)-ethyl 7-(3,5-diphenyl-1-(2-(phenylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3,5-dihydroxyhept-6-enoate, 28 (0.227 g), ammonium formate (0.500 g) and palladium on carbon (0.050 g) in ethanol (10 mL) is heated to 80° C. for 2 h adding extra portions of catalyst and ammonium formate every 45 min. The reaction mixture is left at ambient temperature for 16 h, then filtered through celite and concentrated. The resulting residue is partitioned between ethyl acetate and water and the organic layer dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography affords (3R,5R)-ethyl 7-(3,5-diphenyl-1-(2-(phenylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3,5-dihydroxyheptanoate, 31 (0.162 g) and (4R,6R)-6-(2-(3,5-diphenyl-1-(2-(phenylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)ethyl)-4-hydroxy-tetrahydropyran-2-one, 32 (0.023 g).
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CC(N(C)C)=O>[F:8][C:6]1[CH:5]=[N:4][C:3]2[C:9]([NH2:10])=[N:17][CH:15]=[N:16][C:2]=2[CH:7]=1
Reactant: N=CN
Reactant: N#Cc1ncc(F)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2cc(F)cnc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
3,5-Difluoro-pyridine-2-carbonitrile (2.54 mmol, 356 mg) is dissolved in DMA (5 mL) and then formamidine acetate is added (2.54 mmol, 264.6 mg) followed by DIEA (7.62 mmol, 983 mg). The reaction mixture is stirred for 16 h at 100° C., then poured into saturated NH4Cl aq. and extracted 3 times with CH2Cl2. The organics are dried with Na2SO4, concentrated, and purified on Biotage with 0-20% MeOH in CH2Cl2. This gives the desired product 7-Fluoro-pyrido[3,2-d]pyrimidin-4-ylamine (27 mg, LC/MS m/z=165 [M+H]+) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: CCOc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CCOc1ccccc1N1CCN(C(=O)c2cn(CCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: C(OC(=O)N[C:8]1[C:13]([I:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15])(C)(C)C.N([O-])=O.[Na+].[BrH:21]>C(O)C.O.[Cu]Br>[Br:21][C:8]1[C:13]([I:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1I
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1cccc(I)c1Br
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of (2-fluoro-6-iodo-phenyl)-carbamic acid tert-butyl ester (22.5 g, 67 mmol) in ethanol (100 mL) and 48% aqueous hydrobromic acid (100 mL) was stirred at RT. After 1 h the solvent was removed under reduced pressure and the residue was resuspended in 48% aqueous hydrobromic acid (100 mL). The suspension was heated to 60° C. for 10 min followed by cooling to 0° C. in an ice-water bath. A solution of sodium nitrite (4.9 g, 70 mmol) in water (25 mL) was added dropwise keeping the internal temperature below 5° C. The resulting suspension was stirred for 15 min at 0° C. followed by addition of copper (I) bromide (2.93 g, 20 mmol). The mixture was heated to 80° C. for 1 h and subsequently cooled to RT. The mixture was extracted with dichloromethane (2×250 mL) and the organic layer was washed with brine (150 mL), 10% aqueous sodium hydroxide solution (250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% ethyl acetate:hexanes) to afford 10.5 g (50%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.01-7.05 (m, 1H), 7.08-7.12 (m, 1H), 7.67 (d, J=4.8 Hz); 13C NMR (100 MHz, CDCl3): δ 102.5, 115.9 (d, J=22 Hz), 117.6 (d, J=21 Hz), 129.8 (d, J=14 Hz), 135.4 (d, J=21 Hz), 158.7 (d, J=250 Hz); 19F NMR (282 MHz, CDCl3): δ−96.3 (m, 1F).
Reaction SMILES: B.[OH:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:16][CH2:15][N:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.ClC1C=C([C@H](CCN2CCC(C3C=CC=CC=3C(OC)=O)CC2)CN(C)C(C2C3C(=CC=CC=3)C=C(C#N)C=2)=O)C=CC=1Cl.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Li+]>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:16][CH2:15][N:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NN1CCC(c2ccccc2C(=O)O)CC1
Agent: B
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: COC(=O)c1ccccc1C1CCN(CC[C@H](CN(C)C(=O)c2cc(C#N)cc3ccccc23)c2ccc(Cl)c(Cl)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN1CCC(c2ccccc2CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
A 1M borane solution in tetrahydrofuran (6 mL) was added to a solution of tert-butyl 4-(2-hydroxycarbonylphenyl)piperidinecarbamate (0.915 g) (prepared from 4-(2-methoxycarbonylphenyl)piperidine [Example 20] by N-protection using di-tert-butyldicarbonate followed by saponification of the methyl ester with lithium hydroxide) in tetrahydrofuran (20 mL) at 0° C. The reaction was warmed to ambient temperature and stirred overnight. The reaction was quenched with methanol and 1N aqueous HCl then extracted with diethyl ether. The organic phase was separated and extracted sequentially with aqueous sodium bicarbonate and brine. The organic phase was dried and evaporated to give the title compound (0.906 g) as a colorless oil. MS: m/z=192 (M-Boc). 1H NMR (CDCl3) δ 7.28 (m, 4H, Ar—H), 4.75 (d, 2H, Ar—CH2—O), 3.05 (m, 1H), 2.83 (m, 3H), 1.70 (m, 5H), 1.49 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:27]([OH:29])=O)[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:65]1[CH2:70][CH2:69][CH:68]([N:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C@H:16]([CH2:17][C:18]3[CH:19]=[C:20]([CH3:26])[C:21]([OH:25])=[C:22]([CH3:24])[CH:23]=3)[C:27](=[O:29])[N:74]3[CH2:73][CH2:72][N:71]([CH:68]4[CH2:69][CH2:70][O:65][CH2:66][CH2:67]4)[CH2:76][CH2:75]3)=[O:14])[CH2:11][CH2:12]2)[N:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 100 mg (0.21 mmol) (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate, 74 mg (0.23 mmol) TBTU and 35 μL (0.26 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 35 mg (0.21 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the reaction mixture was stirred for a further 5 h at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]([CH3:29])[NH:26][CH:25]([CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]([CH3:29])[N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)N1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 3,5-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])CCCC1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:38]=[C:36]([NH:35][CH3:30])[N:37]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nccc(-c2c(-c3ccncc3)nn3c(NC4CCCC4)cccc23)n1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (From example 1, 0.13 g, 0.35 mmol) in tetrahydrofuran (10 mL) was added cyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated at reflux for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:20 methanol-ethyl acetate) to give the title compound (100 mg, 75%) as a yellow solid. 1H NMR (CDCl3): δ 8.72 (d, 2H), 8.13 (d, 1H), 7.65 (m, 3H), 7.35 (t, 1H), 6.43 (d, 1H), 6.10 (d, 1H), 6.05 (d, 1H), 5.10 (m, 1H), 4.05 (m, 1H), 3.05 (d, 3H), 1.2–2.2 (m, 8H); MS m/z 386 (M+1).