Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C@@H:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:20]([CH3:29])([CH3:28])[O:19][C:18]4=[O:30])=[CH:13][CH:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.[C:31]([Zn]C#N)#[N:32]>CN(C=O)C.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>[CH3:29][C:20]1([CH3:28])[O:19][C:18](=[O:30])[N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([C:31]#[N:32])=[CH:3][C:4]4=[N:10][N:9]=3)=[CH:16][CH:15]=2)[C@H:21]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#C[Zn]C#N
Reactant: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(I)ccn34)cc2)[C@H]1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(C#N)ccn34)cc2)[C@H]1c1ccccc1
Temperature: 85 °C
Yield: 35.6 %

Procedure:
To a 2 mL sealable tube were added (S)-3-(4-(7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (70 mg, 0.137 mmol), dicyanozinc (16.11 mg, 0.137 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and Pd(Ph3P)4 (15.85 mg, 0.014 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) in DMF (457 μL). The mixture was purged with nitrogen for 5 minutes and then the tube was sealed. The vessel was heated to 85° C. in a microwave oven for 1 hour. LC-MS indicated complete conversion to the desired product. The final reaction mixture was passed through a syringe filter, and the material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-3-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (20 mg, 0.049 mmol, 35.6% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J=1.37 Hz, 1H), 8.66 (dd, J=1.17, 7.34 Hz, 1H), 7.84-7.90 (m, 2H), 7.72-7.78 (m, 2H), 7.37-7.44 (m, 2H), 7.28-7.37 (m, 3H), 7.22 (dd, J=1.56, 7.34 Hz, 1H), 5.56 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 410.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([N:26]6[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]6)[N:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5CC5)c4)cc32)n1
Product: c1cc(N2CCNCC2)nc(-n2ncc3cnc(-c4cncc(C5CC5)c4)cc32)c1
Yield: 31 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-cyclopropylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 111 was obtained as an off-white solid (41.7 mg, 31%). 1H NMR (400 MHz, DMSO) δ 9.33-9.28 (s, 1H), 9.06-8.99 (d, J=2.5 Hz, 2H), 8.66-8.61 (s, 1H), 8.50-8.45 (d, J=2.1 Hz, 1H), 8.09-8.03 (t, J=2.0 Hz, 1H), 7.81-7.73 (t, J=8.1 Hz, 1H), 7.29-7.20 (d, J=7.7 Hz, 1H), 6.85-6.76 (d, J=8.5 Hz, 1H), 3.65-3.56 (m, 4H), 2.94-2.84 (m, 4H), 2.13-2.04 (m, 1H), 1.12-1.04 (m, 2H), 0.88-0.81 (m, 2H); MS (ESI) m/z: 398.2 [M+H]+
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1csc(N=C=O)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cc(C)cs3)c(=O)n(C3CCCC3)c12
Yield: 63.8 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 2-isocyanato-4-methyl-thiophene (0.5 mmol) following general procedure C. LCMS: m/z 408 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.44 (s, 1H), 8.32 (s, 1H), 7.80 (d, 1H), 7.63 (t, 1H), 7.28 (d, 1H), 6.89 (s, 1H), 5.05 (p, 1H), 4.10 (s, 3H), 3.02 (s, 3H), 2.29 (m, 2H), 2.11-2.19 (m, 4H), 1.25 (m, 2H) ppm.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.CC([O-])(C)C.[K+].CS(C)=O.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[C:34](=[CH:35][C:36](F)=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:6][CH:4]4[CH2:5][NH:2][CH2:3]4)=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: OC1CNC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OC4CNC4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106 %

Procedure:
A mixture of Azetidin-3-ol hydrochloride (Oakwood) (461 mg, 4.21 mmol), KOtBu (1.02 g, 9.11 mmol), and dry DMSO (4.2 mL) was stirred at rt for 30 min until a translucent solution resulted. Then 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.46 g, 4.41 mmol), as prepared in Example 65b, was added, and the resulting opaque orange mixture (no visible precipitate) was stirred at rt for 3.5 hr. The reaction was then shaken with water (40 mL) and extracted with DCM (1×20 mL) and 9:1 DCM/MeOH (1×20 mL). The combined organic layers were washed with 0.2 M K2CO3 (3×20 mL), dried (Na2SO4), and concentrated to give 1.715 g of the title compound as an off-white solid (“106%” crude yield). LC/MS (ESI): calcd mass 384.2, found 385.3 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[CH:22]=1)([OH:20])=[O:19]>>[F:30][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3F)c(C(F)(F)F)nc2c1
Yield: 19 %

Procedure:
Followed the coupling procedure described in Step 1 of Compound VIII-2 (Example 65), where the starting materials were 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11) and 4-carboxy-2-fluorobezeneboronic acid. After H2O quench, the aqueous layer was acidified with 0.1M HCl to pH=1, followed by EtOAc/aqueous workup and column purification to give 3-fluoro-4-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid (50 mg, yield 19%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:31]1[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)cc1

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.45 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 4-methylphenylboronic acid (0.3 g) in ethanol (1 ml). The mixture was heated under reflux for 2 hours. After cooling the organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions followed by trituration with hexane gave the title compound as an off-white crystalline solid, m.p.243-4° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=O.[NH2:16]O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO>[CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]#[N:16]
Reactant: NO
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[Si](C)(C)CCOCn1ccnc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (1.5 g, 6.6 mmol) in 5 mL of MeOH was added hydroxylamine (0.6 mL, 9.1 mmol, 50% aqueous soln) and the reaction stirred for 10 min at RT and then concentrated. The residue was dissolved in 10 mL of DCM and 5 mL of pyridine and cooled in an ice bath. To this mixture was added trifluoroacetic anhydride (4.2 g, 20 mmol) and the reaction stirred for 8 h at RT. The mixture was concentrated and then dissolved in EtOAc (50 mL) and washed with NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated to give 1.2 g (81%) of a brown oil of sufficient purity to use in the next step. 1H-NMR (CDCl3, 400 MHz): δ 7.28 (s, 2H), 5.48 (s, 2H), 3.56 (m, 2H), 0.96 (m, 2H), 0.00 (s, 9H). Mass spectrum (APCI, m/z): Calcd. for C10H17N3OSi, 224.1 (M+H), found 223.6.
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:16])=[CH:10][C:11]=32)[CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl.O1CCOCC1>CC(O)C>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]2[CH2:15][CH2:14][CH:12]3[CH2:13][N:3]([CH2:1][CH3:2])[CH2:4]2)=[N:19][CH:20]=1
Reactant: CCN1CC2CCC(C1)c1cc(N)ccc12
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 130 °C
Yield: 57.7 %

Procedure:
10-Ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trien-4-ylamine (29.8 mg, 0.138 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (45 mg, 0.152 mmol, 1.1 eq) were dissolved in IPA (1.5 mL). 4.0 M HCl in dioxane (38 μL, 0.152 mmol, 1.1 eq) was added and the reaction was heated at 130° C. in a microwave for 10 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-5% MeOH/CH2Cl2 as the eluting solvent to obtain 2-[5-chloro-2-(10-ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a yellow solid (38 mg, 58%). m.p. dec. at 106° C.; LCMS (m/e) 477 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.67 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.50-7.40 (m, 2H), 7.34 (d, 1H, J=2.3 Hz), 7.30-7.20 (m, 1H), 7.02 (t, 1H, J=7.6 Hz), 7.00 (d, 1H, J=7.9 Hz), 6.87 (s, 1H), 6.19 (bs, 1H), 3.03 (d, 3H, 4.9 Hz), 3.00-2.90 (m, 4H), 2.44 (q, 2H, J=7.1 Hz), 2.21-2.16 (m, 4H), 1.64-1.60 (m, 2H), 1.00 (t, 3H, J=7.1 Hz).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][CH3:13])[C:9]=2[CH:14]=1
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCCc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 80.6 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (63 mg, 0.207 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 60° C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 35 mg of a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.2 (m, 3H), 3.3-3.0 (m, 7H), 1.9-1.6 (m, 2H), 0.91 (t, J=7 Hz, 3H). MS calculated for C12H16ClN+H: 210, observed: 210.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8](Cl)=[O:9].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][C:21]=1[Cl:25])=[O:9]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Clc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 80 °C

Procedure:
6 g of aluminium chloride are added to 5 g of 2-chloro-5-nitrobenzoyl chloride in 60 ml of dichloromethane, and 30 ml of 1,3-dichlorobenzene are then added dropwise. The reaction medium is heated for 2 hours at 80° C. and then cooled, and poured onto crushed ice. After extracting with dichloromethane, washing with water and drying over sodium sulphate, the organic phase is evaporated to dryness under vacuum and the crystalline residue is recrystallized in cyclohexane (3.6 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ncsc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1scnc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
To a solution of methyl 5-methyl-1,3-thiazole-4-carboxylate (1.17 g, 7.4 mmol) in methanol (15 mL) was added 8N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 18 hr. 6N Hydrochloric acid (2.67 mL) was added to the mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the precipitate was collected by filtration, and washed with water. The precipitate was suspended in a mixed solvent of ethyl acetate (9 mL) and ethanol (1 mL), and the mixture was stirred at 80° C. for 3 min. After allowing to cool to room temperature, the precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (531 mg, yield 50%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Li+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Agent: [H-]
Agent: [Li+]
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Yield: 92.7 %

Procedure:
Following the general procedure of Examples 2 and 3, 791.0 mg (8.404 mM) of 4-aminopyridine was reacted with 212.5 mg (26.73 mM) of lithium hydride and 3002.4 mg (8.4 mM) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one to give 92.7% yield (95.9% purity) of 2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[O:21])[CH:14]=2)[C:9]2[N:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)([OH:3])=[O:2].[CH2:35](O)[CH3:36]>>[CH2:35]([O:2][C:1]([CH2:4][CH2:5][C:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[O:21])[CH:14]=2)[C:9]2[N:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)=[O:3])[CH3:36]
Reactant: CCO
Reactant: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)O)nc3cccnc32)c1
Product: CCOC(=O)CCc1nc2cccnc2n(-c2cccc(NC(=O)Nc3ccccc3OC)c2)c1=O

Procedure:
To a suspension of 2-(2-carboxyethyl)-3-oxo-4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (0.15 g) in ethanol (9 ml) was added conc. sulfonic acid (0.9 ml) and the mixture was refluxed for 30 minutes. After cooling, the reaction mixture was neutralized and ethanol was evaporated. Crystalline materials formed were collected, washed with water and dried to give 2-(2-ethoxycarbonylethyl)-3-oxo-4-[3-[3-(2-methoxyphenyl)-ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (0.12 g).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=[N:20][OH:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1C(=O)CCC1=O.[CH2:30]([Br:33])[C:31]#[CH:32].C(N(CC)CC)C>ClCCl>[Br:33][CH2:30][C:31]1[O:21][N:20]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[CH:32]=1
Reactant: C#CCBr
Reactant: COc1cccc2c(C=NO)cn(CC3CCCCC3)c12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c(-c3cc(CBr)on3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carbaldehyde oxime (170 mg, 0.59 mmol) in dichloromethane (5 ml) cooled to 0° C., was added N-chlorosuccinimide (119 mg, 0.89 mmol) and the mixture allowed to warm to room temperature with stirring for 1 h. Propargyl bromide (8 μl, 0.65 mmol) and triethylamine (9 μl, 0.65 mmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 60-80% (v/v) dichloromethane in n-heptane to afford 3-(5-bromomethyl-isoxazol-3-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (150 mg, 0.37 mmol) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:12][C:13]3[N:14]=[C:15]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23]4)[C:16]4[CH:21]=[CH:20][NH:19][C:17]=4[N:18]=3)[CH:8]=2)[NH:3]1.C1C=CC2N(O)N=[N:38]C=2C=1.C(Cl)CCl.N>CN(C=O)C>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:12][C:13]3[N:14]=[C:15]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([NH2:38])=[O:31])[CH2:24][CH2:23]4)[C:16]4[CH:21]=[CH:20][NH:19][C:17]=4[N:18]=3)[CH:8]=2)[NH:3]1
Reactant: O=C(O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Reaction time: 0.67 h
Yield: 76.9 %

Procedure:
To a solution of 2-(1-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)acetic acid (26 mg, 0.062 mmol) and HOBt (35 mg, 0.23 mmol) in DMF (2 mL), EDC (40 mg, 0.21 mmol) was added. After being stirred for 40 min, NH3 (0.5 M in dioxane, 1.00 mL, 0.500 mmol) was added. The mixture was stirred for 20 h. It was then purified by HPLC to give the titled compound (20 mg). MS 420.3 (M+H); UV 201.8, 279.8 nm.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[CH:17]=[CH:6][C:5]1[C:8]([F:10])=[CH:9][C:2]([Br:1])=[CH:3][C:4]=1[F:11])[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(F)cc(Br)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1c(F)cc(Br)cc1F
Yield: 91.6 %

Procedure:
A mixture of 4-bromo-2,6-difluoro-benzaldehyde (1 g, 4.5 mmol), (carbethoxymethylene)-triphenyl-phosphorane (2 g, 5.7 mmol) in 30 mL of toluene was heated at reflux for 6 hours, and was evaporated to dryness. The solid was stirred in 200 mL of petroleum ether, and was filtered. The filtrate was evaporated to give the product as oil (1.2 g, yield 91%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]([C:19]([OH:21])=[O:20])[CH2:9][S:8]2)[CH:2]=1.[CH3:22]N1CCOCC1.C(OC(Cl)=O)C(C)C.CO>O1CCCC1>[CH3:22][O:20][C:19]([CH:10]1[CH2:9][S:8][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:11]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:21]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxylic acid (78 g, 251 mmol), prepared as in Example 1, step 2, and 4-methylmorpholine (43 g, 427 mmol) were dissolved in tetrahydrofuran (500 mL ), and cooled in the ice bath. Isobutylchloroformate (38 g, 276 mmol) was added and the yellow suspension was stirred for 0.5 hours. Methanol (250 mL) was added, the cold bath was removed, and the reaction mixture was stirred for 60 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give Methyl-2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxylate (38 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[C:15]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([N:23]1[CH2:28][CH2:27][C:26]2([CH2:13][C:12](=[O:14])[C:3]3[CH:4]=[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: CC(=O)c1cc(S(C)(=O)=O)ccc1O
Product: CS(=O)(=O)c1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3ccccc3)CC1)O2

Procedure:
2'-Hydroxy-5'-methanesulfonylacetophenone and 1-benzoyl-4-piperidone were condensed according to the method of Example 434 to give the ketone as a white solid, m.p. 155°-157° C.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([F:27])[CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:37]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([F:27])[CH:13]=2)=[O:8])=[CH:29][CH:30]=1)(=[S:37])[NH2:2]
Reactant: S
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1F

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (504 mg), pyridine (35 ml), triethylamine (5 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-2-fluorophenoxyacetate (509 mg): m/Z 447 (M)+. ; 460 (M+Na)+.