Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.O1CCCC1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Dissolve 2,6-dichloronicotinic acid (1000 mg, 5.21 mmol) in anhydrous tetrahydrofuran (5 mL). Cool to 0° C. Add borane-tetrahydrofuran complex (7.82 mL, 7.82 mmol, 1.0 M in tetrahydrofuran) slowly. Stir the mixture at room temperature overnight. Add water (1 mL) and potassium carbonate, stir for 2 hours, filter and concentrate to give a residue. Chromatograph the residue on silica gel eluting with 10:90 to 20:80 ethyl acetate:hexanes to give (2,6-dichloropyridin-3-yl)-methanol (876 mg, 94%). 1H NMR (400 MHz, MeOH-d4) δ 7.96 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=8.0 Hz), 4.64 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:37]
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+].[CH:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>CN(C=O)C>[CH2:38]([O:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[C:13]([NH:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[C:2]([OH:1])[CH:3]=1)=[O:14])[C:35]1[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)c1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2cnc3ccccc3c2OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (428) (6.7 mg, 0.02 mmol) and Cs2CO3 (13 mg, 0.04 mmol) in DMF (0.2 mL) was added BnBr (10 uL, 0.08 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and purified using HPLC to give 4-benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide (275). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.47 (s, 1H), 9.20 (s, 1H), 8.43 (d, J=7.9 Hz, 1H), 7.79 (t, J=2.0 Hz, 2H), 7.56 (m, 1H), 7.38-7.26 (m, 6H), 7.11 (d, J=8.4 Hz, 1H), 6.99 (dd, J=8.4, 2.1 Hz, 1H), 5.85 (s, 2H), 1.35 (s, 9H). HPLC ret. time 3.93 min, 10-99% CH3CN, 5 min run; ESI-MS 427.1 m/z (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:20](=[O:21])[N:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[CH:45][CH:46]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[N:43][C:44]([NH:47][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[C:20](=[O:21])[N:19]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:11]=4[N:12]=3)=[CH:45][CH:46]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CS(=O)c1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 105 °C
Yield: 16.8 %

Procedure:
(8-Cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (1.2 g, 3.06 ml, prepared according to Example 9) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.36 g, 8.48 mmol) were combined in toluene (4 ml) and heated to 105° C. for 12 hours. The resulting paste was diluted with toluene, filtered, washed with toluene and partitioned between diethyl ether and 1 N citric acid. The mixture was filtered, and the solid was washed with water and diethyl ether. The solid then was dissolved in chloroform, dried over anhydrous magnesium sulfate, filtered, and the filtrate diluted with diethyl ether, giving a solid precipitate. This solid was collected by filtration and dried in vacuo to give 4-[6-(6-tert-butoxycarbonylamino-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.311 g, 17%). MS (APCI) M++1; Calc'd, 607.3. Found, 607.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.CO>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:34])([F:35])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccn2)c1=O)C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccn2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[2-(4-Fluorophenyl)-6-oxo-5-(2-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to a procedure similar to that described in Example 1. Chromatography, with methanol:dichloromethane (gradient, 0:100, 5:95, 7:93) as the eluent, gave 2-[2-(4-fluorophenyl)-6-oxo-5-(2-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid; NMR (DMSO/H2O): 8.54 (d,2), 8.43 (s,1), 7.82 (m,1), 7.53 (m,3), 7.30 (m,3), 5.22 (s,2), 4.62 (d,1), 4.42 (d,1), 4.00, (d,1), 2.19 (m,1), 0.81 (d,3), 0.70 (d,3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC2C=CC=[C:26]([OH:27])C1=2.C(Cl)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].COC(Cl)Cl>CN(C)C=O.ClCCl>[CH2:1]([O:8][C:9]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[C:12]([CH:26]=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3ccsc23)cc1
Reactant: Oc1cccc2ccsc12
Agent: COC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCc1ccccc1
Solvent: ClCCl
Product: O=Cc1ccc(OCc2ccccc2)c2sccc12

Procedure:
In analogy to the procedure described in example 2 a], 7-benzyloxy-benzo[b]thiophene (prepared from benzo[b]thiophen-7-ol [J. Chem. Soc., Perkin Trans. 1 (1983), (12), 2973-71 and benzylchloride by treatment with potassium carbonate in N,N-dimethylformamide at room temperature) was reacted with dichloromethyl methyl ether in dichloromethane at 0° C. to give 7-benzyloxy-benzo[b]thiophene-4-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:34][C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:38])[CH:36]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[C:30]([C:31]#[N:32])=[CH:38][C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:34])[CH3:36])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Solvent: CCO
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)C(C#N)=CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 35 %

Procedure:
To a sealed tube was added N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]-2-cyano-acetamide (160 mg, 0.36 mmol), tert-butyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (0.13 mL, 0.54 mmol) piperidine (0.02 mL, 0.18 mmol) and ethanol (4 mL). The tube was capped and heated to 110° C. for 2 hrs. The reaction was cooled and concentrated then dissolved in ethyl acetate (30 mL) and washed with water (30 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified by isolera (25 g column, 2%-7% MeOH/DCM) to obtain 77 mg, (35%) of tert-butyl N-[4-[[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]amino]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]carbamate as a solid. MS (pos. ion) m/z: 615 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2ccc(F)cc2)cn1
Reaction time: 1 h

Procedure:
3.8 g (25 mmol) of methyl 5-amino-pyridine-2-carboxylate were dissolved in 75 ml of anhydrous pyridine, and 5.8 g (30 mmol) of 4-fluorobenzenesulfonyl chloride were added in portions, whereupon the temperature of the reaction solution rose to 35° C. After 1 hour, the mixture was concentrated in vacuo and the residue was triturated with water, filtered off with suction, washed with water and dried. This gave 7.3 g of product, melting point 183° to 185° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][N:17]([CH2:27][CH2:28][NH:29]C(=O)C3C=CC=CC=3)[C:16]=2[CH:38]=1.O.Cl>N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][N:17]([CH2:27][CH2:28][NH:29][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[C:16]=2[CH:38]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc2c(c1)N(CCNC(=O)c1ccccc1)CC(c1ccccc1)O2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2c(c1)N(CCNC(=O)Nc1ccccc1)CC(c1ccccc1)O2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.011 mol of phenyl isocyanate are added to a suspension of 0.01 mol of the amine hydrochloride obtained in Example 24 (before acylation) in 5 cm3 of pyridine. After stirring for 1 hour at 80° C., the reaction mixture is poured into iced water and then acidified with 1N HCl. The precipitate formed is suction-filtered off, washed, dried, and then recystallised to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([OH:13])[CH:3]=1.[Br:14][CH2:15][CH2:16]Br>>[Br:14][CH2:15][CH2:16][O:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2
Reactant: Cc1ccc2c(O)cc(Cl)cc2n1
Reactant: BrCCBr
Product: Cc1ccc2c(OCCBr)cc(Cl)cc2n1

Procedure:
The title compound was prepared from 7-chloro-5-hydroxy-2-methylquinoline and 1,2-dibromoethane using a similar procedure to Description 16.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][O:54][CH2:55][CH2:56][NH2:57]>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][NH:57][CH2:56][CH2:55][O:54][CH3:53])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: COCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCNCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 40 °C
Reaction time: 12 h
Yield: 11.8 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (17 μl, 0.10 mmol) was added 2-methoxyethylamine (7.0 μl, 0.08 mmol). The reaction mixture was heated to 40° C. and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(2-methoxyethylamino)acetamide (Example 11) as an off-white solid (6 mg, 11%): m/z 637 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.71 (2H, t), 3.24 (3H, s), 3.33 (2H, m (obscured by DHO)), 3.40 (2H, t), 5.38 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.36 (2H, d), 7.43 (2H, d), 7.64-7.57 (3H, m), 7.92 (1H, m), 8.36-8.30 (3H, m), 8.59 (1H, s), 8.79 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=O)[NH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[S:21])[NH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1
Reactant: Cc1cc(Nc2cc(N)ncn2)c(=O)[nH]c1C(=O)O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1cc(Nc2cc(N)ncn2)c(=S)[nH]c1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (4, 0.5 g, 1.91 mmol) in pyridine (10 mL) is added phosphorus pentasulfide (1.27 g, 5.73 mmol). The reaction is refluxed overnight. The resulting mixture is cooled to room temperature and concentrated. The crude is purified via column chromatography to afford 5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylic acid (5).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([C@H:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:38][OH:39])=[N:35][CH:36]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)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]>[F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:13]=[CH:14][C:15]([C:31]3[CH:32]=[CH:33][C:34]([C@H:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:38][OH:39])=[N:35][CH:36]=3)=[CH:16][CH:17]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1ccc(Br)cn1
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](CO)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 80 °C
Yield: 60.6 %

Procedure:
To a solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (339 mg, 0.820 mmol) in a mixture of toluene (5 ml) and ethanol (3 ml) is added (S)-tert-butyl 1-(5-bromopyridin-2-yl)-2-hydroxyethylcarbamate (260 mg, 0.82 mmol), aqueous sodium bicarbonate solution (2M, 3.28 mmol, 1.64 ml), and [1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (30 mg, 0.04 mmol). The stirred reaction mixture is heated at 80° C. under a blanket of nitrogen for 1 hour. The reaction is concentrated to dryness and partitioned between methylene chloride (25 ml) and water (25 ml). The organic phase is washed with saturated brine (25 ml) and concentrated on to silica gel (1 g). Purification by column chromatography (12 g silica gel, ethyl acetate/heptane 0-100%, 16cvs) affords the title compound (260 mg): m/z M+H 524.2. Retention time 2.73 min.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25](Cl)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.CCN(CC)CC>C(Cl)Cl>[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:3]1[CH2:4][CH2:5][C@@H:6]2[C@@H:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)=[O:26]
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1-c1ccccc1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1
Yield: 119.1 %

Procedure:
A mixture of (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (179 mg, 0.745 mmol), biphenyl-2-carbonyl chloride (210 mg, 0.97 mmol), Et3N (196 mg, 1.95 mmol) was stirred into DCM (7.0 mL) for 18 h at room temperature. Then reaction mixture was diluted with more DCM (25 mL) and washed successively with 1N aq. NaOH (5 mL) and water (2×15 mL). The organic phase was concentrated under reduced pressure. The crude residue was purified on HPLC (basic system) to yield pure title compound (373 mg, 99%). MS (ESI) mass calcd. for C27H24N4O, 420.52; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.00-7.32 (m, 11H), 7.29-7.18 (m, 1H), 6.75 (dd, J=9.9, 4.2, 2H), 4.70-4.42 (m, 1H), 4.30-3.90 (m, 3H), 3.8-3.74 (m, 0.66H), 3.51-3.30 (m, 1.35H), 3.13-3.03 (m, 0.5H), 2.90-2.80 (m, 0.5H), 2.68-2.51 (m, 0.5H), 1.96-1.68 (m, 2H), 1.59-1.43 (m, 0.5H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[C:17]([O:19][CH3:20])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[C:17]([O:19][CH3:20])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1nc2cc(CCc3nc(C(C)C)cs3)ccn2c(=O)c1/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2cc(CCc3nc(C(C)C)cs3)ccn2c(=O)c1/C=C/C(=O)O
Yield: 122.6 %

Procedure:
The tert-butyl (E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-methoxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (6.7 mg) obtained in (A) was treated with trifluoroacetic acid (0.5 ml) in the dark for 30 minutes, and then the solvent was evaporated. The residue was added with methanol and methylene chloride, and insoluble matters were collected by filtration to obtain the title compound (7.2 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][CH:22]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)c1
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: COCCOC
Product: COc1cccc(COc2ccc(-c3cnn(C)c3)cc2C(=O)Nc2cccnc2)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-({[3-(methyloxy)phenyl]methyl}oxy)-N-3-pyridinylbenzamide ((may be prepared as described in Example 18; 120 mg, 0.29 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66.5 mg, 0.32 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.58 ml, 0.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.13 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 24 mg.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])(CC)C.C1CCCCC1.[C:40]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:41]1([C:40]2([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:10]3[CH2:9][N:8]([CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:13][CH2:12][N:11]3[C:14](=[O:15])[O:47]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CCN12
Temperature: -78 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
1,1-Dimethylethyl 4-(phenylmethyl)-1-piperazine carboxylate (20 g, 72 mmol) and tetramethylethylenediamine (18 g, 0.16 mol) were dissolved in tetrahydrofuran (100 mL), and the solution was cooled to −78° C. A 1.0 M solution of sec-butyllithium in hexane and cyclohexane (150 mL, 0.15 mol) was added thereto, and the mixture was stirred for 2 hours and the temperature was elevated to −30° C. After cooling to −78° C. again, a solution of benzophenone (28 g, 0.15 mol) in tetrahydrofuran (70 mL) was added dropwise thereto, and the mixture was stirred for 18 hours while elevating the temperature to room temperature. To the reaction solution was added an aqueous saturated ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (18 g, yield 64%) as crystals.