Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C(=O)C(N[C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])(C)C(=O)NC1=O)C.[NH2:26][C:27]1([CH2:42][CH3:43])[C:32](=[O:33])[N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30](=[O:40])[NH:29][C:28]1=[O:41]>>[CH2:42]([C:27]1([NH:26][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])[C:32](=[O:33])[N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30](=[O:40])[NH:29][C:28]1=[O:41])[CH3:43]
Reactant: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Reactant: CCC1(N)C(=O)NC(=O)N(c2ccccc2)C1=O
Product: CCC1(NC(=O)c2cc(F)c(F)c(F)c2F)C(=O)NC(=O)N(c2ccccc2)C1=O

Procedure:
Compound 20k was prepared by the same method described for 20f using 5-amino-5-ethyl-1-phenylbarbituric acid (0.50 g, 2 mmol). The crude 5-ethyl-1-phenyl-5-(tetrafluorobenz-amido)barbituric acid (20k) was obtained as yellow crystals that were pure.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(C(F)(F)F)cc1
Reactant: CSc1ccccc1B(O)O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Yield: 88 %

Procedure:
A solution of 4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.12 mmol) in dioxane/H2O (3:1, 4.8 mL) was mixed with 2-methylthiophenyl boronic acid (30.4 mg, 0.18 mmol) and K2CO3 (50.1 mg, 0.36 mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (2.8 mg, 0.0024 mmol). The reaction tube was sealed and heated with “Smith Creator” (microwave, 150° C.) for 15 minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (88%): MS (ES) m/z 503 (M+H)+; 1H-NMR(CDCl3) δ 2.48 (s, 3H), 2.65 (s, br, 2H), 3.70 (m, br, 5H), 6.20 (m, br, 1H), 6.45 (m, 1H), 7.43 (m, 6H), 7.68 (m, 1H), 7.83 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2].[OH-].[K+].[CH:19](I)([CH3:21])[CH3:20].O>CC(C)=O>[CH:19]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)n1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
6-Nitro-1,2,3,4-tetrahydrocarbazole (5.04 g) prepared by the method described in Journal of Chemical Society, p.833 (1924) was dissolved in 50 mL of acetone, and the solution was added with 2.25 g of potassium hydroxide and 8.45 g of isopropyl iodide, warmed to 50° C. and stirred for 3 hours. The reaction mixture was added with water and the deposited precipitates were collected to obtain 2.60 g of N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole. The resulting N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole (2.60 g) was dissolved in 100 mL of acetic acid, and the solution was added with 2.75 g of iron powder, warmed to 50° C., and stirred for 3 hours. The reaction mixture was filtered and the filtrate was diluted by adding water. The reaction mixture was made basic with 1 N sodium hydroxide and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane/ethyl acetate=7/3) to obtain 1.35 g of N-isopropyl-6-amino-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:35]=[CH:34][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][C:27]2[CH:34]=[CH:35][C:24]([C:23]([F:22])([F:36])[F:37])=[CH:25][CH:26]=2)[CH2:30]1)=[O:15]
Reactant: FC(F)(F)c1ccc(CC2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(Cc2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)benzyl]pyrrolidine oxalate (19.2 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (9.2 mg). Calcd for C22H18ClF3N2O2: 434.1009, found 434.1003.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH3:30][O:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:32][O:31][CH3:30])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CON
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: CONC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and O-methylhydroxylamine gave 189. MS: (ESI+) 443.1
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.[C-:22]#[N:23].[Na+]>CS(C)=O>[C:10]1([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][CH2:6][C:22]#[N:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCCC(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCC(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of 4,4-diphenylbutyl methanesulfonate (7.5 g) and sodium cyanide (2.5 g) in dimethyl sulfoxide (70 mL) was stirred at 60° C. for 15 hours. After the reaction mixture was allowed to cool, it was extracted with diethyl ether. The extract was dried over MgSO4 and concentrated, whereby 5.8 g of the title compound was obtained quantitatively.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
Trimethylaluminium (2M in toluene) (4.97 mL, 9.94 mmol) was added carefully to 5-methylpyridin-2-amine (1.075 g, 9.94 mmol) in toluene (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (2 g, 4.97 mmol) in toluene (4 mL) was added. The reaction was heated to 120° C. for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was concentrated. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product (1.800 g, 76%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 2.29 (3H, s), 3.65 (2H, t), 3.76-3.90 (5H, m), 4.31-4.37 (1H, m), 7.34-7.45 (6H, m), 7.48-7.54 (1H, m), 7.64-7.71 (4H, m), 8.07-8.13 (2H, m), 9.13 (1H, s); m/z (ES+) (M+H)+=479.60; HPLC tR=3.16 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:27]1([NH:30][C:31]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:31](=[O:32])[C:33]2[CH:40]=[CH:39][C:36]([C:37]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:35][CH:34]=2)[CH2:28][CH2:29]1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(C(=O)NC4CC4)cc3)nc2c1)c1ccc(N2CCCC2)cc1

Procedure:
Compound 228 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C28H27N5O2: 466.23; found: 466.55.
Reaction SMILES: [OH:1][N:2]=[C:3]([C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([O:15][CH3:16])[O:6]1)[NH2:4].[C:17](O)(=O)[CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC>COCCOCCOC>[CH3:16][O:15][C@H:7]1[C@@H:8]2[O:9][C:10]([CH3:13])([CH3:14])[O:11][C@@H:12]2[C@@H:5]([C:3]2[N:4]=[C:17]([CH2:18][CH3:19])[O:1][N:2]=2)[O:6]1
Reactant: CCC(=O)O
Reactant: CO[C@@H]1O[C@H](C(N)=NO)[C@H]2OC(C)(C)O[C@@H]12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COCCOCCOC
Product: CCc1nc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)no1
Temperature: 60 °C
Yield: 67.9 %

Procedure:
A solution of (3aR,4R,6R,6aR)-N′-hydroxy-6-methoxy-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxole-4-carboximidamide (Preparation 35) (1.1 g, 4.74 mmol), propionic acid (0.39 g, 5.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 g, 5.74 mmol) in diethylene glycol dimethyl ether (10 ml) was heated under reflux at 60° C. for twelve hours and then heated at 110° C. for a further 3 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water (50 ml) and a mixture of ether (25 ml) and pentane (25 ml). The organic phase was separated and the aqueous layer was extracted with more ether/pentane mixture (50 ml). The combined organic extracts were dried (anhydrous magnesium sulphate) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of diethyl ether:pentane (1:2 by volume) gradually changing to diethyl ether:pentane (1:1 by volume) to give the title compound (0.87 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[NH3:10]>CO>[CH3:9][S:8][C:4]1[N:3]=[C:2]([NH2:10])[CH:7]=[CH:6][N:5]=1
Reactant: N
Reactant: CSc1nccc(Cl)n1
Solvent: CO
Product: CSc1nccc(N)n1
Reaction time: 48 h

Procedure:
A mixture of 4-chloro-2-methylsulfanylpyrimidine (8 g) and 7N ammonia in methanol (100 mL) at 100° C. was stirred for 2 days in a sealed tube, cooled, concentrated, treated with water, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was triturated with ethyl ether and filtered. 1H NMR (300 MHz, CDCl3) δ 8.06 (d, 1H), 6.12 (d, 1H), 4.83 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29](O)=[O:30])[C:22]3=[O:32])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([NH:37][CH3:36])=[O:30])[C:22]3=[O:32])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)O)C3=O)CC2)c2ccc(Cl)cc2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described as example 208, (3S)-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid, methyl amine, HATU, and diisopropylethylamine are reacted to afford the product. LC-MS 488 (M++1). 1H NMR (CD3OD) δ 7.86 (d, 1H), 7.50 (s, 1H), 7.30 (d, 1H), 6.30 (s, 1H), 4.65 (m, 1H), 4.00 (m, 2H), 3.70 (m, 5H), 3.30 (m, 5H), 2.75 (s, 3H), 1.98 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)=[CH:11][C:12]2[CH:17]=[N:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:14][C:13]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([NH:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)=[CH:11][C:12]2[CH:17]=[N:16][C:15]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[C:39](=[O:42])[CH:40]=[CH2:41])=[N:14][C:13]=2[N:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3cc(OC)cc(OC)c3)c(NC(=O)NC(C)(C)C)nc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N(CCCCN(CC)CC)c1ncc2cc(-c3cc(OC)cc(OC)c3)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material 1-(tert-butyl)-3-(2-((4-(diethylamino)butyl)amino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (PD173074) can be purchased from, e.g., SelleckChem.com. In a dried vessel, acryloyl chloride (2 equiv.) and diisopropylethylamine (4.3 equiv.) are added to a solution of 1-(tert-butyl)-3-(2-((4-(diethylamino)butyl)amino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (1 equiv.) in anhydrous dichloromethane at 0° C. After stirring at room temperature for 2 hours, the reaction mixture is concentrated, diluted with DMSO and purified by reverse phase HPLC (5-95% water/acetonitrile). After concentrating the fractions, the product N-(7-(3-(tert-butyl)ureido)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-yl)-N-(4-(diethylamino)butyl)acrylamide is obtained as a pale yellow foam. LCMS (M+1)=578.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-fluorobenzoic acid (1.0 g, 0.0046 mol), thionyl chloride (0.65 mL, 0.0089 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL, 0.2 mol) and aluminum trichloride (0.576 g, 0.00432 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=7.45-7.55 (m, 3H), 7.58 (dd, J=8.84, 1.77 Hz, 1H), 7.60-7.66 (m, 1H), 7.70 (dd, J=8.21, 6.69 Hz, 1H), 7.75-7.82 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23]>>[OH:24][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCCO
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCCCc1cccc(C#CCCCO)c1

Procedure:
Sonogashira reaction of bromide 57 with 4-pentyn-1-ol gave tert-butyl 3-(3-(5-hydroxypent-1-ynyl)phenyl)propylcarbamate as yellow oil. Yield (0.653 g, 59%): 1H NMR (400 MHz, CDCl3) δ 7.17-7.23 (m, 3H), 7.08 (d, J=7.2 Hz, 1H), 4.53 (bs, 1H), 3.83 (t, J=6.0 Hz, 2H), 3.10-3.18 (m, 2H), 2.60 (t, J=7.8 Hz, 2H), 2.54 (t, J=7.0 Hz, 2H), 1.83-1.90 (m, 2H), 1.74-1.82 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1>>[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][S:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)Cc1cccc(Br)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3cccc(Br)c3)cc2)c2ccc3ccccc3c2N1
Yield: 92 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and (3-bromophenyl)methanesulfonyl chloride, the title compound (yield 92%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][O:7][C@H:6]([CH2:9][OH:10])[CH2:5][O:4]1)=[CH2:2].[H-].[Na+].I[CH3:14]>C1COCC1.O>[CH3:14][O:10][CH2:9][C@@H:6]1[CH2:5][O:4][C@@H:3]([CH:1]=[CH2:2])[CH2:8][O:7]1
Reactant: C=C[C@H]1CO[C@H](CO)CO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@H]1CO[C@H](COC)CO1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 36.5 %

Procedure:
To a solution of ((2R,5S)-5-vinyl-1,4-dioxan-2-yl)methanol (Preparation #17, 0.25 g, 1.734 mmol) in THF (3 mL) was added NaH (41.6 mg, 1.734 mmol) at 0° C. The reaction mixture was slowly warmed to RT and stirred for 25 min. The reaction mixture was cooled to about 0° C. and iodomethane (0.108 mL, 1.734 mmol) was added. Upon completion of addition, the reaction mixture was slowly warmed to RT and stirred for about 2.5 h. The reaction mixture was diluted with water (20 mL) and the product extracted with EtOAc (2×10 mL). The organic layer dried over sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by column chromatography eluting with 10% EtOAc in hexane to afford (2R,5S)-2-(methoxymethyl)-5-vinyl-1,4-dioxane 0.1 g (36.5%), 1H NMR (400 MHz, CDCl3): δ 5.75-5.67 (m, 1H), 5.36-5.32 (m, 1H), 5.23-5.20 (m, 1H), 4.05-4.00 (m, 1H), 3.87-3.70 (m, 3H), 3.55-3.49 (m, 1H), 3.42-3.35 (m, 6H), ES-MS: m/z 158 (m+H).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCCCCl)cc1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of methyl 4-sulfanylbenzoate (2.00 g, 11.9 mmol) in N,N-dimethylformamide (13 mL) was added potassium carbonate (6.57 g, 47.6 mmol) and 1-bromo-3-chloro-propane (2.35 mL, 23.8 mmol). The mixture was heated at 60° C. for 16 h. The reaction mixture was filtered and the solvent removed in vacuo. The material was dissolved in dichloromethane (10 mL) and washed with water (3×10 mL) and a saturated aqueous NH4Cl (10 mL). The organic layer was dried over Na2SO4, filtered and the solvent removed in vacuo. Silica gel chromatography (0-100% dichloromethane/hexane) provided methyl 4-(3-chloropropylsulfanyl)benzoate (1.87 g, 64%) as a colorless viscous liquid. ESI-MS m/z calc. 244.0. found 245.1 (M+1)+; Retention time: 1.83 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 3.84 (s, 3H), 3.79-3.61 (m, 2H), 3.18 (t, J=7.2 Hz, 2H), 2.20-1.97 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17]CC)=[O:16].CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C=CC=Cc1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=CC=CC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To 9.44 g (36.0 mmol) of said ethyl 5-(2,4-dimethoxyphenyl)-2,4-pentadienoate was added 80 ml of methanol to give a solution. To thesolution was then added a solution of 14.40 g (360 mmol) of sodium hydroxide dissolved in 20 ml of water, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure followed by addition of water and a hydrochloric acid solution to adjust the pH to 1 and extraction with chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 7.70 g (32.9 mmol) of 5-(2,4-dimethoxyphenyl)-2,4-pentadienoic acid.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:38])([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1.COC(C)(C)C>C1(C)C=CC=CC=1>[F:31][C:30]([F:32])([F:33])[C:29]([C:26]1[CH:25]=[CH:24][C:23]([N:13]2[CH2:12][CH2:11][CH:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH2:15][CH2:14]2)=[CH:28][CH:27]=1)([OH:38])[C:34]([F:35])([F:37])[F:36]
Reactant: O=S(=O)(c1ccccc1)C1CCNCC1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)C1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A 15-mL reaction vial was charged with 4-(phenylsulfonyl)piperidine (1.05 g, 4.66 mmol, BetaPharma, Brandford, Conn.), sodium t-butoxide (0.98 g, 10.24 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.50 g, 4.66 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos Palladacycle) (0.170 g, 0.233 mmol, Strem Chemicals, Inc, Newburyport, Mass.), and toluene (10 mL). The vial was closed and purged with nitrogen for several minutes. The reaction mixture was heated at 100° C. for 2.5 h and allowed to cool to room temperature. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (5 mL) and dried over Na2SO4. The solution was filtered and concentrated and then absorbed onto a plug of silica gel and purified by column chromatography (40 g of silica gel, 10 to 30% EtOAc in hexanes) to provide 1,1,1,3,3,3-hexafluoro-2-(4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-2-propanol (1.94 g) as white solid