Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]#[N:15])=[CH:12][NH:11][CH:10]=1.C=O.[C:18](O)(=O)C.[CH3:22][CH:23]1[O:28][CH:27]([CH3:29])[CH2:26][NH:25][CH2:24]1>C(O)C.O>[CH3:29][CH:27]1[O:28][CH:23]([CH3:22])[CH2:24][N:25]([CH2:18][N:11]2[CH:12]=[C:13]([C:14]#[N:15])[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])=[CH:10]2)[CH2:26]1
Reactant: CC1CNCC(C)O1
Reactant: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Solvent: CCO
Product: CC1CN(Cn2cc(C#N)c(-c3cccc(Cl)c3Cl)c2)CC(C)O1
Reaction time: 8 h

Procedure:
To a suspension of 10 g of 3-(2,3-dichlorophenyl)-4-cyanopyrrole in 35 ml of ethanol are added 5 ml of a 38% aqueous solution of formaldehyde and 0.4 ml of acetic acid. With stirring, 8.3 ml of 2,6-dimethylmorpholine (mixture of cis/trans isomers) are added dropwise, the temperature rising to 37° C. Then 14 ml of water are added dropwise and the solution is left to stand overnight at room temperature. Water is again added until the onset of turbidity. The batch is then cooled in an ice bath and the product begins to crystallise. The crystals are isolated by filtration and dried over phosphorus pentoxide, affording 8.5 g of brown crystals of the desired product as a mixture of cis/trans isomers. Melting point: 91°-97° C. The mother liquor is concentrated to a small volume and the residue is extracted with ethyl acetate and water. The organic phase is separated, washed twice with a semisaturated solution of sodium chloride, dried over sodium sulfate and concentrated. The residue is recrystallised from ether/petroleum ether, affording 0.8 g of a homogeneous diastereoisomer of the above product in the form of colourless crystals. Melting point: 102°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:13]([O:15][C:16](=[O:21])[C@H:17]([CH2:19][SH:20])N)[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16]([C@@H:17]1[CH2:19][S:20][C:5]([C:4]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=2[O:2][CH3:1])=[N:6]1)=[O:21])[CH3:14]
Reactant: COc1ccc(C#N)c(OC)c1
Reactant: CCOC(=O)[C@@H](N)CS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H]1CSC(c2ccc(OC)cc2OC)=N1

Procedure:
2,4-Dimethoxybenzonitrile, (R)-cysteine ethyl ester and about 5 equivalents of triethylamine are refluxed in ethanol for about 6–8 hours to obtain ethyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylate.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)C.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[C:25]([N:29]1[C:12]2[C:11](=[CH:16][C:15]([F:17])=[C:14]([F:18])[CH:13]=2)[C:10](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cn(C(C)(C)C)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of ethyl 3-(dimethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (64 g, 212 mmol) in a mixed solvent of Ethanol (150 mL)/Diethyl ether (300 mL) was added tert-Butylamine (44.6 mL, 425 mmol), and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure, the resulting oily residue was dissolved in N,N-Dimethylformamide (DMF) (250 mL) and potassium carbonate (88 g, 637 mmol) was added. LCMS showed completion of the reaction after being stirred at 100° C. for 2 h. Cold water was added to the mixture, and the precipitates were collected by filtration and dried to afford ethyl 1-(tert-butyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (60 g, 194 mmol, 91% yield) as pale yellow solid. LCMS: (M+H)+: 310.1
Reaction SMILES: [Cl:1][Si](C)(C)C.C([O:10][C:11](=[O:30])[C@@H:12]([NH:22]C(OC(C)(C)C)=O)[CH2:13][CH:14]([S:19][S:20][CH3:21])[CH2:15][N:16]=[N+:17]=[N-:18])(C)(C)C>FC(F)(F)CO>[ClH:1].[NH2:22][C@@H:12]([CH2:13][CH:14]([S:19][S:20][CH3:21])[CH2:15][N:16]=[N+:17]=[N-:18])[C:11]([OH:30])=[O:10]
Reactant: C[Si](C)(C)Cl
Reactant: CSSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: OCC(F)(F)F
Product: CSSC(CN=[N+]=[N-])C[C@H](N)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Chlorotrimethylsilane (297 μl, 2.344 mmol) was added to a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-methyldisulfanyl-pentanoic acid tert-butyl ester (Compound 33) (92 mg, 0.234 mmol) in 2,2,2-trifluoroethanol (0.9 ml), and the mixture was stirred at room temperature for 2 hours. Chlorotrimethylsilane (150 μl, 1.184 mmol) was further added, and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of hexane/ethyl acetate/dichloromethane (3:1:0.1) to afford (S)-2-amino-5-azido-4-methyldisulfanyl-pentanoic acid hydrochloride (Compound 34) (58 mg, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1>O.O1CCOCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:15]2[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1cc(Br)ccc1C=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Br)ccc1C=C1C(=O)OC(C)(C)OC1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 4-bromo-2-methylbenzaldehyde (1.99 g, 10.00 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2.16 g, 15.0 mmol) in water (20 mL) and 1-4-dioxane (2 mL) was heated at about 75° C. for about 2 h. Additional 2,2-dimethyl-1,3-dioxane-4,6-dione (0.72 g, 5.0 mmol) was added and heating at about 75° C. was continued for about 2 h. The reaction was cooled to rt and solids were filtered off and rinsed with water (25 mL). The resulting solid was air dried on the funnel and then triturated with Et2O (about 20 mL) and filtered. The product was dried overnight in the vacuum oven at about 50° C. to yield 5-(4-bromo-2-methylbenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.75 g, 8.46 mmol, 85%) as a pale yellow solid: LC-MS (Table 1, Method g) Rt=2.43 min, m/z 341/343 (M−H+NH3)−; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.51-7.42 (m, 2H), 2.33 (s, 3H), 1.77 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[C:8](=[CH:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc2c(c1)OCCC2=O
Product: COc1ccc2c(c1)OCC(=Cc1cccnc1)C2=O

Procedure:
By the method of Example 22, 7-methoxy-4-chromanone (10 g, 56 mmol) and 3-pyridinecarbaldehyde (7.8 g, 73 mmol) were converted to present title product, isolated directly from the reaction mixture by cooling to 0° C., 11.9 g; mp 176°-178° C.; MS 267 (M+, base peak). Anal. C. 71.94, H 4.93, N 5.05, calcd. C 71.90, H 4.90, N 5.24.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=1
Reactant: CCS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCS(=O)(=O)c1ccc(CBr)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of 1-(ethylsulfonyl)-4-methylbenzene (5 g, 25.7 mmol) in CCl4 (30 mL) was added N-bromosuccinimide (5.54 g, 30.8 mmol) and azobisisobutyronitrile (0.46 g, 2.57 mmol). The mixture was stirred at 80° C. overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was added to water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×40 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude 1-(bromomethyl)-4-(ethylsulfonyl)benzene (6.62 g, 98%) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.O>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 98.5 %

Procedure:
To a stirred suspension of 19.9 grams (0.204 mole) of N-methoxy-N-methylamine hydrochloride in 500 mL of methylene chloride was added 39.3 grams (0.388 mole) of triethylamine. Upon completion of addition, the reaction mixture was stirred for ten minutes, and a solution of 38.4 grams (0.185 mole) of 4-trifluoromethylbenzoyl chloride in 25 mL of methylene chloride was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then stirred vigorously with 300 mL of water. The aqueous layer was separated from the organic layer and washed with three portions of methylene chloride. The washes were combined with the organic layer, and the combination was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 42.5 grams of N-methoxy-N-methyl-4-trifluoromethylbenzamide as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]2[C:8]([N:15]=1)=[N:9][C:10]([CH3:14])=[CH:11][C:12]=2[CH3:13])[CH3:4].[Br:16][C:17]1[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:35]=[N:36][N:37]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:38]=2)[N:19]=[C:20]2[C:25]=1[CH:24]=[C:23]([CH2:26]Br)[CH:22]=[CH:21]2>CN(C=O)C>[Br:16][C:17]1[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:35]=[N:36][N:37]([C:39]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:38]=2)[N:19]=[C:20]2[C:25]=1[CH:24]=[C:23]([CH2:26][N:15]1[C:8]3=[N:9][C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:7]3[N:6]=[C:5]1[CH2:3][CH3:4])[CH:22]=[CH:21]2
Reactant: BrCc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution obtained by adding sodium hydride (15 mg, 0.366 mmol) to 2-ethyl-5,7-dimethyl-1H-imidazo[4,5-b]pyridine (58 mg, 0.333 mmol) in DMF (2 ml) and stirring for 30 minutes was added 5-[2-(3-bromo-5-(bromomethyl)-2H-indazol-2-yl)phenyl]-2-(triphenylmethyl)-2H-tetrazol (0.250 g, 0.370 mmol) as obtained in Reference Example 9. The mixture was stirred at room temperature for 16 hours. After concentration, it was partitioned by ethyl acetate (10 ml) and water (5 ml). The organic layer was dried over magnesium sulfate, and filtered. The filtrate was concentrated, and subjected to flash chromatography on silica gel using a mixed solvent of dichloromethane/methanol (100:1), whereby 0.134 g of 3-{[3 -bromo-2-[2-(2-(triphenylmethyl)-2H-tetrazol-5-yl)phenyl]-2H-indazol-5-yl]methyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:43][C@H:44]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[C:45]([O:47][CH3:48])=[O:46]>>[ClH:1].[CH3:48][O:47][C:45](=[O:46])[C@H:44]([NH:43][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)[CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: COC(=O)CC[C@@H](N)C(=O)OC
Product: COC(=O)CC[C@@H](NC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1)C(=O)OC
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with (R)-dimethyl 2-aminopentanedioate to give (R)-2-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoylamino)-pentanedioic acid dimethyl ester, hydrochloride. MS (ES+) m/z calcd. for C38H41Cl2F2N4O7: [(M+H)+]773. found: 773.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.C(S([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[N:26]1)(=O)=O)C.[CH3:34][S:35](C1C2C(=CN=CC=2)NN=1)(=[O:37])=[O:36]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12]3)[C:7]([CH2:9][N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([S:35]([CH3:34])(=[O:37])=[O:36])=[N:26]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: O=S1(=O)CCC(n2c(CCl)nc3cc(Cl)ccc32)C1
Reactant: CCS(=O)(=O)n1ncc2ccccc21
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCS(=O)(=O)C2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-M ethanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2

Procedure:
63.3 mg (0.23 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 70 mg (0.23 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.08 mL (0.46 mmol) DIPEA were stirred in 2 mL of DMF for 2 h at RT. The mixture was diluted with methanol. The precipitate was suction filtered, washed with methanol and diethyl ether and dried in the CAD.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](=O)[CH2:16]Br)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]2[N:9]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[O:8][CH:16]=2)=[CH:13][CH:12]=1
Reactant: NC(=O)c1sccc1Cl
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: Clc1ccc(-c2coc(-c3sccc3Cl)n2)cc1

Procedure:
The title compound was prepared from 3-chloro-thiophene-2-carboxamide (0.100 g, 1.03 mmol) and 4-chloro-phenacyl bromide (0.200 g, 0.856 mmol) by a procedure similar to Example 101 as a white solid (0.006 g, 3.2%). 1H NMR (Acetone-d6): 8.45 (s, 1H), 7.80 (d, J=6.6 Hz, 2H), 7.70 (d, J=6.0 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.08 (d, J=6.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.Cl.[CH:19]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][O:21][CH2:20]2.C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([N:26]2[CH:19]3[CH2:25][CH2:24][CH:23]2[CH2:22][O:21][CH2:20]3)[CH:7]=1
Reactant: C1CC2COCC1N2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4CCC3COC4)n2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
In a 250 mL round-bottomed flask was placed 4,6-dichloro-2-(4-nitrophenyl)pyrimidine (59, 192 mg, 0.711 mmol) in dichloromethane (8 mL) to give a colorless solution. 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (33, 106 mg, 0.711 mmol) was added and the solution was cooled to 0° C. Triethylamine (0.297 mL, 2.133 mmol) was added slowly and the mixture was allowed to slowly warm to room temperature, and stirred for 16 hours at room temperature. The mixture was heated under reflux for 2 hours, diluted with dichloromethane and washed with saturated NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated. the crude product was applied to a silica gel column and eluted with 5-40% EtOAc in hexanes to give the title compound (212 mg, 86%). The sample was identical to the same compound prepared according to Scheme 16. HRMS: For [M+H]+ mass error=0.1 mDa or 0.39 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C@H:7]2[NH:11][C:10](=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.B.[CH2:14]1COCC1>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:8][CH2:9][CH2:10][N:11]2[CH3:14])[O:4][N:3]=1
Reactant: Cc1cc([C@@H]2CCC(=O)N2)on1
Reactant: C1CCOC1
Agent: B
Product: Cc1cc([C@@H]2CCCN2C)on1

Procedure:
To a solution of crude 5(S)-(3-methyl-5-isoxazolyl)-2-pyrrolidinone (5.33 g, 32.1 mmol, the product of step 13b) in THF (50 mL) was added borane-THF (99.5 mL, 1.0M, 99.5 mmol) slowly at room temperature. The reaction mixture was heated at reflux for two hours. After removal of THF under vacuum, a solution of formaldehyde (10.0 mL) and formic acid (5.0 mL) was carefully added, and the reaction mixture was refluxed for one hour. Ethyl acetate (300 mL) was added, followed by the addition of sodium carbonate until basic. The organic layer was decanted, and the residue was washed with ethyl acetate (4×20 mL). The combined organic solvents were dried over sodium carbonate. The solvent was evaporated, and the residue was distilled (bp. ~150° C./~50 mm Hg) to give the title compound (3.12 g, 59%; 24% overall yield). The compound was further purified by HPLC chromatography (CHCl3 /MeOH, 20: 1 and 10: 1). HPLC (analytical Chiralark OD column) analysis indicated >99% ee. [α]D23 ° =-13.1° (c 0.9, MeOH). MS (DCl/NH3) m/e: 153 (M+H)+. 1H NMR (CDCl3) δ1.80-2.00 (m, 3H), 1.99 (br s, 1H, NH), 2.14-2.21 (m, 1H), 2.28 (s, 3H), 2.96-3.16 (m, 2H), 4.32 (dd, 1H), 5.95 (s, 1H).
Reaction SMILES: [Li].[C:2]1([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(C)(C)C.ClC1C=CC([Si:33]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=CC=1.[O:43]1CCCC1>>[C:15]1([P:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:9]2[CH:14]=[CH:13][C:12]([Si:33]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:11][CH:10]=2)=[O:43])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCOC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCO[Si](OCC)(OCC)c1ccc(Cl)cc1
Agent: [Li]
Solvent: CC(C)(C)Cl
Product: CCO[Si](OCC)(OCC)c1ccc(P(=O)(c2ccccc2)c2ccccc2)cc1
Yield: 15 %

Procedure:
To a suspension of lithium (2.1 g, 0.3 g atom) in 150 ml of anhydrous tetrahydrofuran held under nitrogen, a solution of triphenylphosphine (26.2 g, 0.1 ml) in 150 ml dry tetrahydrofuran is added in a period of 1/2 hour. The temperature rises from 25° C to 55° C. The solution turns blood-red and nearly all of the lithium dissolves in 3 hours. To this solution t-butyl chloride (9.3 g, 0.1 mol) is added to destroy the phenyl lithium. The solution is filtered, and to it 4-chlorophenyl triethoxysilane (27.5 g, 0.1 mol) dissolved in 50 ml of dry tetrahydrofuran is added and the solution refluxed 4 hours. The red color is not fully discharged in this time due to the sluggish nature of the nucleophilic displacement of the aryl chloride. The excess lithium diphenylphosphide is destroyed by addition of 25 ml of ethanol and finally, water. The solvents are removed in vacuum. The liquid is taken up in toluene and filtered to remove precipitated lithium chloride. Gas-liquid chromatographic analysis of this solution shows the presence of recovered chlorophenyl silane, triphenylphosphine, and only a small amount (estimated 15 percent yield) of 4-(diphenylphosphinyl)phenyl triethoxysilane.
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[C:15]([F:21])[CH:14]=1.ClC1C=CC(N2[C:37](=[O:38])[C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3N2)=CC=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:37](=[O:38])[C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[NH:20]2)=[C:15]([F:21])[CH:14]=1
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCCC2
Reactant: NNc1ccc(Cl)cc1F
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2

Procedure:
By substituting 4-chlorophenylhydrazine hydrochloride in the above procedure for 4-chloro-2-fluorophenylhydrazine hydrochloride, 2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one was prepared, m.p. 183.5°-185° (Lit 186°-187°, Chem. Abs., 67, 11452h).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([CH3:36])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH2:38].C1COCC1>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:38][CH3:37])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([CH3:36])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4C)c(F)cc3Cl)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4C)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 23 %

Procedure:
Using a procedure analogous to example A1, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.2, 0.38 mmol) and 2 M methylamine in THF (3 eq) were combined and purified via C-18 chromatography to provide 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.045 g, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.95 (brs, 2H), 8.61 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.87 (brs, 1H), 7.75 (s, 1H), 7.55 (d, J=10.8 Hz, 1H), 6.04 (s, 1H), 3.58-3.51 (m, 6H), 2.90 (s, 3H), 1.16 (s, 9H); MS (ESI) m/z: 513.3 (M+H+).