Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=N[CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41](=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:20]3[C:19](=[CH:24][C:23]([O:25][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:22][CH:41]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(C)c1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ncc(O)cc2n1-c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(OCC(=O)OC(C)(C)C)cc2n1-c1ccccc1

Procedure:
The compound of example 56 (60 mg, 111 μmol), cesium carbonate (108 mg, 332 μmol) and tert-butyl bromoacetate (17.9 μl, 23.7 μmol) were stirred in DMF at room temperature for 2 h. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EA/HEP). Yield: 67 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[F:10][C:11]1[CH:26]=[CH:25][C:14]([C:15](ON2C(=O)CCC2=O)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:10][C:11]1[CH:26]=[CH:25][C:14]([C:15](=[O:16])[CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8]#[N:9])=[CH:13][CH:12]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(F)cc1
Reactant: N#CCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C(=O)c1ccc(F)cc1)c1ccncc1
Temperature: 25 °C
Yield: 103 %

Procedure:
32 g of 4-pyridylacetonitrile and 86 g of 2,5-dioxo-pyrrolidinyl 4-fluorobenzoate were dissolved in 1.3 L of dimethylformamide. After the addition of 164 g of potassium carbonate, the resulting mixture was stirred at room temperature for a day. After the reaction mixture was filtered through cerite, the filtrate was concentrated under reduced pressure. After water was added to the residue, this solution was neutralized with an aqueous solution of hydrochloric acid. The precipitated crystals were collected by filtration, washed with diethyl ether, and then dried in a stream of air to obtain 67 g (103% yield) of the title compound.
Reaction SMILES: Br.[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[S:21][N:20]=[C:19]([NH:22]C(=O)C)[N:18]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:2]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[S:21][N:20]=[C:19]([NH2:22])[N:18]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Nc1nsc(C2CCCN2C(=O)OCc2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Nc1nsc(C2CCCN2C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
2-(3-Acetylamino-[1,2,4]thiadiazol-5-yl)-pyrrolidine-1-carboxylic acid benzyl ester hydrobromide (14.0 g, 37.8 mmol) was dissolved in ethanol (80 mL). The reaction mixture was cooled to 0° C. and a solution of K2CO3 (15.0 g, 108.7 mmol) in H2O (40 mL) was added. The solution was allowed to return to room temperature while stirring for 30 mins. The solution was concentrated down, redissolved in water (100 mL) and extracted with DCM (3×50 mL). The organic layers were combined and washed with brine (3×50 mL). The organic layer was partitioned from the aqueous layer, dried over MgSO4 and concentrated under vacuo to afford 9.4 g (94%) of 2-(3-amino-[1,2,4]thiadiazol-5-yl)-pyrrolidine-1-carboxylic acid benzyl ester as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](OC2C=CC=CC=2)=[O:20])=[CH:4][C:5]2[C:6]([CH:18]=1)=[C:7]1[C:15](=[CH:16][CH:17]=2)C2C(=CC=CC=2)[NH:8]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[OH:1][C:2]1[C:3]([C:19]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:20])=[CH:4][C:5]2[C:6]([CH:18]=1)=[C:7]1[C:15](=[CH:16][CH:17]=2)[C:3]2[C:2](=[CH:18][CH:6]=[CH:5][CH:4]=2)[NH:8]1
Reactant: Nc1ccccc1
Reactant: O=C(Oc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Product: O=C(Nc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Temperature: 25 °C

Procedure:
The aromatic ester is reacted with an aniline in a solvent and heating to form the anilide product. The reaction temperature can be varied to from about 140° C. to about 280° C. or above. Specifically, phenyl 2-hydroxy-11H-benzo(a)carbazole-3-carboxylate can be reacted with aniline in methyl N-pyrrolidinone at about 250° C. The ratio of the phenyl ester to aniline can vary, for example, from about 1:1 equivalent and up to about 20 equivalents. After the reaction is completed, the product mixture is cooled to room temperature, about 25° C., and discharged into an acidic aqueous solution, such as a 5 percent HCl ice cold solution. The precipitated anilide product, such as 2-hydroxy-11H-benzo(a)carbazole-3-carboxanilide, is isolated by filtration and washed with water and methanol. Purification can be accomplished by first dissolving the crude product in a hot solvent, such as DMF, and then precipitating the product by adding water or methanol, or a mixture of methanol and water. The purified product is then characterized by melting point, IR, mass spectrometry, NMR spectroscopy, especially 13C NMR as well as elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]2[C:16]([C:19]([OH:21])=O)=[CH:17][CH:18]=[C:7]2[CH2:6]1)=[O:4].[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[OH:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[C:19]([C:16]1[N:8]2[C:7]([CH2:6][N:5]([C:3]([O:2][CH3:1])=[O:4])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9]2)=[CH:18][CH:17]=1)=[O:21]
Reactant: COC(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: OCCNCCO
Product: COC(=O)N1Cc2ccc(C(=O)N(CCO)CCO)n2Cc2ccccc21

Procedure:
The title compound was prepared by coupling the 10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of step A with diethanolamine (1.2 equiv.), in the manner of Example 1, Step G,
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=1.B([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:10][O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[CH:3]=[N:4][CH:5]=1
Reactant: COCc1cncc(Br)c1
Reactant: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
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: O
Solvent: COCCOC
Product: COCc1cncc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
3-bromo-5-(methoxymethyl)pyridine (example 32b) (4.8 g, 23.56 mmol), 2-(4-boronophenyl)-2-methylpropanoic acid (example 21b) (5.4 g, 25.92 mmol) and K2CO3 (6.5 g, 47.12 mmol) were mixed in DME (60 mL) and 15 ml of water (15 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (0.55 g, 0.47 mmol) was added. The reaction mixture was heated to reflux for 16 hr then cooled to room temperature, and evaporated under reduced pressure. The residue was diluted with aqueous NaOH (0.5 N, 60 mL) and stirred for 30 min., and the solution extracted with ether (20 mL×3). The aqueous phase was cooled to 0° C., acidified with 2 N HCl to PH=5˜6, then extracted with EtOAc. The organic phase was washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane, filtered and evaporated to give 5.9 g of 2-(4-(5-(methoxymethyl)pyridine-3-yl)phenyl)-2-methylpropanoic acid as a light brown solid in 88% yield. 1H NMR (400 MHz, CDCl3): δ 1.66 (s, 6H), 3.44 (s, 3H), 4.54 (s, 2H), 7.54-7.56 (d, 4H), 7.92 (s, 1H), 8.56 (s, 1H), 8.76 (s, 1H). MS (M+H, 286).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([Cl:13])=[C:7]([OH:14])[CH:6]=2.[OH-:16].[Na+]>>[Cl:13][C:8]1[C:7]([OH:14])=[CH:6][C:5]2[O:4][C:2]([C:3]([OH:15])=[O:16])=[C:11]([CH3:12])[C:10]=2[CH:9]=1
Reactant: [OH-]
Reactant: Cc1c(Cl)c(=O)oc2cc(O)c(Cl)cc12
Agent: [Na+]
Product: Cc1c(C(=O)O)oc2cc(O)c(Cl)cc12
Yield: 54 %

Procedure:
3-Chloro-4-methyl-6-chloro-7-hydroxycoumarin was refluxed with NaOH (30 ml, 1N) for 1 hour. The mixture was washed with three 50 ml portions of ethyl acetate. Then acidification (HCl, 3N) of the aqueous phase followed by filtration of the solid that precipitated gave 0.5 g (54% yield) of the desired acid, m.p. 279°-280° C. In the ethyl acetate extract 0.2 g of decarboxylate product was recovered as a by product,
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17][C:18]1[S:19][C:20]([CH2:23][CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[CH:21][CH:22]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[NH3:11].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[S:19][C:20]([CH2:23][CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[CH:21][CH:22]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=Cc1ccc(CC2CCCCCN2)s1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1ccc(CC2CCCCCN2)s1)NC(=O)OCc1ccccc1
Product: N
Reaction time: 72 h
Yield: 11.8 %

Procedure:
In an atmosphere of argon, 30 ml of methanol solution containing 2.03 g of the compound of Example 39 was mixed with 500 mg of palladium black and stirred for 3 days to effect hydrogenation. Then, 1 g of activated carbon was added and the mixture was filtered. The filtrate was evaporated under reduced pressure and then the residue was subjected to silica gel column chromatography and elution was carried out with a series of mixed solutions of chloroform:methanol=40:1 and 20:1 and chloroform:methanol:concentrated aqueous ammonia=300:10:1 and 100:10:1 in that order to obtain 120 mg of methyl 2-benzyloxycarbonylamino-3-[5-(1-hexahydroazepinylmethyl)-2-thienyl]propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[N:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccccc1Sc1ncc[nH]1
Reactant: CCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1ccnc1Sc1ccccc1Cl
Product: Cl
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 0.3 g (1.42 mmoles) of the product from Example 33 in 2 ml of dry N,N-dimethylformamide was added 0.18 g (1.56 mmoles) of potassium t-butoxide with stirring and under nitrogen. After stirring for 20 minutes the reaction was cooled in an icebath and 0.33 g (1.70 mmoles) of 1-bromooctane was added. The mixture was stirred for 15 minutes and then warmed to room temperature and stirred for 18 hours. The mixture was partitioned between ether and water. The organics were combined, washed with sodium chloride solution, dried and concentrated. The crude product was converted to the hydrochloride salt by the addition of ethanolic hydrogen chloride. The solution was concentrated to dryness and the residue recrystallized from 2-propanol/ether to give the salt as colorless needles (0.25 g, 49%), mp 114°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([OH:22])=O)=[CH:16][C:10]=3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:41])[CH2:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:25]=[CH:24][CH:23]=[C:19]([C:20](=[O:22])[NH:41][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:38][CH2:39][CH2:40]5)[CH:18]=4)=[CH:16][C:10]=3[C:9]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:6][CH:7]=1
Reactant: NC1(c2ccccc2)CCC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CCC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclobutylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 1-phenylcyclobutanamine hydrochloride (0.041 g, 0.22 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.18 (s, 1H), 8.42 (d, J=4.58 Hz, 1H), 8.14-8.22 (m, 2H), 7.97 (s, 1H), 7.88 (dd, J=16.02, 7.48 Hz, 2H), 7.82 (d, J=8.54 Hz, 1H), 7.66 (dd, J=8.24, 5.80 Hz, 2H), 7.59 (t, J=7.63 Hz, 1H), 7.52 (d, J=7.63 Hz, 2H), 7.31-7.40 (m, 4H), 7.21 (t, J=7.32 Hz, 1H), 2.77 (d, J=4.58 Hz, 3H), 2.62-2.71 (m, 2H), 2.53-2.60 (m, 2H), 2.02-2.11 (m, 1H), 1.83-1.92 (m, 1H). LCMS: retention time: 3.370 mM. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 535 (MH+).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18])[CH:14]=[CH2:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH:14]=[CH2:15]
Reactant: CCCCS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCCC)n1

Procedure:
A mixture of 5.7 g. 3-butylsulphonyl-1,2,4-triazole, 5.3 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to give 1-diallylcarbamoyl-3-butylsulphonyl-1,2,4-triazole as an oil which was heated under reduced pressure (100° C./0.5 mm.) for 30 minutes to remove all traces of volatile material. Refractive index of product nD26 1.5132. Elemental analysis satisfactory.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:27])[CH:23]([CH3:26])[CH2:24][CH3:25])[CH2:18][CH2:17]1>C(Cl)Cl>[CH3:26][CH:23]([CH2:24][CH3:25])[C:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)=[O:12])[CH2:21][CH2:20]1)=[O:27]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCC(C)C(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: CCC(C)C(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 12 h
Yield: 895.9 %

Procedure:
4-(Trifluoromethoxy)phenylisocyanate (100 mg, 0.49 mmol) and 1-(4-aminopiperidin-1-yl)-2-methylbutan-1-one (90 mg, 0.49 mmol) was dissolved in CH2Cl2 (100 mL) and stirred for 12 h. The reaction was quenched by addition of water. The organic layer was isolated and the aqueous layer was extracted with EtOAc for 4 times. The combined organic layer was concentrated under vacuo and was further purified by flash chromatography (EtOAc:Hex/1:1) yielding final product (168 mg, 4.39 mmol, 89%). H-NMR (DMSO-d6) ∂ 0.80 (m, 3H), 0.97 (m, 3H), 1.28 (m, 3H), 1.53 (m, 1H), 1.85 (tbr, 2H), 2.71 (m, 1H), 2.78 (m, 1H), 3.16 (t, J=12 Hz, 1H), 3.71 (m, 1H), 3.88 (d, J=12 Hz, 1H), 4.21 (br, 1H), 6.26 (tbr, 1H), 7.22 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 8.55 (d, J=9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[C:13]1([C@H:19]([CH2:21][OH:22])[NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(O)=O.[BH4-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH:20][C@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:21][OH:22])[CH2:3]1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C[C@H](N[C@@H](CO)c2ccccc2)c2ccccc21
Temperature: 0 °C
Yield: 91.8 %

Procedure:
To a solution of 3,3-dimethylindan-1-one (925 mg, 5.77 mmol) and (R)-(−)-2-phenylglycinol (893 mg, 6.51 mmol) in toluene (10.0 mL) was added p-toluenesulfonic acid monohydrate (62.5 mg, 0.328 mmol). The reaction was heated to reflux under an atmosphere of nitrogen for 90 min. At this point, the mixture was cooled and diluted with toluene (10.0 mL). The mixture was washed with saturated aqueous NaHCO3 solution and H2O. The organic layer was concentrated in vacuo and the residue was dissolved in THF (10.0 mL) and cooled to 0° C. AcOH (1.13 mL, 19.9 mmol) was added, followed by sodium borohydride (251 mg, 6.64 mmol) and the reaction was allowed to warm to 23° C. overnight. The mixture was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was concentrated and silica gel chromatography eluting with a gradient of 5 to 35% EtOAc in DCM afforded the title compound (1.49 g, 74%). LC/MS: Rt=1.92 min, ES+ 282 (AA standard).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]2[CH:11]=[C:10]([N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]=[C:13]3[CH:21]([F:23])[F:22])[N:9]=[C:8]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:7]=2)[CH2:2]1.[CH3:30][O:31][CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[F:23][CH:21]([F:22])[C:13]1[N:12]([C:10]2[N:9]=[C:8]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:7]=[C:6]([NH:5][CH:3]3[CH2:2][N:1]([C:38]([C@H:35]4[CH2:36][CH2:37][C@@H:32]([O:31][CH3:30])[CH2:33][CH2:34]4)=[O:39])[CH2:4]3)[CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=1.[F:23][CH:21]([F:22])[C:13]1[N:12]([C:10]2[N:9]=[C:8]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:7]=[C:6]([NH:5][CH:3]3[CH2:2][N:1]([C:38]([C@H:35]4[CH2:34][CH2:33][C@H:32]([O:31][CH3:30])[CH2:37][CH2:36]4)=[O:40])[CH2:4]3)[CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: COC1CCC(C(=O)O)CC1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(NC2CNC2)nc(N2CCOCC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CO[C@H]1CC[C@@H](C(=O)N2CC(Nc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)C2)CC1
Product: CO[C@H]1CC[C@H](C(=O)N2CC(Nc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Azetidin-3-yl)-6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-amine (100 mg) was dissolved in N,N-dimethylformamide (1 ml), and 4-methoxycyclohexanecarboxylic acid (43 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (142 mg), and N,N-diisopropyl ethylamine (213 μL) were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was added water (100 ml), followed by extraction with ethyl acetate (100 ml). The extracts were washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was separated/purified by silica gel column chromatography (from hexane:ethyl acetate=50:50-0:100 to chloroform:methanol=100:0-80:20) to obtain [3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl](cis-4-methoxycyclohexyl)methanone (26 mg) (Example 249-1) and [3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl](trans-4-methoxycyclohexyl)methanone (7.1 mg) (Example 249-2).
Reaction SMILES: [H-].[Na+].CN([C:6]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[C:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[CH:8]=O)C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].P([O-])(O)(O)=O.[Na+]>CN(C)C=O.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[NH:30][C:28](=[O:29])[C:27]([C:25]#[N:26])=[CH:8][C:7]=2[C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: CSc1ccc(C(C=O)=C(c2ccc(F)cc2)N(C)C)cc1
Reactant: N#CCC(N)=O
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To 1.45 g of 60% dispersion of sodium hydride in mineral oil (containing 869 mg, 36.2 mMol), washed once with hexane, in 20 ml of dry dimethylformamide, was added dropwise a solution of 9.42 g (29.9 mMol) of 1-(N,N-dimethylamino)-1-(4-fluorophenyl)-2-(4-methylthiophenyl)prop-1-en-3-one from Step 4, cyanoacetamide (2.59 g, 30.3 mMol), and 2.9 ml of methanol in 50 ml of dimethylformamide. After the addition was complete, the resulting dark solution was stirred overnight at 70-80° C. After cooling, the mixture was added in portions to 500 ml of 1M aqueous sodium dihydrogen phosphate, producing a yellow solid. The solid was filtered, washed with water, and dried to give 9.24 g of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile.
Reaction SMILES: [C:1]([OH:6])(=S)[CH:2]([CH3:4])O.O[S:8](O)(=O)=O.[CH:12]([OH:15])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:1](=[O:6])[CH:2]([SH:8])[CH3:4])([CH3:14])[CH3:13]
Reactant: CC(O)C(O)=S
Reactant: CC(C)O
Reactant: O=S(=O)(O)O
Product: CC(C)OC(=O)C(C)S

Procedure:
To a suitable reaction vessel equipped with a thermometer, agitator and venting means are charged approximately 500 parts by weight of isopropyl alcohol and approximately 53 parts by weight of thiolactic acid (about 1/2 mole). To the so-charged mass is added about 1 part by weight of concentrated H2SO4. The contents of the so-charged vessel are heated with agitation under a nitrogen atmosphere to reflux temperature and maintained at that temperature for about 4 hours. The contents are cooled to about room temperature. Excess alcohol is stripped off by distillation under vacuum. The liquid product may be vacuum distilled if a high purity product is desired. Isopropyl-alpha-mercapto-propionate is obtained.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[H][H].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14](F)[CH:13]=1>CS(C)=O>[Br:11][C:12]1[CH:19]=[CH:18][C:15]2[CH:16]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[S:3][C:14]=2[CH:13]=1
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(Br)cc2s1
Temperature: 0 °C

Procedure:
Under an argon atmosphere, 1.93 g (48.3 mmol) of sodium hydride (60% in liquid paraffin) are introduced into 60 ml of absolute DMSO. At room temperature, 3.76 g (35.5 mmol) of methyl mercaptoacetate are slowly added dropwise to the reaction mixture, which is stirred at room temperature until hydrogen evolution ceases (about 15 min). A solution of 6.54 g (32.2 mmol) of 4-bromo-2-fluorobenzaldehyde and 15 ml of absolute DMSO are added at room temperature to the reaction mixture. The latter is stirred until the reaction is complete and then poured into ice-water. The resulting precipitate is filtered off with suction and dried in vacuo at 40° C. overnight. 4.06 g (46.4% of theory) of the title compound are obtained.