Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]1[C:33](=O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[O-]CC.[Na+]>C(O)C>[CH2:34]([C:33]1[C:21]2[CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25][C:20]=2[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)Cc2ccccc2)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Yield: 91.8 %

Procedure:
1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (300 mg, 1.22 mmol, example 43a), tert-butyl 4-oxo-3-(2-phenylacetyl)piperidine-1-carboxylate (466 mg, 1.47 mmol, example 41d) and sodium ethoxide (83 mg, 1.22 mmol) in ethanol (4 mL) were heated at 100° C. in a microwave reactor for 20 minutes. The reaction mixture was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude was dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO4 and the solvent was evaporated under reduced pressure yielding tert-butyl 4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (590 mg, 92%) which was used in the subsequent step as such. MS (ES+) m/z 527.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2C(N[C:20](=[O:21])[C:15]=12)=O)(OCC)=[O:10]>CN(C=O)C.CCOC(C)=O>[CH3:8][C:7]1[C:2]([N:1]2[C:9](=[O:10])[C:14]3=[CH:24][CH:23]=[CH:22][CH:16]=[C:15]3[C:20]2=[O:21])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: Cc1cccnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccnc1N1C(=O)c2ccccc2C1=O
Temperature: 23 °C
Reaction time: 15 h

Procedure:
2-Amino-3-picoline (1.00 mL, 8.62 mmol) was dissolved in DMF (30 mL) at 23° C., and treated with solid carboethoxy-phthalimide (1.89 g, 8.64 mmol), followed by TEA (1.44 mL, 10.3 mmol). The resulting solution was stirred at 23° C. for 15 h. After 15 h, the mixture was diluted with EtOAc (50 mL), and washed with saturated NaCl (1×50 mL), H2O (1×50 mL), dried (MgSO4), and concentrated in vacuo to a yellow solid. Purification over silica gel (0 to 50% EtOAc/Hexanes) provided the title compound as a white solid.
Reaction SMILES: C(C1[CH:15]=[CH:14][CH:13]=[C:12]2[C:4]=1[CH2:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=12)#N.[OH-:16].[K+].[CH2:18]([OH:21])[CH2:19]O>O>[S:9]1[CH:10]=[CH:11][C:7]2[CH2:6][CH2:5][C:4]3[C:19]([C:18]([OH:21])=[O:16])=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]1=2
Reactant: [OH-]
Reactant: N#Cc1cccc2c1CCc1ccsc1-2
Reactant: OCCO
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccc2c1CCc1ccsc1-2

Procedure:
To a stirred solution of 6-cyano-4,5-dihydronaphtho[1,2-b]-thiophene (4.1 g, 0.019 mole) in 75 ml of ethylene glycol, under a nitrogen atmosphere, was added potassium hydroxide [12.5 g, 0.19 mole). The reaction mixture was heated at 156°±5° for 18 hours. The cooled reaction mixture was diluted with 200 ml of cold water. The mixture was extracted with two 50 ml portions of diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid. The mixture was cooled and extracted with three 200 ml portions of diethyl ether. The extracts were combined, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 4.4 grams of 4,5-dihydronaphtho[1,2-b]thiophen-6-carboxylic acid; mp 182°-184°.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N([CH2:25][CH3:26])CC)C.[OH:27][P:28]([O:30][P:31]([OH:33])[OH:32])[OH:29].Cl[C:35](Cl)([C:37]([CH2:42][OH:43])([CH2:40][OH:41])[CH2:38][OH:39])[OH:36]>C1(C)C=CC=CC=1>[OH:27][P:28]([O:30][P:31]([OH:33])[OH:32])[OH:29].[CH2:1]([C:35]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:25][CH3:26])([C:37]([CH2:42][OH:43])([CH2:40][OH:41])[CH2:38][OH:39])[OH:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: OCC(CO)(CO)C(O)(Cl)Cl
Reactant: CCN(CC)CC
Agent: OP(O)OP(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCC(O)(CCCCCCCCCCCCCCCCCC)C(CO)(CO)CO
Reaction time: 1 h

Procedure:
To a stirred solution of 567 g. (2.1 mols) of octadecyl alcohol and 212 g. (2.1 mols) of triethyl amine in 1800 ml. of toluene, at 30° C., there is added a solution of 265 g. (1.0 mol) of dichloropentaerythritol diphosphite in 600 ml. of toluene; the addition is made portionwise over a period of one hour, then the mixture is warmed with continued stirring at 45°-50° C. The cooled mixture is filtered to separate the triethylamine hydrochloride and the filtrate is stripped of toluene to a final temperature of 85° C./20 mm. The solid residue consitutes a quantitative yield of distearyl pentaerythritol diphosphite, M.P., 68°-70° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:15]>CN(C=O)C>[Cl:15][C:7]1[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=c1cc[nH]c2c(I)cccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccnc2c(I)cccc12
Yield: 97.8 %

Procedure:
8-Iodo-1H-quinolin-4-one (3.36 g, 8.72 mmol) was suspended in POCl3 (8 mL, 87.2 mmol) and catalytic anhydrous DMF (6.72 μL) was added. The mixture was refluxed for 1 h. The hot crude was poured over ice and the mixture stirred until ice was completely melted. Solid was filtered off, thoroughly washed with water and kept in the vacuum oven overnight to afford 4-chloro-8-iodo-quinoline as a grayish solid (2.47 g, 98%). 1H NMR (DMSO-d6, 400MHz) δ 7.45 (t, 1H), 7.81 (d, 1H), 8.19 (dd, 1H), 8.45 (dd, 1H), 8.87 (d, 1H). Exact mass calculated for C9H5ClIN 288.92, found 289.9 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH:9]1[C:18](=[O:35])[NH:19][CH:20]([CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1)[CH:21]([CH3:23])[CH3:22])=O)(C)(C)C.[C-:36]#[N:37].[Na+]>>[CH3:22][CH:21]([CH3:23])[CH:20]([NH:19][C:18]([CH:9]1[CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:36]#[N:37])[CH2:12][CH2:13][NH:8]1)=[O:35])[CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1
Reactant: [C-]#N
Reactant: CSC1OC(C(NC(=O)C2CC(CCCO)CCN2C(=O)OC(C)(C)C)C(C)C)C(O)C(O)C1O
Agent: [Na+]
Product: CSC1OC(C(NC(=O)C2CC(CCCC#N)CCN2)C(C)C)C(O)C(O)C1O

Procedure:
The title compound of example 23 was prepared from protected tosylate intermediate prepared in example 19, 11h according to the procedure used in examples 19-21 using sodium cyanide nucleophile in the displacement step; MS (ESPOS): 430.3 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Cl.[N:4]1[CH:9]=[CH:8][C:7](C#N)=[N:6][CH:5]=1.S(=O)(=O)(O)O.[C:17](=[O:20])([O-])[O-].[Na+].[Na+]>CCOCC.O1CCCC1>[N:4]1[CH:9]=[CH:8][C:7]([C:17]([CH3:1])=[O:20])=[N:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccncn1
Reactant: C[Mg]Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccncn1

Procedure:
To a solution of 22.2 g. of methyl magnesium chloride in ether is added 10.5 g. of 4-pyrimidinecarbonitrile in tetrahydrofuran. The resulting mixture is heated at reflux for 24 hours, then poured onto ice. To the mixture is added 75 ml. of 25% sulfuric acid. The solution is then made basic with 10% aqueous sodium carbonate solution and extracted with ether. The extracts are dried and concentrated to give methyl 4-pyrimidyl ketone.
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].[NH2:12][C:13]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16]([CH2:22][CH2:23][CH3:24])=[N:15][C:14]=1C#N>C(Cl)(Cl)Cl>[I:11][C:10]1[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:16]([CH2:22][CH2:23][CH3:24])=[N:15][C:14]=1[C:13]#[N:12]
Reactant: CCCc1nc(C#N)c(N)n1CC(C)C
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C#N)c(I)n1CC(C)C
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of isoamylnitrite (6.1 mL, 45 mmol) and diiodomethane (20 mL) was heated at 85° C. under a nitrogen atmosphere. A solution of 5-amino-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile (2.50 g, 12.1 mmol) in chloroform (60 mL) was added over a period of 30 minutes. The temperature reached 70° C. during the addition. The reaction was heated for an additional 15 minutes, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified by suction filter chromatography on silica gel (eluting with a gradient of 10% to 25% ethyl acetate in hexane) to provide 2.88 g (75%) of 5-iodo-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile as an orange oil that crystallized upon standing.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]12[CH:17]([CH2:18][OH:19])[CH:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12]2.C(N(CC)CC)C>ClCCl>[CH:14]12[CH:17]([CH:18]=[O:19])[CH:11]([CH2:16][CH2:15]1)[CH2:12][CH2:13]2
Reactant: OCC1C2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC1C2CCC1CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
In a flask under argon was placed dichloromethane (10 mL) and a 2M solution of oxalyl chloride in dichloromethane (1.43 mL, 2.85 mmol) cooled to −78° C. To this mixture was slowly added dimethyl sulfoxide (303 μL, 4.26 mmol) and gas evolution occurred. The mixture was stirred at −78° C. for 30 min. After this time, a solution of bicyclo[2.2.1]hept-7-yl-methanol (180 mg, 1.43 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was stirred at −78° C. for another 15 min and triethylamine (784 μL, 5.58 mmol) was added and the reaction was slowly warmed to 0° C. and stirred for 1 h. After this time, the mixture was quenched with a 1M aqueous sodium bisulfate solution (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography system (4 g column, 10% ethyl acetate/hexanes) afforded bicyclo[2.2.1]heptane-7-carbaldehyde (170 mg, 96%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.[NH2:19][C:20]1[CH2:40][O:39][CH2:38][C@@:22]2([C:35]3[CH:34]=[C:33](Br)[CH:32]=[CH:31][C:30]=3[O:29][C:28]3[C:23]2=[CH:24][C:25]([OH:37])=[CH:26][CH:27]=3)[N:21]=1.O>O1CCOCC1>[NH2:19][C:20]1[CH2:40][O:39][CH2:38][C@@:22]2([C:35]3[CH:34]=[C:33]([C:15]4[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=4)[CH:32]=[CH:31][C:30]=3[O:29][C:28]3[C:23]2=[CH:24][C:25]([OH:37])=[CH:26][CH:27]=3)[N:21]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@]2(COC1)c1cc(O)ccc1Oc1ccc(Br)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@]2(COC1)c1cc(O)ccc1Oc1ccc(-c3cccnc3F)cc12
Temperature: 100 °C

Procedure:
In a microwave vial, potassium phosphate (0.615 g, 2.90 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (0.068 g, 0.097 mmol), 2-fluoropyridin-3-ylboronic acid (0.170 g, 1.208 mmol) and (R)-5-amino-2′-bromo-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (0.349 g, 0.966 mmol) were suspended in dioxane (8 mL). Water (2 mL) was added, and argon gas was blown through the vessel, which was then sealed and heated in a 100° C. oil bath for 3 h. The reaction was concentrated to remove the dioxane. The residue was diluted with aqueous NH4Cl (15 mL) and the aqueous phase was extracted with 5% MeOH/DCM (3×33 mL). The organics were combined, washed with dilute brine (8 mL), dried over sodium sulfate and concentrated to afford crude (S)-5-amino-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol which was used directly in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:40]>ClC(Cl)C.ClCCl.C(OCC)C>[ClH:40].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)[CH2:12][CH2:13]1.[ClH:40]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(NC2CCNCC2)c1

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 2.51 mmol), 3-trifluoromethyl-phenylamine (404 mg; 2.51 mmol) and sodium triacetoxyborohydride (1.59 g; 7.53 mmol) are suspended in dichloroethane (25 mL). After 1 day reaction time at room temperature, the mixture is diluted with dichloromethane (100 mL) and the organic layer is washed with aq. sat ammonium chloride (2×50 mL) and water (3×50 mL), is then dried over magnesium sulfate and is concentrated under reduced pressure. The residue obtained is triturated with cold diethylether (10 mL) until precipitation is observed. The precipitate is filtered and dried under vacuum. The crude product is dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) is added dropwise under vigorous stirring. After 30 minutes reaction time, the mixture is concentrated under reduced pressure and co-evaporated with dichloromethane (2×10 mL). The residue obtained is then dissolved in diethylether (5 mL) and a molar solution of hydrochloric acid in diethylether (5 mL) is added. The precipitate formed is filtered and dried under high vacuum to afford the desired product as hydrochloride (289 mg; 1.03 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7](/[N:8]=N/C2C=CC(C)=CC=2)=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.[H][H]>CC(O)C.[Pt]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: CCCSc1nc(Cl)c(/N=N/c2ccc(C)cc2)c(Cl)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(C)O
Product: CCCSc1nc(Cl)c(N)c(Cl)n1
Temperature: 20 °C

Procedure:
A stirred solution of 4,6-dichloro-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine (Step (3), 1.1 kg) in 2-propanol (16.6 kg) was hydrogenated for 1 h at 40° C./3.2 bar over a platinum on carbon catalyst (0.81 kg, 50% w/w Pt/C). The hydrogen gas pressure was released and the reactor flushed with nitrogen. The reaction mixture was filtered. The collected solid was washed with 2-propanol (1.7 kg) and the combined filtrates were concentrated under reduced pressure. The residual oil was cooled to 20° C. and dissolved in ethyl acetate (5 kg) and water (5.5 l) was added. The pH of the stirred mixture was adjusted to pH 2 by the addition of 3M aqueous hydrochloric acid (800 ml). The phases were allowed to separate and the aqueous phase was discharged. Water (2.75 l) was added to the organic phase and the pH was adjusted to 2 by the addition of a small amount of 3M HCl (45 ml). The aqueous phase was separated and the organic phase concentrated under reduced pressure at 30–50° C., to give 4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine as a reddish viscous oil containing ethyl acetate that was dissolved in ethanol (8.5 kg). Solvent (6.5 l of ethanol/ethyl acetate) was then removed by distillation at reduced pressure. A further portion of ethanol (4.5 kg) was added to the residue and the distillation repeated to remove 6.5 l of solvent. The ethanol solution of the product was used without further purification in the following step.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:13].[Na+].[OH2:15]>CO>[OH:13][C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:4][CH2:3][CH2:2][CH2:1][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:11][CH:12]=2)=[CH:2][CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1

Procedure:
In 25 ml of methanol was dissolved 5.0 g of biphenyl, and a solution comprising 1.3 g of sodium hydroxide, 1 ml of water and 5 ml of methanol was added to the above solution. The mixture was refluxed under heating, a solution of 5.4 g of n-bromodecane in 5 ml of methanol was dropped into the formed solution, and the mixture was refluxed overnight. The reaction liquid was concentrated under a reduced pressure and the pH value was adjusted to 2 to 3 by water and hydrochloric acid. The mixture was extracted three times with chloroform, and the extract layer was washed with a saturated aqueous sodium chloride solution dried on magnesium sulfate, concentrated under a reduced pressure and purified by 4-hydroxy-4'-decyloxybiphenyl.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH3:2].C=O.[BrH:13].[C:14](O)(=O)C>O.C(OCC)C>[Br:13][CH2:14][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1ccccc1CC
Reactant: Br
Reactant: CC(=O)O
Agent: C=O
Solvent: CCOCC
Solvent: O
Product: CCc1ccc(CBr)cc1CC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1,2-Diethylbenzene (3.4 g, 23.3 mmol) and paraformaldehyde (2.5 g, 84 mmol) were suspended in glacial acetic acid (60 mL), hydrobromic acid (38% in acetic acid, 8 mL) was added, the reaction flask was sealed with a rubber septum and heated to 80° C. After 4 hours the solution was cooled to ambient temperature and paraformaldehyde (2.5 g, 84 mmol) and hydrobromic acid (38% in acetic acid, 8 mL) were added. The mixture was reheated to 80° C. for 4 hours. Further paraformaldehyde (2.5 g, 84 mmol) and hydrobromic acid (38% in acetic acid, 8 mL) were and the reaction let stir at 80° C. overnight. After a total of 24 hours of reaction time the solution was cooled, diluted with water and diethyl ether, then the layers separated. The organic layers were washed carefully with saturated sodium bicarbonate (4×50 mL), brine, then dried with sodium sulfate, filtered and concentrated in the presence of silica. Purified by column chromatography eluting with 100% hexanes. Concentrated fractions to a yield 4-(bromomethyl)-1,2-diethylbenzene (4.05 g, 77%) 1H NMR (300 MHz, CDCl3) δ 1.21 (m, 6H) 2.64 (m, 4H), 4.47 (s, 2H), 7.1-7.2 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([N:38]4[CH2:39][C:36]([F:40])([F:35])[CH2:37]4)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (1.4428 g, 2.57 mmol) from Step A, 3,3-difluoroazetidine hydrochloride (0.997 g, 7.70 mmol), triethylamine (1.788 ml, 12.83 mmol) and THF (25 mL) were heated in a 63° C. oil bath overnight. The reaction crude was purified by flash chromatography (SiO2, Isolute Flash Si; 100 g prepacked cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated to afford a light yellow solid foam as the titled compound. LCMS calc.=574.03. found=575.09 (M+H)+.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.O>CN(C)C=O>[N:21]1([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]2=3)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(n1ccnc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Add 4.0 gm of methyl 6,11-dihydro-11-chlordibenz[b,e]oxepin-2-carboxylate to a 78° C. solution of 2.0 gm of imidazole in 15 ml of dimethylformamide. Stir under a nitrogen atmosphere for 1 hour. Cool to room temperature and pour into 25 ml of water. Extract twice with 125 ml of ether. Wash the combined ether extracts twice with 50 ml of water and with 25 ml of saturated aqueous sodium chloride. Dry over anhydrous sodium sulfate and evaporate to dryness to obtain the title product (Yield 3.12 gm).
Reaction SMILES: Br.[Br:2][C:3]1[C:4]([CH3:12])=[N:5][C:6]([CH3:11])=[C:7]([Br:10])[C:8]=1O.O=P(Cl)(Cl)[Cl:15].CN(C)C1C=CC=CC=1>CCOCC>[Br:2][C:3]1[C:4]([CH3:12])=[N:5][C:6]([CH3:11])=[C:7]([Br:10])[C:8]=1[Cl:15]
Reactant: Cc1nc(C)c(Br)c(O)c1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: Br
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: Cc1nc(C)c(Br)c(Cl)c1Br
Temperature: 130 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A 500-mL RB-flask was charged with solid 3,5-dibromo-2,6-dimethylpyridin-4-ol, hydrobromide (94 g, 260 mmol) and POCl3 (150 ml, 1609 mmol) was added. To this white slurry was added N,N-dimethylaniline (39.5 ml, 312 mmol) and the reaction mixture was heated to 130° C. (oil bath temp). After stirring for 2 h, the reaction mixture was cooled, concentrated and the brown residue taken up in toluene (100 mL) and concentrated to remove any unreacted POCl3. Then, the residue was treated with ice (250 g) for 30 min and carefully neutralized with powder Na2CO3, extracted with CH2Cl2 (3×250 mL). The combined organic layers dried (MgSO4/C), filtered, concentrated to give slurry which was dissolved in ether (500 mL), filtered through a plug of silica gel. The silica gel pad was washed with 1:1 Ether/Hex (1.5-lit). The filtrate was concentrated to give white slurry which was triturated with hexanes (200 mL) and left in the freezer (−10° C., 2 h). The liquid was decanted and solids were rinsed with cold hexanes (4×50 mL) and dried overnight under high vacuum (required to remove dimethylaniline) to afford 3,5-dibromo-4-chloro-2,6-dimethylpyridine (49.2 g, 164 mmol, 63.3% yield) as pale greenish-yellow solid. The decanted solvent was concentrated and purified by flash chromatography using 1-lit each hexanes, 0.5, 1, 2 and 5% EtOAc/Hex to afford additional 3,5-dibromo-4-chloro-2,6-dimethylpyridine (18.763 g, 62.7 mmol, 24.13% yield) as greenish-yellow solid. 1H NMR (500 MHz, CDCl3) δ 2.59 (s, 6H). LCMS (M+H)=300.0.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:9][C:10]1=[O:14]
Reactant: ClCCCCBr
Reactant: Cc1cccc(-c2cc[nH]c(=O)n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2ccn(CCCCCl)c(=O)n2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 4-(6-methyl-pyridin-2-yl)-1H-pyrimidin-2-one (200 mg, 1.06 mmol) in dry DMF (20 ml), 60% NaH (55 mg, 1.39 mmol) was added portionwise. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (187 μl 1.39 mmol) was added and the mixture was stirred overnight at room temperature. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated. The residue was triturated with petroleum ether to give 173 mg of the title compound as a solid (58% yield).