Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.OS([O-])(=O)=O.[K+]>CN(C=O)C>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:18]([C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:14])([F:25])[F:26])=[O:19])[CH2:9]1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H]1CCN(C(=O)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.363 g (1.95 mmol) (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (commercially available), 0.38 g (2 mmol) 2-trifluoromethyl-benzoic acid (commercially available), 0.69 g (2.15 mmol) TBTU and 0.378 g (2.92 mmol) DIPEA in 8 mL DMF was stirred at room temperature for 16 h. KHSO4 aq. was added and the mixture was extracted with ethyl acetate. The combined organic layers were evaporated and the residue was treated with 4.87 mL 4N HCl in dioxane and stirred for 16 h at room temperature. The mixture was concentrated and methanol and water was added and the mixture was passed over a basic solid phase extraction cartridge eluting with methanol. The title compound was obtained after evaporation and used without further purification in the consecutive step. (MH+) 259.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1cccc(Cl)c1
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3cccc(Cl)c3)n2)ccc1F
Yield: 79.1 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(3-chlorophenyl)-1-propanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a yellow crystalline powder (yield: 79.1%).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[NH:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2.[H-].[Na+].Cl[CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29]>CN(C=O)C>[OH:29][C@@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][N:19]1[C:11]2=[N:10][C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)=[CH:14][C:13](=[O:15])[N:12]2[CH2:16][CH2:17][C@H:18]1[C:20]([F:22])([F:21])[F:23]
Reactant: O[C@H](CCl)c1ccccc1
Reactant: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2C[C@@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a suspension of 60 mg (1.51 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is heated at 50° C. for 10 minutes. After addition of 142 mg (0.91 mmol) of (S)-2-chloro-1-phenylethanol, the reaction is continued at 90° C. overnight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). The isolated fraction is recrystallized from acetonitrile to give 33 mg of (8S)-9-((S)-2-hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: Cl.[CH2:2]([NH:4][C@@H:5]([CH3:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH3:3].C(N(CC)CC)C.[O:23]=[C:24]1[N:29]([CH2:30][CH2:31][CH2:32][CH:33]=O)[CH2:28][CH2:27][CH2:26][O:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([N:4]([C@@H:5]([CH3:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][CH3:14])=[CH:11][CH:12]=1)[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:28][CH2:27][CH2:26][O:25][C:24]1=[O:23])[CH3:3]
Reactant: O=CCCCN1CCCOC1=O
Reactant: CCN[C@@H](C)Cc1ccc(SC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCN(CCCCN1CCCOC1=O)[C@@H](C)Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of ethyl-[(S)-2-(4-methylsulfanylphenyl)-1-methylethyl]-amine hydrochloride (0.25 g, 1 mmole) in 1,2-dichloroethane (10 mL) was added triethylamine (0.2 mL, 1.5 mmole). To this mixture was added 4-(2-oxo-[1,3]oxazinan-3-yl)butyraldehyde (0.18 g, 1.05 mmole) and sodium triacetoxyborohydride (0.32 g, 1.5 mmole). The reaction mixture was stirred at room temperature for 15 hours, concentrated, and the residue was partitioned between 5% sodium hydroxide (5 mL) and diethyl ether (20 mL). The organic phase was dried (magnesium sulfate) and concentrated to give 3-(4-{ethyl-[(S)-2-(4-methylsulfanyl-phenyl)-1-methylethyl]amino}butyl)-[1,3]oxazinan-2-one, (0.33 g,) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][NH:9][C:10](=O)[C@H:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=2[CH3:25])[C@@H:12]([OH:14])[CH3:13])=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:24][C:18]1[C:17]([CH3:25])=[C:16]([NH:15][C@@H:11]([C:10]2[O:7][C:6]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=3)=[N:8][N:9]=2)[C@@H:12]([OH:14])[CH3:13])[CH:21]=[CH:20][C:19]=1[C:22]#[N:23]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Cl)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
To a 500 mL round bottom flask was added 4-chloro-N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 4a) (880 mg, 2.09 mmol, 1.0 equiv.) and anhydrous THF (209 mL). After being flushed with nitrogen, p-toluenesulfonic acid (439 mg, 2.3 mmol, 1.1 equiv.) was added and the solution was stirred for 10 min at room temperature. Then PS-BEMP (2.85 g, 6.27 mmol, 3.0 equiv.) was added. The reaction was stirred at room temperature for 8 h. The contents of the flask were filtered over Celite® in a ground glass fritted funnel and the Celite® was rinsed with several portions of acetone. The solvent was removed in vacuo to yield a yellow solid. The product was purified via flash chromatography (0→50% EtOAc/hexanes, 110 g of silica gel; TLC Rf=0.51, 100% EtOAc, vanillin stain) to provide the desired product as an off-white solid (150 mg, 18%). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.01 (d, J=8.79 Hz, 2H), 7.62 (d, J=8.79 Hz, 2H), 7.49 (d, J=8.54 Hz, 1H), 6.86 (d, J=8.54 Hz, 1H), 5.68 (br. d, J=8.31 Hz, 1H), 5.12 (dd, J=3.91, 8.55 Hz, 1H), 4.82 (br. d, J=5.29 Hz, 1H), 4.62 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6.35 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H16Cl2N4O2 [M]+ 403.26, found 403.4.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([CH3:13])[CH:9]=1
Reactant: COc1cc(C=O)c(Br)cc1Cl
Reactant: CB1OB(C)OB(C)O1
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
Product: COc1cc(C=O)c(C)cc1Cl
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a degassed solution of 2-bromo-4-chloro-5-methoxybenzaldehyde (1.46 g, 5.9 mmol) and trimethylboroxine (0.82 mL, 5.9 mmol) in 1,4-dioxane (80 mL) was added potassium carbonate (2.43 g, 17.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.68 g, 0.6 mmol). The mixture was heated under reflux for about 23 h, then more tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) and trimethylboroxine (0.2 mL, 1.4 mmol) were added and the mixture was heated under reflux for about another 8 h. After cooling to rt the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:6) to give 4-chloro-5-methoxy-2-methylbenzaldehyde (0.87 g, 4.7 mmol, 81%) as a pale yellow solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.60 (3 H, s); 3.95 (3 H, s); 7.29 (1 H, s); 7.37 (1 H, s); 10.3 (1 H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccnc2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc2cccnc2n1

Procedure:
A solution of 2-methyl-1,8-naphthyridine (Chem. Pharm. Bull., 19, 1857 (1971)), N-chlorosuccinimide (1.1 equivalent), and a catalytic amount of benzoylperoxide in CCl4 were irradiated at reflux with a 225 watt lamp for 5 hours. After cooling, the solid was filtered and the filtrate evaporated to dryness. The crude residue was chromatographed to give the title product.
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[F:26].ClC1C=CN=C(C#N)C=1>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:14])[CH:7]=2)=[CH:21][C:20]=1[F:26]
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: N#Cc1cc(Cl)ccn1
Product: N#Cc1cc(Oc2ccc(N)c(F)c2)ccn1

Procedure:
4-(4-Amino-3-fluorophenoxy) pyridine-2-carbonitrile (2G) was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-amino-3-fluorophenol and 4-chloro-2-cyanopyridine, MS ES: 230 (M+H)+, calcd 230, RT=2.85 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:14]3[CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:17]=[CH:18][C:13]=3[N:12]=[C:11]([NH:34][NH2:35])[CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.[N:36]([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:14]3[CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:17]=[CH:18][C:13]=3[N:12]3[N:36]=[N:35][N:34]=[C:11]3[CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(NN)=N2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A mixture of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-2-hydrazino-3,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)-4,1-benzothiazepine-7-methanol (described in Example B15a) (0.0082 mol) in HCl 1N (45 ml) was cooled on an ice bath. A solution of NaNO2 (0.009 mol) in water (12 ml) was added. The mixture was stirred at 5° C. for 30 min. Ice was added. The mixture was basified with K2CO3 10% and extracted with DCM. The organic, layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1; 20–45 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN/2-propanone/DIPE. The precipitate was filtered off and dried, yielding 1 g (23.2%) of 6-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-4H,6H-tetrazolo[1,5-a][4,1]benzothiazepine-8-methanol, mp. 217° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>ClCCl>[CH:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:11][CH2:10]1)=[O:8]
Reactant: O=CN1CCN(CCO)CC1
Reactant: C=C(C)C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCN1CCN(C=O)CC1
Reaction time: 2 h

Procedure:
105.5 g (1.01 mol) of methacryloyl chloride were added dropwise between -30° and -35° C. to a stirred solution of 160 g (1.01 mol) of N-formyl-N-'-2-hydroxyethylpiperazine, 111 g (1.10 mol) of triethylamine and 100 mg of 2,6-di-tert.-butyl-4-methylphenol in 300 ml of dichloromethane and the mixture was stirred for two hours at the same temperature. The precipitate which deposited was filtered off and the filtrate was washed with sodium chloride solution, dried and concentrated to give 166.8 g (73% of theory) of a clear oil of N-formyl-N'-(methacryloyloxyethyl)piperazine. It was possible to elute this with methanol in high purity from a silica gel column after separating small amounts of by-products with ether/n-hexane (6:4).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])=[CH:11][CH:12]=2)[O:7][CH2:6]1)[CH2:2][CH3:3].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.O>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])=[CH:11][CH:12]=2)[O:7][CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCNC1COc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN(Cc1ccccc1)C1COc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Yield: 30 %

Procedure:
Trifluoro-methanesulfonic acid 3-propylamino-chroman-7-yl ester (1.62 g, 4.78 mmol) and benzaldehyde (975 μl, 9.56 mmol) were dissolved in dichloromethane (60 ml). Acetic acid (710 μl, 12.37 mmol) and sodium trisacetoxyborohydride (3.04 g, 14.34 mmol) were sequentially added to the reaction mixture and stirred over the weekend at room temperature. Dichloromethane and water were added to the reaction mixture. The aqueous phase was adjusted to a pH=6 with a 1 molar solution of NaOH. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude product was purified by chromatography on silica gel using cyclohexane/ethyl acetate (100:0 to 95:5) as eluent, yielding the purified product (1.24 g, 50% purity, 30% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:22][C:23](=[O:29])[O:24]C(C)(C)C)[C@H:10](O)[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=3)[O:29][C:23](=[O:24])[NH:22]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2ccc(C(F)(F)F)cc2)O1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a 25 mL round bottom flask was added tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethylcarbamate (250 mg, 0.53 mmol) in dichloromethane (8 mL). To this solution was added trifluoroacetic acid (1.021 mL, 13.25 mmol) and the reaction was allowed to stir over night at room temperature. The reaction solvent was evaporated in vacuo and the crude oil was diluted with ethylacetate and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and the solvent was then evaporated in vacuo and the crude residue was diluted with dry tetrahydrofuran. The solution was cooled to 0° C. and carbonyldiimidazole (86 mg, 0.530 mmol) was added and the reaction was allowed to stir overnight. The reaction solvent was then evaporated in vacuo and the crude solid was purified by silica gel chromatography 15% EtOAc/85% Hexanes to 50% EtOAc/50% Hexanes affording (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(4-(trifluoromethyl)phenyl)oxazolidin-2-one (84 mg, 0.207 mmol, 39.1% yield) and its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=2.44 min. Mass=406.91 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4]3=[C:5]([C:12](=[O:15])[C:13](=[O:14])[N:3]13)[CH:6]=[CH:7][CH:8]=2.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4]3=[C:5]([C:12](=[O:15])[C:13](=[O:14])[N:3]3[CH:2]([CH3:1])[CH2:11][CH2:10]2)[CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1CCc2cccc3c2N1C(=O)C3=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1CCc2cc(Cl)cc3c2N1C(=O)C3=O
Yield: 46.7 %

Procedure:
To a suspension of 8.05 g (0.04 mole) of 5,6-dihydro-4-methyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione in carbon tetrachloride (50 ml) was added 5.74 g (0.043 mole) of sulfuryl chloride and the mixture was refluxed for 24 hours. After cooling, there was obtained 4.4 g of red crystals. Recrystallization from ethanol afforded 2.93 g (31.1%) of red prisms, melted at 152°-154° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:42][CH:43]1[CH2:45][CH2:44]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C>O1CCCC1>[CH:43]1([CH2:42][N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]3([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:15]=2)=[O:13])[CH2:45][CH2:44]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (329) (580 mg, crude) in tetrahydrofuran (30 mL) was added 1N aq.HCl (6 mL) at room temperature and stirring was continued for 1 h (TLC; 100% ethyl acetate/UV/SiO2, Rf=0.2). Tetrahydrofuran was removed in vacuo and the crude mass was dissolved in ethyl acetate (50 mL) and washed with NaHCO3 solution (10 mL), water (20 mL) and brine (20 mL); The organic phase was dried and concentrated in vacuo to get a crude mass which was purified by CombiFlash using a gradient eluent mixture of ethyl acetate and hexane to get pure 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid cyclopropylmethyl-(2-hydroxyethyl)-amide (330) (390 mg, 94% two steps) as an off-white sticky solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N>O1CCCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(Cl)cc(F)c1C(=O)O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1c(N)cc(Cl)cc1F
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of 2-amino-4-chloro-6-fluorobenzoic acid (3.22 g, 17.04 mmol) in tetrahydrofuran (100 mL) was added EDCI.HCl (6.5 g, 34.1 mmol, Aldrich), HOBT (4.6 g, 34 mmol) and ammonia as a 0.5M solution in dioxanes (170 mL, 85 mmol, Aldrich). The resultant slurry was stirred for 24 hours, and then solids removed by filtration through celite. The filtrate was taken to a residue under reduced pressure and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by chromatography on SiO2 (Ethyl acetate/Hexanes) to afford analytically pure 2-amino-4-chloro-6-fluorobenzamide as a white crystalline solid (2.98 g, 92% Yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.40 (s, 2 H), 6.44 (dd, J=10.81, 2.02 Hz, 1 H), 6.57 (s, 1 H), 7.56 (s, 1 H), 7.60 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[CH:13]=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH2:44])[CH3:40].O>CN(C)C=O>[CH2:39]([O:41][C:42](=[O:45])[CH2:43][NH:44][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)[CH3:40]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)O)c2)n1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
A mixture of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid [127 mg, 0.3 mmol, Example 35(w)], O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (116 mg, 0.36 mmol), diisopropylethylamine (131 μL, 0.75 mmol) and glycine ethyl ester hydrochloride (63 mg, 0.45 mmol) in dimethylformamide (3 mL) is stirred at ambient temperature for 18 hours. The mixture is poured into water and extracted three times with EtOAc (20 mL). The organic extracts are combined and washed twice with water (20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator to provide a solid. The solid is absorbed onto silica and subjected to flash column chromatography on silica (40 g) eluting with 0% to 50% ethyl acetate/heptane gradient, to afford (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoylamino)-acetic acid ethyl ester [120 mg, 79%, Example 58]. MS: 503 (M+H).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:12]1(=O)[CH2:15][CH2:14][CH2:13]1>CO>[CH:12]1([N:9]2[CH2:10][CH2:11][CH:6]([OH:5])[CH2:7][CH2:8]2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCC1
Reactant: OC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OC1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 1082.2 %

Procedure:
A methanol solution (48 mL) of 0.3 N sodium cyanoborohydride/0.15 N zinc(II) chloride was added to a methanol (50 mL) solution of 4-hydroxypiperidine (1.1 g, 1.0 mmol) and cyclobutanone (1 g), and stirred at room temperature for 24 hours. The solvent was concentrated under reduced pressure, distilled water was added, and extracted eight times with chloroform. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure to obtain the entitled compound (1.68 g, 98%) as a yellow oil.