Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[H-].[Na+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1.O>CN(C)C=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=2)[O:6][C:5](=[O:7])[N:4]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:3]1
Reactant: BrCC1CC1
Reactant: CCOc1cc(C2(C)CNC(=O)O2)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C2(C)CN(CC3CC3)C(=O)O2)ccc1OC
Yield: 71.7 %

Procedure:
500 mg (2.0 mmol) of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 60 mg (2.5 mmol) of sodium hydride in 14 ml of dimethylformamide for 30 minutes and, after addition of 0.26 ml (3.0 mmol) of (bromomethyl)cyclopropane for 17 hours at room temperature. The reaction mixture was combined with 50 ml of water and then extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over sodium sulfate, filtered, and concentrated (766 mg of a yellow oil). Chromatography on silica gel with methylene chloride/ether (1:1) yielded 438 mg of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-3-cyclopropylmethyl-2-oxazolidinone as an oil.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:13])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[N+:10]([O-:12])=[O:11].[OH-].[Na+]>>[N+:10]([C:6]1[N:5]([CH2:4][C@H:3]2[CH2:2][O:13]2)[CH:9]=[CH:8][N:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1nccn1C[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1nccn1C[C@H]1CO1
Yield: 65.1 %

Procedure:
Alternatively, reaction of 0.56 g of (S)-(+)-α-(chloromethyl)-2-nitro-1H-imidazole-1-ethanol with 3 mL of 10% aqueous sodium hydroxide at 25° C. for 30 minutes followed by further processing as above gives 0.3 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+:11].CC1C=C(F)C=CC=1[N+]([O-])=O>O>[CH:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([O-:9])[CH:4]=1.[K+:11]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: [O-]c1ccc(Cl)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Potassium 2,4-dichlorophenate is prepared by dissolving 6.5 g. (0.04 mole) of 2,4-dichlorophenol and 2.6 g. (0.04 mole) of 85% potassium hydroxide in 30 ml. of methanol and removing the solvent under reduced pressure. The solid residue is dissolved in 60 ml. of sulfolane and 6.2 g. (0.04 mole) of 3-methyl-4-nitrofluorobenzene is added. The resulting solution is heated at 85° C. for 3 hours then at 150° C. for 1 hour, cooled, diluted with water and extracted with ether/benzene. The extract is dried and the solvent removed. The residue is dissolved in hot isopropanol and on cooling 8.2 g. (69%) of 2,4-dichloro-3'-methyl-4'-nitrodiphenyl ether (m.p. 72.5°-73.5° C.) separated and is isolated by filtration.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([N:25]([CH:34]([CH3:36])[CH3:35])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:24]>CN(C=O)C>[CH:34]([N:25]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:23](=[O:24])[CH2:22][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:35])[CH3:36]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a solution of N-phenyl-benzene-1, 2-diamine(3.08 g) in DMF (35 mL) was added potassium carbonate (2.31 g) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (4.79 g) and stirred 18 h at ambient temperature. The solvent was evaporated in vacuo and the resultant oil was dissolved in ethyl acetate (250 mL), washed with 1N HCl (4×100 mL), dried over sodium sulfate, filtered, and concentrated to a brown oil. The oil was subjected to flash chromatogaraphy on silica gel (70 g) eluted with ethyl acetate/hexanes (1:4, 1 L). Fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a tan foam (3.95 g). 1H NMR (300 MHz, CDCl3): d 1.05 (d, J=6.9 Hz, 6H), 3.44 (s, 2H), 3.87 (s, 3H), 4.97 (m, 1H), 5.37 (br s, 1 H) 6.36 (d, J=7.4 Hz, 1H), 6.69 (t, 1H), 6.71-7.21 (m, 11H) TLC (EtOAc/Hexane (1:4)): Rf =0.18.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:25]([O-])([O-:27])=[O:26].[NH4+].O>C(Cl)(Cl)Cl.ClCCl>[N+:25]([C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:27])=[O:26]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)Cc1ccsc1
Agent: [NH4+]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccsc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Ethyl thiophene-3-acetate, (10 g, 64.1 mmol) was dissolved in chloroform (90 ml) and trifluoroacetic anhydride (40 ml) at 0° C. Ammonium nitrate (5.2 g, 64.1 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour then warmed slowly to room temperature for 2 hours. The reaction mixture was cooled in an ice-bath and diluted with dichloromethane (60 ml) and then water (50 ml). The aqueous phase was extracted with dichloromethane and the combined organic fractions were washed with saturated brine solution. The organic phase was dried over magnesium sulfate, evaporated to give a red/brown liquid which was chromatographed on silica gel using hexane/ethyl acetate (4:1) as eluent to give 8.2 g of ethyl 2-nitrothiophene-3-acetate as a red/brown viscous oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][N:13]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]1[C:21]([OH:23])=O>>[CH3:12][N:13]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]1[C:21]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH:11][C:21]([C:14]3[N:13]([CH3:12])[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=3)=[O:23])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:23]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Reactant: Nc1ccc2nc(N)sc2c1
Product: Cn1cc([N+](=O)[O-])cc1C(=O)Nc1ccc2nc(NC(=O)c3cc([N+](=O)[O-])cn3C)sc2c1

Procedure:
The compound 8b was prepared according to the above described method using compound 7 (165 mg, 1 mmol) and 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid (340 mg, 2 mmol). Yield 290 mg, 60%; 1H NMR (DMSO-d6) δ 10.9 (bs, 1H, —NH), 8.54 (s, 1H), 7.95 (s, 2H), 7.74-7.71 (m, 2H), 7.50 (s, 2H), 3.96 (s, 6H); ESIMS: m/z 470 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:21][C:22]([O:24][CH3:25])=[O:23]>O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)CNc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
A mixture of 3-phenoxyaniline (25 g, 0.135 mol), sodium bicarbonate (22.7 g, 0.27 mol) and methyl chloroacetate (15.5 ml, 0.2025 mol) was heated at 90°-100° C. with vigorous stirring for 20 h. The mixture was allowed to cool to room temperature and was then poured into water (200 ml) and extracted with dichloromethane (2×100 ml). The organic extract was washed with 2N hydrochloric acid (2×100 ml), water (2×100 ml) and then dried and evaporated to give a grey/green solid. This was triturated with hexane (400 ml) and filtered to give the title compound as a grey/green solid (18.4 g, 53%), m.p 44°-45°.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[CH:26]1([B-](F)(F)F)[CH2:28][CH2:27]1.[K+]>>[NH2:2][C:1](=[O:3])[C@@H:4]([NH:9][C:10](=[O:11])[C:12]1[CH:17]=[CH:16][C:15]([CH:26]2[CH2:28][CH2:27]2)=[C:14]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[N:13]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Br)c(OCC2CCCO2)n1)C(N)=O
Reactant: F[B-](F)(F)C1CC1
Agent: [K+]
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 166 b, using 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (Example 186 a) and potassium cyclopropyltrifluoroborate as starting materials, MS (EI): m/e=376.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:34]=[CH:33][CH:32]=[CH:31]5)=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: BrCc1ccc(-n2cccc2)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(-n4cccc4)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-(4-bromomethyl-phenyl)-1H-pyrrole as described in Example 49 and isolated as a white solid (0.08 g, 52% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.54-8.57 (m, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.26-7.43 (m, 6H), 7.07 (d, J=8 Hz, 2H), 6.86 (s, 1H), 6.35 (d, J=4 Hz, 2H), 6.18-6.25 (m, 1H), 5.36 (s, 2H), J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=455.2; Rt=1.38 min; HRMS (M+H)+=455.17.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][C@H:19]([CH2:22]O)[C@@H:18]([CH2:24]O)[C@@H:17]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:48]([N:55]1[CH2:24][C@H:18]2[C@H:17]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=3)[CH3:14])[O:21][CH2:20][C@@H:19]2[CH2:22]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@H](CO)[C@H]1CO
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The intermediate from step I (2.44 g, 4.87 mmol) was combined with DMAP (0.15 g, 1.2 mmol) and dissolved in 38 mL DCM. The reaction vessel was cooled 0° C. followed by the sequential addition of triethylamine (2.72 mL, 19.5 mmol) and methanesulfonyl chloride (0.95 mL, 12.2 mmol). After 5 minutes, the reaction vessel was warmed to ambient temperature where it remained for 0.5 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3. The aqueous mixture was extracted several times with DCM. The combined organic extracts were washed with 1 M HCl, brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude bis-mesylate was dissolved in 50 mL n-butanol followed by the addition of benzylamine (3.19 mL, 29.2 mmol). The reaction vessel was heated to 100° C. for 3.5 hr. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a combination of EtOAc/hexanes (35-95% EtOAc/hexanes linear gradient) which furnished the title compound. MS: (MH)+582.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1.O=[C:21]1C2C=CC(C(O)=O)=CC=2SC2C=CC=CC=2N1>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([O:19][CH3:21])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1C(=O)N2

Procedure:
Repeat the process of Example 31, substituting 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-7-carboxylic acid for the 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylic acid of Step A, in order to obtain the title product.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1.[NH4+].[Cl-]>O1CCCC1.O=O>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][C:6]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[CH:24]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: COc1cccc([Mg]Br)c1
Agent: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCC(c3ccccc3)(N(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(dimethylamino)-4-phenylcyclohexanone (4.34 g, 20 mmol) was dissolved in absolute tetrahydrofuran (60 ml) with the exclusion of oxygen, mixed with 3-methoxyphenyl magnesium bromide solution (45 ml, 45 mmol, 1N) with ice cooling and boiled to reflux for 2 h. For work up the batch was mixed with saturated NH4Cl solution (50 ml) with ice cooling and stirred for 10 min at room temperature. The aqueous phase was separated off and extracted with ethyl acetate (3×25 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. A raw product was isolated that was purified by chromatography [silica gel 60 (50 g); ethyl acetate (1000 ml), methanol (1000 ml)]. 2.5 g (38%, mp 116-117° C.) of more non-polar and 2.78 g (43%, mp 139-140° C.) of more polar product were obtained. Both could be recrystallised from ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11](=[O:12])[NH:10][C:9]([NH2:13])=[N:8][C:7]=1[NH2:14])[CH3:2]>C(OC(=O)C)(=O)C>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11](=[O:12])[NH:10][C:9]([NH:13][C:1](=[O:3])[CH3:2])=[N:8][C:7]=1[N:14]([C:4](=[O:15])[CH3:5])[C:11](=[O:12])[CH3:6])[CH3:2]
Reactant: CCOC(Cc1c(N)nc(N)[nH]c1=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(Cc1c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c1=O)OCC
Reaction time: 120 h
Yield: 60.6 %

Procedure:
Freshly distilled acetic anhydride (250 ml) was added to a solution of 2-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)acetaldehyde diethyl acetal (Chem. Ber., 1977, 110, 1462) (50.0 g, 0.206 mol). The solution was protected from moisture and heated on a steam bath with magnetic stirring for 5 days. The reaction was spin evaporated in vacuo with the addition of ethylene glycol monomethyl either under aspirator and finally mechanical pump vacuum. The residue was recrystallized from ether to yield 23.0 g (30% of theory) of 2-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)acetaldehyde diethyl acetal, mp 128°-130°. The analytical sample was prepared by dissolving the sample in chloroform and washing the solution through Superfiltrol μ19 (Filtrol Corporation). The solution was spin evaporated in vacuo and the residue was recrystallized from ether/cyclohexanes, to give analytically pure material, mp 129°-130°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Yield: 71.6 %

Procedure:
tert-Butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (230 mg, 0.609 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (123 mg, 0.534 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (199 mg, 71%) as a colorless oil: ESI MS m/z 521 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@@H:17]([NH:18][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=2[CH:7]=1)=[O:12])[C:16]([O:15][CH3:14])=[O:23]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: Cc1ccc2oc(C(=O)O)cc2c1
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc2cc(C)ccc2o1

Procedure:
Prepared in a similar manner to example 4 using 5-methylbenzofuran-2-carboxylic acid (example 26a) and D-leucine methyl ester. 1H NMR (500 MHz, CDCl3): 0.98 (d, 3H, J=6.26 Hz), 1.00 (d, 3H, J=6.17 Hz), 1.56 (s, 3H), 1.76 (m, 3H), 2.48 (s, 3H), 3.78 (s, 3H), 4.86 (m, 1H), 6.95 (m, 1H), 7.23 (dd, 1H, J=8.54 Hz, J=1.55 Hz), 7.40 (m, 2H). 7.44 (dd, 1H, J=1.72, J=0.9 Hz). MS 304 (M+H, 304)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([NH:33]C(OC(C)(C)C)=O)=[N:25]C(OC(C)(C)C)=O)=[CH:18][C:17]=2[Br:41])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([NH2:33])=[NH:25])=[CH:18][C:17]=2[Br:41])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N=C(NCc1ccc(OCCCOS(=O)(=O)c2ccc(Br)cc2)c(Br)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NCc1ccc(OCCCOS(=O)(=O)c2ccc(Br)cc2)c(Br)c1
Reaction time: 4 h

Procedure:
A 25 mL round bottom flask was charged with Compound 4 (3.00 g, 4.15 mmol) then CH2Cl2 (6 mL), and the resulting suspension stirred until complete dissolution was observed. Trifluoroacetic acid (6 mL, 78.3 mmol) was then added and the mixture stirred an additional 4 h. All volatiles were then removed, and the residue treated with EtOAc (20 mL). The resulting mixture was stirred at room temperature for 3 h, during which time a white solid precipitated. The solids were collected on a sintered glass funnel of medium porosity then exhaustively washed with EtOAc (20 mL) and dried to constant weight (2.5 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.54 (m, 4H), 7.4 (d, 1H), 7.15 (m, 1H), 6.9 (d, 1H), 4.15 (m, 4H), 3.86 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].CS(O)(=O)=O.[OH-].[Na+].C(OC(=O)C)(=O)C>O1CCOCC1.ClCCl.O.CN(C1C=CN=CC=1)C>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)c1ccnc(Cl)n1
Reactant: Nc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: FC(F)c1ccnc(Nc2cccc(Br)c2)n1
Temperature: 95 °C
Reaction time: 10 h

Procedure:
2-Chloro-4-(difluoromethyl)pyrimidine (69 wt % in DCM, 24.2 g, 101 mmol) was diluted with 1,4-dioxane (200 mL) to which was added 3-bromoaniline (14.9 mL, 137 mmol) followed by methanesulfonic acid (8.89 mL, 137 mmol). The resulting mixture was heated to an internal temperature of 95° C. where it was stirred for 10 h at which point the reaction mixture was cooled to room temperature and diluted with dichloromethane and water. NaOH (1N) was added until the pH of the aq layer was ˜7, the layers were separated and the aqueous layer was extracted a second time with additional of dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. To facilitate purification, the crude residue was diluted with dichloromethane (200 mL) and DMAP (0.84 g, 6.84 mmol) followed by acetic anhydride (3.87 mL, 41.1 mmol) were added. After stirring for 30 min all excess 3-bromoaniline had been acetylated, silica gel was added and the mixture concentrated under reduced pressure and the desired product isolated by purification by column chromatography on silida (0 to 100% EtOAc/Hex) to afford N-(3-bromophenyl)-4-(difluoromethyl)pyrimidin-2-amine as a white solid, MS ESI calcd. for C11H9BrF2N3 [M+H]+ 300. found 300. 1H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.71 (d, J=4.9 Hz, 1H), 8.06 (s, 1H), 7.70 (dd, J=8.2, 1.3 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.09 (d, J=4.9 Hz, 1H), 6.85 (t, J=54.4 Hz, 1H).
Reaction SMILES: C(OC(C1C(O)=C2C=C(C3C=CC(F)=CC=3)N(C3C=CC=CC=3)C2=CN=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35]([OH:59])=[C:36]2[C:42](Br)=[C:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[N:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[C:37]2=[CH:38][N:39]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1[C:35]([OH:59])=[C:36]2[CH:42]=[C:41]([C:44]3[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=3)[N:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[C:37]2=[CH:38][N:39]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(F)cc1)n2-c1ccc(OC)cc1
Agent: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccccc2)c1O
Product: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccc(OC)cc2)c1O

Procedure:
Prepared in analogy to that of 2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 3-bromo-2-(4-fluoro-phenyl)-4-hydroxy-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 407 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:31])[C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:14][CH2:13][N:12]([C:32]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[O:33])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[OH:40][C:41]1([C:44](O)=[O:45])[CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:31])[C:17](=[O:30])[C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)[CH2:14][CH2:13][N:12]([C:32]([CH:34]3[CH2:39][CH2:38][N:37]([C:44]([C:41]4([OH:40])[CH2:43][CH2:42]4)=[O:45])[CH2:36][CH2:35]3)=[O:33])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)C1(O)CC1
Reactant: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3(O)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.1 %

Procedure:
To a solution of N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-(piperidin-4-ylcarbonyl)piperidin-4-yl]-N-methyl-4-morpholin-4-ylbenzamide monohydrochloride (200 mg) obtained in Example 621, 1-hydroxycyclopropanecarboxylic acid (44.5 mg) and triethylamine (143 μL) in acetonitrile (5 mL) were added WSC.HCl (96 mg) and HOBt (76.8 mg), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (119 mg, 55%) as a white crystal powder.