Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:20]C(OC(C)(C)C)=O)[CH2:5][S:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][S:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[NH:20]1)=[O:28]
Reactant: COC(=O)C(CSCC(=O)c1ccc(OC)c(OC)c1)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CSCC(c2ccc(OC)c(OC)c2)N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice chilled solution of 2-tert-butoxycarbonylamino-3-[2-(3,4-dimethoxy-phenyl)-2-oxo-ethylsulfanyl]-propionic acid methyl ester (2.00 g, 9.34 mmol, 1.0 equivalents) in dichloromethane (9 ml) was added trifluoroacetic acid (9 ml). The reaction solution was stirred on ice for 4 hours. The solution was concentrated, coevaporated with toluene. The residue was dissolved in dichloromethane (30 ml) and chilled on ice. To this was added sodium triacetoxyborohydride (2.97 g, 14.02 mmol, 1.5 equivalents) followed by dichloromethane (7 ml). The reaction was stirred 18 hours at room temperature. Saturated sodium bicarbonate was added, and the reaction mixture was extracted with dichloromethane. The dichloromethane extracts were dried with MgSO4, filtered and concentrated. 5-(3,4-Dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid methyl ester was obtained as an oil (1.63 g, 59% yield). Analysis H1 NMR (400 MHz, CDCl3): 6.92 (2H, m), 6.83 (1H, d), 3.95 (3H, s), 3.93 (3H, s), 3.87 (2H, m), 3.85 (3H, s), 2.77 (3H, m), 2.42 (1H, m). MS (LC-MS): Calculated for C14H19NO4S 297.10. Found 298.17.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:8]1([CH2:14][NH:15][C:16](=[N:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=2)SC)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([CH2:14][NH:15][C:16](=[N:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)[NH:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ccc(N=C(NCC2CCCCC2)SC)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=Nc1ccc(C(=O)O)cc1)NCC1CCCCC1
Yield: 79 %

Procedure:
This compound is obtained (yield 79%; melting point 164° C.), by saponification of N-[N-cyclohexylmethylamino(4-caraboxyphenylimino)methyl]-2-aminoethanoic acid (melting point 163° C.) in a 1N sodium hydroxide solution, whereby the former was prepared from glycine and N-cyclohexylmethyl-N'-(4-methoxycarbonylphenyl)-S-methylisothiourea according to the experimental procedure described in Example 2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1([CH2:53][C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:54](=[O:55])[CH2:53][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.125 g, 0.207 mmol), in tetrahydrofuran (5 mL), were added, phenyl acetyl chloride (0.049 g, 0.315 mmol, 0.025 mL) and triethyl amine (0.107 g, 1.06 mmol, 0.147 mL). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification (0.186 g, 99% yield): ES-MS (m/z) 721 [M+1]+.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[C:10]#[C:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:11]1[C:10]([C:9]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1)[CH3:13]
Reactant: N[n+]1ccccc1
Reactant: CCC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)nn2ccccc12

Procedure:
A solution of 1-aminopyridinium iodide (10 g, 40 mmol) [Aldrich 441503], ethyl 2-pentynoate (5.7 g, 45 mmol) [Aldrich 632112] and potassium carbonate (12.0 g, 90 mmol) were stirred in N,N-dimethylformamide (200 mL) at 20° C. for 16 h. The mixture was poured into water to give a tan suspension. The solid was filtered and washed with water to give the desired to compound (5.0 g, 57%). LCMS for C12H15N2O2 (M+H)+: m/z=219.1. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (m, 1H), 8.00 (m, 1H), 7.52 (m, 1H), 7.05 (m, 1H), 4.28 (m, 2H), 3.00 (m, 2H), 1.33 (m, 3H), 1.24 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7](/[CH:16]=[C:17]2/[C:18](=[O:24])[N:19]([CH3:23])[CH2:20][CH2:21][S:22]/2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[CH3:4][C:2]([C:5]1[CH:6]=[C:7](/[CH:16]=[C:17]2/[C:18](=[O:24])[N:19]([CH3:23])[CH2:20][CH2:21][S:22]/2=[O:30])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CN1CCS/C(=C\c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN1CCS(=O)/C(=C\c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 0.42 h
Yield: 79.5 %

Procedure:
A solution of (Z)-2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-methyl-3-thiomorpholinone (1.25 g, 3.6 mmol) in dichloromethane (18 ml) was cooled under nitrogen to 0° C. A solution of m-chioroperoxybenzoic acid (0.78 g, 3.6 mmol) in dichloromethane (llml) was then added dropwise over 5 minutes. The reaction mixture was stirred an additional 25 minutes and washed once with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate. Rotary evaporation gave crude product which was crystallized from ethyl acetate-hexane to give desired product (1.04 g, 79%):
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:22])[CH2:17][CH2:16]2)[N:3]=1.[CH3:35][O-:36].[Na+]>>[CH3:35][O:36][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:22])[CH2:17][CH2:16]2)[N:3]=1
Reactant: C[O-]
Reactant: CN1CCN(c2nc(Cl)nc(N3CCC(C(=O)NCc4ccccc4C(F)(F)F)CC3)n2)CC1
Agent: [Na+]
Product: COc1nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1
Temperature: 80 °C
Yield: 4.6 %

Procedure:
⅕ of the suspension prepared in step b of Example 20 (0.542 mmol, 1.00 equiv) was concentrated under reduced pressure. Then, sodium methoxide (1.24 mL of 25 wt % solution in MeOH, 5.42 mmol, 10.0 equiv) was added. The resulting mixture was heated to 80° C. for 1 h. The final solution was purified by reverse-phase HPLC (Sunfire, 20-40% CH3CN, H2O, 0.1% TFA, 12 min) to afford 12.2 mg of the title compound. MS (ES+): m/e 493.8 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[N:24]=[N:23]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27]([C:25]3[N:24]=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Cn1cc(C(=O)O)nn1
Product: Cn1cc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)nn1

Procedure:
Methyl-1H-[1,2,3]triazole-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-methyl-1H-[1,2,3]triazole-4-carboxylic acid. MS calcd. for C20H17ClN5O2 [(M+H)+] 394.1, obsd. 394.0.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10][C:9]=1Cl)=[O:6])=O.[ClH:19]>[OH-].[K+].CO>[Cl:19][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:5](=[O:6])[NH:4][N:3]=[CH:1]2)=[CH:13][C:12]=1[C:14]([OH:16])=[O:15]
Reactant: Cl
Reactant: COC(=O)c1ccc(Cl)c(NC(=O)NNC=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-n2cn[nH]c2=O)ccc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 1-formyl-4-(2-chloro-5-carbomethoxyphenyl)semicarbazide (0.03 g, 0.11 mmol) in 1.0 M KOH in methanol (MeOH) (0.44 mL) was heated at 80° C. for 72 hours and cooled to room temperature. 1.0 N HCl (0.8 mL) was added and the mixture evaporated to dryness in vacuo. The residue was taken up in MeOH (1.5 mL) and filtered. The filtrate was concentrated in vacuo to yield 0.028 g (100%) of the title intermediate as an amorphous solid. Mass Spectrum (M−H): 3:1 ratio of 238 and 240.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(Br)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)NCC(=O)OCc1ccccc1

Procedure:
60.97 g (355.7 mmol) of α-bromopropionyl chloride is added in drops at 0° C. to 100 g (296.4 mmol) of glycine benzyl ester p-toluenesulfonic acid salt and 89.98 g (889.2 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature is kept between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is recrystallized from diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)cnc1C
Solvent: ClCCl
Product: Cc1cc(F)c[n+]([O-])c1C
Reaction time: 16 h

Procedure:
A mixture of 3-fluoro-5,6-dimethyl-pyridine (0.230 g, 1.84 mmol) (Ife, R. J. Eur. Pat. Appl. (1987), EP 246774), 3-chloroperoxybenzoic acid (77%, 1.24 g, 5.5 mmol) in CH2Cl2 (25 mL) was stirred for 16 h. The solution was concentrated, and the residue was purified by flash chromatography on a silica gel column (8:1 EtOAc/MeOH), affording 3-fluoro-5,6-dimethyl-pyridine-1-oxide as a white solid (0.225 g 87%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.CON(C)[C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:18]([C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:28])[CH3:2]
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C#CC(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(=O)c1ccc([N+](=O)[O-])cc1)OCC
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
3,3-Diethoxyprop-1-yne (8.5 ml, 59 mmol) was dissolved in THF (100 ml). The solution was cooled to −70° C., and nBuLi (19 ml of 2.5 M soln in hexanes, 47.5 mmol) was added over 5 min. The solution was warmed to 0° C. for 15 min, then cooled to −70 ° C. again. A solution of N-methoxy-N-methyl-4-nitrobenzamide (Intermediate 8, 8.04 g, 38.1 mmol) in THF (50 ml) was added dropwise over 15 min. The solution was warmed to 0° C. after 15 min, and held there for 45 min. The reaction mixture was poured into 1M HCl, extracted with ethyl acetate and dried over sodium sulfate. Purification by chromatography on silica gel eluting with 30 to 50% dichloromethane: hexane, gave the title compound as a light orange oil which solidified on standing (7.14 g).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:10]=1[N:11]([CH3:14])[CH:12]=O)(=[O:8])[CH3:7].[OH2:20]>ClCCl>[C:6]([O:8][C:7]1[C:6](=[O:8])[C:9]2[C:10](=[C:15]([F:19])[CH:16]=[CH:17][CH:18]=2)[N:11]([CH3:14])[CH:12]=1)(=[O:20])[C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:10]=1
Reactant: CC(=O)c1cccc(F)c1N(C)C=O
Reactant: O
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: Cn1cc(OC(=O)c2ccccc2)c(=O)c2cccc(F)c21
Reaction time: 3.25 h

Procedure:
A solution of sulphuryl chloride (11.9 ml) in dichloromethane (200 ml) was added dropwise to the solution of 2'-acetyl-6'-fluoro-N-methylformanilide at 0° under a nitrogen atmosphere. The reaction mixture was stirred at 0° for 3.25 hours. Water (100 ml) was added dropwise and the mixture stirred for 30 minutes. The dichloromethane layer was separated, washed with water (160 ml) and dried over magnesium sulphate before removing the solvent under reduced pressure at ambient temperature. The residue was added to a mixture of benzoic acid (22.6 g), potassium carbonate (42.5 g), 25 molecular sieves (4A°, 50 g) and dry dimethylformamide (200 ml) and the resultant mixture stirred at ambient temperature for 3 hours and then at 60° for 2 hours. Further dimethylformamide (600 ml) and potassium carbonate (17 g) were added and the mixture was heated at 60° overnight. The mixture was cooled, filtered and the solvent removed from the filtrate under reduced pressure at 60°. The residue was triturated with water (400 ml) and then with diethyl ether (400 ml). The resultant solid was crystallised from industrial methylated spirit (200 ml) to give the novel compound 8-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl benzoate, m.p. 179°-181°.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C1COCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:7]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccnc1F
Reaction time: 4 h
Yield: 94.6 %

Procedure:
A mixture of 2-fluoro-3-iodopyridine (5 g), trimethylsilylacetylene (2.86 g) copper(I) iodide (0.015 g) and bis(triphenylphosphine)palladium dichloride (0.06 g) in a mixture of THF (20 mL) and triethylamine (30 mL) was stirred under argon for 4 hours. The solvents were evaporated and the residue was taken up in water/ethyl acetate. The organic phase was separated, dried and evaporated. Distillation of the residue gave 2-fluoro-3-(trimethylsilylethynyl)pyridine as an oil (4.10 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]1=[S:15]>CC[O-].[Na+]>[N:9]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[S:15][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: S=c1nccc[nH]1
Reactant: Clc1ncc(Br)cn1
Agent: CC[O-]
Agent: [Na+]
Product: Brc1cnc(Sc2ncccn2)nc1
Yield: 35 %

Procedure:
2-Chloro-5-bromopyrimidine (10 mmol) was added to a solution of pyrimidine-2-thione (10 mmol) in ethanolic 0.24 M NaOEt (45 ml), the mixture heated under reflux for 2 hours, the solvent distilled off, the residue extracted with chloroform (70 ml), the chloroform solution shaken with 2 M NaOH and with water, the dried (MgSO4) solution evaporated and the residue repeatedly extracted with pet. ether leaving the title compound. Yield 35%, m.p. 178°-180° C. (iPrOH). 1H NMR (CDCl3): δ7.13 (H-5'), 8.60 (H-4', H-6'), 8.66 (H-4, H-6).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([NH:38][C:16]([C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:18])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(C(=O)NCc3ccccc3)ccc21
Yield: 83.7 %

Procedure:
To a suspension of 9-Ethyl-9H-carbazole-3-carboxylic acid (75 mg, 0.313 mmol) in CH2Cl2 (1 ml) at room temperature was added CDI (56 mg, 0.344 mmol) ) in CH2Cl2 (1 ml), and after stirring for 30 minutes benzylamine (38 μl, 0. 344 mmol) was added. When the reaction was complete the reaction mixture was directly loaded onto a silica column and eluted with CH2Cl2 to afforded the desired product as a white foam (86 mg, 84% yield). MS m/z @ 329 (m+1).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([C:18]4(C(O)=O)[CH2:20][CH2:19]4)[CH:15]=[N:16][CH:17]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:24].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:39][C:18]1([C:14]2[CH:13]=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:24])[CH:4]=[CH:5]4)[CH:17]=[N:16][CH:15]=2)[CH2:20][CH2:19]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CCc2cc(-c3cncc(C4(C(=O)O)CC4)c3)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1c(=O)ccc2cc(-c3cncc(C4(N)CC4)c3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To solution of 1-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)cyclopropanecarboxylic acid (example 59 [C], 0.3 g, 0.931 mmol) in toluene (15 mL) were added TEA (0.141 g, 1.4 mmol) and diphenylphosphoryl azide (0.384 g, 1.4 mmol) and then the reaction mixture was heated to reflux for 4 h. The mixture was concentrated in vacuo, the residue was dissolved in THF (30 mL) and the solution cooled to 0° C. Then, a solution of KOtBu (0.627 g, 5.58 mmol) in THF (13 mL) was added and the mixture was stirred for 1 h at 0° C. and then over night at room temperature. The mixture was concentrated in vacuo, the residue was preadsorbed on silica gel and purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give a yellow amorphous solid (0.104 g). This material was then further purified by reverse phase HPLC on a Gemini-NX column, eluting with a MeOH—H2O (0.05% TEA) gradient to give the title compound (0.02 g, 7%) as a colorless amorphous solid. MS: 292.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[H-].[Na+].I[C:12]1[O:13][CH:14]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:16]=1>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:12]1[O:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[N:16]=1
Reactant: CC1(C)COC(=O)N1
Reactant: N#Cc1ccc(-c2coc(I)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)co1
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 3.7 %

Procedure:
A 5 mL flask was charged with 4,4-dimethyl-oxazolidin-2-one (1.0 g, 8.7 mmol) and sodium hydride (60% wt suspension in mineral oil) (40 mg, 1.2 mmol) was added and the mixture was stirred for 20 min. 4-(2-Iodo-1,3-oxazol-4-yl)benzonitrile (0.257 g, 0.87 mmol), prepared in the previous step, was added and the mixture was heated to 170° C. for 2 h then cooled and diluted with ethyl acetate. The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (15% acetone in hexane) afforded the title compound (9 mg, 4%). HRMS: calcd for C15H13N3O3+H+, 284.10297; found (ESI, [M+H]+), 284.1024; Analytical HPLC: purity 95.3% at 210-370 nm, 8.1 min; 98.3% at 278 nm, 8.1 min; the Xterra® RP18 column, 3.5%, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20]O)=[CH:10][C:9]=2[F:22])=[N:6][CH:7]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH2:20][C:15]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:22])[CH:10]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3CO)cc2F)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(-c3ccccc3CCl)cc2F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A mixture of (4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methanol (1.8 g, 6.1 mmol) and SOCl2 (6 mL) in DCM (20 mL) was stirred at 70° C. for 4 h. The reaction mixture was cooled to rt and concentrated to dryness to give the title compound (1.86 g, 98%). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.66-7.57 (m, 1H), 7.51-7.42 (m, 2H), 7.40-7.30 (m, 3H), 6.89-6.62 (m, 2H), 4.73 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:35])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C@H:21]([OH:34])[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:23]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.[OH-].[Na+].C(O)(=O)C>C(O)C>[OH:34][C@H:21]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[CH:23]=1)[CH2:20][NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[C:4]([OH:35])=[O:3])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)/C=C/c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(/C=C/C(=O)O)cc3)CC2)ccc1O
Reaction time: 18 h
Yield: 94.6 %

Procedure:
A solution of 0.10 g (0.2 mmol) of (E)-3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-phenyl)-acrylic acid ethyl ester (which was obtained in Example 183) in ethanol (3 mL) was treated with 3 mL of 1 N NaOH. After 18 h at room temperature, the mixture was acidified with acetic acid. The resulting suspension was filtered and the precipitate was washed with water, and dried in vacuo to give 0.09 g of a tan solid; m.p. 220° C.; 1H NMR (DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.57-2.95 (m, 5H), 2.92 (t, 3H), 3.74-3.82 (m, 2H), 4.48-4.52 (m, 1H), 6.22 (s, 1H), 6.27 (s, 1H), 6.81-7.03 (m, 4H), 7.18 (d, 1H), 7.42-7.49 (m, 3H)); MS (ES) m/z: 476.0 (MH+).