Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=3)[CH:36]=[CH:37][CH:38]=2)[N:18]=1>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:45]([C:41]1[CH:40]=[C:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:34]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:46])=[O:47]
Reactant: O=S(=O)(Cl)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: OCCNCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1)N(CCO)CCO
Temperature: 0 °C
Yield: 52.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of diethanolamine (0.12 g, 1.14 mmol), triethylamine (0.06 ml, 0.42 mmol) and THF (2 ml) was added drop wise a solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example I.3) (0.21 g, 0.39 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.125 g, 53%). MS (ISP) 611.6 [(M+H)+]; mp 111.5° C.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=O.[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH:4]1([C:2]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[CH2:1])[CH2:6][CH2:5]1
Reactant: CCNCC
Reactant: CC(=O)C1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(C1CC1)N(CC)CC
Reaction time: 5 h
Yield: 38.1 %

Procedure:
A solution of titanium tetrachloride (10.4 g) in n-hexane (30 ml) was added dropwise with stirring to a solution of cyclopropyl methyl ketone (8.4 g) and diethylamine (43.9 g) in n-hexane (100 ml) whilst maintaining the temperature below 25° C. The mixture was stirred for 5 hours, filtered and the filtrate was evaporated to dryness to give 1-cyclopropyl-1-diethylaminoethene (5.3 g) as a pale yellow oil, NMR (CDCl3)d=0.5-0.8(m, 4H), 1.1(t, 6H), 1.4(m, 1H), 3:2(q, 4H), 3.45(s, 1H), 3.5(s, 1 H).
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[I:18][C:9]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:3]2[N:2]([CH3:1])[C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: II
Reactant: CN(C)c1cccnc1C#Cc1ccncc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(-c2ccncc2)c(I)c2ncccc21
Reaction time: 4 h
Yield: 40.7 %

Procedure:
1 g (4.4 mmoles) of Dimethyl-(2-pyridin-4-ylethynyl-pyridin-3-yl)-amine are dissolved in 60 mL of dichloromethane under argon atmosphere. A solution of 2.27 g of iodine (8.9 mmoles) in 35 mL of dichloromethane is added dropwise in the reaction mixture at 0° C. The reaction mixture is allowed to reach room temperature and further stirred for 4 hours. The reaction mixture is then poured into a solution sodium thiosulfate and extracted with dichloromethane. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is purified by chromatography on silica gel (ethylacetate) to give 600 mg of 3-Iodo-1-methyl-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine as brown solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([OH:12])[C@@H:7]1[OH:13])(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16](OC=C)=[O:17]>C(COC)OC>[C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([O:12][C:16](=[O:17])[CH2:15][Cl:14])[C@@H:7]1[OH:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reactant: C=COC(=O)CCl
Solvent: COCCOC
Product: CC(=O)OC[C@H]1OC=C[C@@H](OC(=O)CCl)[C@@H]1O
Yield: 80 %

Procedure:
1.03 g (5.5 mmol) of 6-O-acetylglucal are taken up in about 2-5 ml of dimethoxyethane and 10 ml of vinyl chloroacetate and stirred with 1 g of lipase P (Amano) at room temperature for about 2-3 h. Filtering off the enzyme, concentration of the solution and chromatography on silica gel (ether/hexane 1:2) result in 6-O-acetyl-3-O-chloroacetyl-glucal in 80-85% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:4]1[CH:3]=[C:2]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: NCC(O)CO
Reactant: Clc1cc(N2CCc3ccccc3C2)nc2ccccc12
Product: OCC(O)CNc1cc(N2CCc3ccccc3C2)nc2ccccc12

Procedure:
The title compound, MS: m/e=349 (M+), was prepared from 4-chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and (RS)-3-amino-1,2-propanediol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10](C)=[N:9]1.N[CH2:25][C@@H]1OC(=O)N(C2C=CC(N3C=C(C)N=N3)=C(F)C=2)C1.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][N:11]([CH3:25])[CH:10]=[N:9]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CN)OC3=O)cc2F)nn1
Reactant: Cc1ncn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)n1
Solvent: CO
Solvent: ClCCl
Product: CN1C=NN(c2ccc(N3CC(CN)OC3=O)cc2F)C1

Procedure:
3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-(azidomethyl)oxazolidin-2-one (Intermediate 24) (1.8 g, 5.67 mmol) was hydrogenated as described for Intermediate 16. Chromatography on silica gel with 3-7% methanol in dichloromethane gave the title compound (1.28 g).
Reaction SMILES: C(OC(=O)[N:7]=[C:8]([NH:27]C(OC(C)(C)C)=O)[N:9]([CH3:26])[CH2:10][C:11](=[O:25])[N:12]1[C@H:17]([CH2:18][OH:19])[C@@H:16]([OH:20])[CH:15]([OH:21])[C@H:14]([OH:22])[C@H:13]1[CH2:23][OH:24])(C)(C)C>FC(F)(F)C(O)=O.O>[CH3:26][N:9]([CH2:10][C:11](=[O:25])[N:12]1[C@H:17]([CH2:18][OH:19])[C@@H:16]([OH:20])[CH:15]([OH:21])[C@H:14]([OH:22])[C@H:13]1[CH2:23][OH:24])[C:8]([NH2:27])=[NH:7]
Reactant: CN(CC(=O)N1[C@H](CO)[C@@H](O)C(O)[C@H](O)[C@H]1CO)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)N1[C@H](CO)[C@@H](O)C(O)[C@H](O)[C@H]1CO)C(=N)N

Procedure:
In a dry, round bottomed flask, equipped with a magnetic stirrer, 10.12 g (0.020 mol) of tert-butyl(tert-butoxycarbonylamino)(methyl(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6-bis(hydroxymethyl)piperidin-1-yl)ethyl)amino)methylenecarbamate is dissolved in 150 mL of a trifluoroacetic acid:H2O (1:1) mixture. The resultant mixture is stirred for 2 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash chromatography (ethyl acetate/hexanes; 1/5) to yield the creatine homomannojirimycin amide, 1-methyl-1-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6-bis(hydroxymethyl)piperidin-1-yl)ethyl)guanidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[CH2:31]1[C:39]2[C:34](=[CH:35][C:36](O)=[CH:37][CH:38]=2)[CH2:33][CH2:32]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:31]1[C:39]2[C:34](=[CH:35][C:36]([O:19][C:18]([C@H:15]3[CH2:16][CH2:17][C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:13][CH2:14]3)=[O:20])=[CH:37][CH:38]=2)[CH2:33][CH2:32]1
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)O)CC1)OCc1ccccc1
Reactant: Oc1ccc2c(c1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@@H](C(=O)Oc2ccc3c(c2)CCC3)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
To a stirred, ice-cold solution of the product from part (a) (1.70 g, 6.13 mmole) in dry methylene chloride (30 ml) were added sequentially, 1-hydroxybenzotriazole (0.92 g, 6.77 mmole), 5-indanol (2.0 g, 15 mmole), N-methylmorpholine (0.80 g, 7.92 mmole) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.53 g, 7.98 mmole). After 10 minutes, the resulting solution was concentrated to an oil which was stirred at room temperature for 18 hours and then dissolved in methylene chloride (150 ml). The latter solution was washed in turn with water (2×50 ml), saturated aqueous sodium bicarbonate solution (2×25 ml), 2N hydrochloric acid (2×25 ml) and saturated brine (2×25 ml), then dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent under vacuum, gave an oil which was purified by chromatography on silica gel eluting with hexane-ethyl acetate (4:1). The appropriate fractions were combined and the solvent evaporated under vacuum to furnish the title compound as a white solid (2.20 g, 91%), which was crystallised from a mixture of diethyl ether and n-pentane, m.p. 68°-69° C. Found: C,73.30; H,7.04; N,3.43. C24H27NO4 requires C,73.26; H,6.92; N,3.56%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][CH2:10][NH2:11])[CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([C:17]([NH:11][CH2:10][CH2:9][CH2:8][N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[CH3:1])=[O:18])=[CH:20][CH:21]=1
Reactant: Cc1cn(CCCN)c(C)n1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1cn(CCCNC(=O)c2ccc(Cl)nc2)c(C)n1

Procedure:
When 2,4-dimethyl-1H-imidazole-1-propanamine is treated with a mixture of 6-chloronicotinic acid and 1,1'-carbonyldiimidazole by the procedure of Example 30 the compound of the Example is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[C:15]1([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[CH:21]([NH:28][C:11](=[O:12])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:14])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CC#N
Product: O=C(NC(c1ccccc1)c1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
N-Benzhydryl-2-(1H-indol-3-yl)-2-oxo-acetamide was synthesized following scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and C,C-diphenyl-methylamine. Yield (52%). HPLC ret. time 3.59 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.56 (d, J=9.1 Hz, 1H), 8.56 (d, J=3.2 Hz, 1H), 8.22 (m, 1H), 7.54 (m, 1H), 7.43-7.26 (m, 12H), 6.32 (d, J=9.1 Hz, 1H); ESI-MS 355.5 m/z (MH+).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8]1([C:14]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:22][CH2:21]3)[O:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[ClH:4].[C:8]1([C:14]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([CH2:26][C:27]([Cl:7])=[O:28])[CH2:24][CH2:25]3)[O:16][N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.24 mL) was added dropwise to a 0° C. solution of the compound prepared in Example 58 (615 mg) in dichloromethane (8 mL). The reaction was stirred at room temperature for 30 minutes and then concentrated to obtain the title compound (600 mg) having the following physical data. 1H NMR (DMSO-d6): δ 7.92-7.81 (m, 2H), 7.62-7.48 (m, 3H), 7.38 (s, 1H), 4.59 (s, 2H), 3.50-3.36 (m, 2H), 3.12-2.97 (m, 2H), 2.22-2.09 (m, 2H), 1.99-1.79 (m, 3H), 1.67-1.50 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:15]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:11]=2[N+:12]([O-])=O)[CH2:3][CH2:2]1>CO>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:15]2([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC3CC3)c2)CCCC1
Solvent: CO
Product: CCOC(=O)C1(c2ccc(N)c(OCC3CC3)c2)CCCC1
Reaction time: 6 h
Yield: 82.4 %

Procedure:
To a stirred solution of ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (10 g), in dry MeOH (100 mL) Pd (OH)2 (2 g) was added and the mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered through a pad of Celite™, washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclopentanecarboxylate (7.5 g) as a thick liquid.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:15])([CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][CH3:13])[S:4]1)[OH:2].[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:15])([CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][CH3:13])[S:4]1)=[O:19]
Reactant: CCC(C)=CCC1(C)SC(=NO)N=C1C
Reactant: CN=C=O
Product: CCC(C)=CCC1(C)SC(=NOC(=O)NC)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-(3-methyl-2-pentenyl)-3-thiazoline-oxime was reacted with methylisocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-(3-methyl-2-pentenyl)-3-thiazoline-O-(methylcarbamoyl)-oxime as a viscous oil; nD20 =1.5424.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([CH3:19])[CH3:18])[CH:13]([OH:16])[C:14]#[N:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:17]([CH3:19])[CH3:18])[CH:13]([O:16][C:26](=[O:28])[CH3:27])[C:14]#[N:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(O)C#N
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C#N)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 90.6 %

Procedure:
To a solution containing 3-[(benzyloxycarbonyl)amino]-2-hydroxy-4-methylpentanenitrile (32.0 g, 0.12 mol) and pyridine (59 mL) was added acetic anhydride (73.6 g, 68 mL, 0.72 mol) dropwise at RT. After 3 h the reaction was diluted with ethyl acetate and washed with water. The organic layer was separated, dried (anhydrous magnesium sulfate) and evaporated. The residue was purified by column chromatography (silica gel, 1:1 hexane:ethyl acetate) to give 33.08 g (94.0%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-acetoxy-4-methylpentanenitrile as a viscous yellow oil; TLC Rf =0.70 (silica gel, 1:1 hexane:ethyl acetate).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)(=[O:5])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].S(O[CH2:30][CH2:31][CH2:32][Cl:33])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.O>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:30][CH2:31][CH2:32][Cl:33])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1cccc(OCCCCl)c1
Reaction time: 0.75 h

Procedure:
N-Methyl-3-hydroxybenzene sulfonamide (175 mg, 0.94 mmole) in 15 mL of DMF was treated with Cs2CO3 (305 mg, 0.94 mmole), and stirred for 45 minutes. A solution of 3-Chloro-1-propanol tosylate (223 mg, 0.90 mmole) in 3 mL of DMF was added. The reaction was heated at 55° for 3 hours, and stirred at 23° for 16 hours. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried and the solvent removed. The residue was chromatographed on a silica gel column, and elution with 30% EtOAc in hexane gave the titled product, 75 mg (30%). MS (ESI) 264 (MH+).
Reaction SMILES: [CH3:1]B1OB(C)OB(C)O1.[B:10](OCCCC)([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:1][B:10]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCCCOB(OCCCC)OCCCC
Product: CCCCOB(C)OCCCC
Reaction time: 0.5 h
Yield: 150.4 %

Procedure:
Trimethylboroxin (50 ml of 50 wt % solution in THF, 170 mmol) was placed in a round bottom flask with distillation head and receiver under nitrogen. Tri-n-butyl borate (92 ml, 340 mmol) was added and the mixture stirred 30 min. Methyldi-n-butoxyborane and THF were distilled from the tri-n-butoxyboroxin. The methyldi-n-butoxyborane and THF were separated by further distillation to obtain 44 g of methyldi-n-butoxyborane, 50% yield.
Reaction SMILES: C(O[C:4]([CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)[CH2:7]1)=[O:5])C.[CH2:26]([NH2:28])[CH3:27]>CO>[CH2:26]([NH:28][C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)[CH2:7]1)=[O:5])[CH3:27]
Reactant: CCN
Reactant: CCOC(=O)C1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CCNC(=O)[C@H]1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a stirred solution of 3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester (EXAMPLE 69, within Step 6, 108 mg, 0.31 mmol) in MeOH (1 mL) is added EtNH2 (2 mL, 4.0 mmol, 2.0 M solution in THF). The reaction mixture is stirred for 1 h at room temperature. Solvent is removed and the residue purified by column chromatography (10% MeOH/CH2Cl2) to give the title compound as a pale yellow solid (100 mg, 93%), 1H NMR (300 MHz, DMSO) δ 8.46 (t, 1H), 7.65-7.38 (m, 4H), 5.05 (dd, 1H), 4.99 (d, 1H), 4.27 (t, 1H), 4.01 (dd, 1H), 3.87 (t, 2H), 3.20-3.10 (m, 2H), 1.04 (t, 3H); MS for C17H18FN3O4 m/z 348.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1B(O)O.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16](Cl)[N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reactant: COc1ccc(C)cc1B(O)O
Product: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(Cl)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1 Step B, by reaction of 2-methoxy-5-methylphenylboronic acid with 2,6-dichloro-4-nitropyridine: LCMS m/z 279.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=8.5 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5, 2.1 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 3.72 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[C:19]1([O:18][C:16](=[O:17])[NH:1][C:2]2[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cnc(N)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)Oc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
2-Amino-5-methylpyrazine (5.16 g, 47 mmol) was dissolved in CH2Cl2 (52 mL), stirred and cooled to 0° C. under N2. To this, pyridine (4.8 mL, 59 mmol) was added followed by phenyl chloroformate (6.2 mL, 59 mmol), dropwise, over 15 min, causing a precipitate to form. The mixture was stirred at 0° C. for 1 h. Then the reaction was quenched with 0.25 M HCl (40 mL) and anhydrous ether (50 mL), and stirred at 0° C., for 30 min. The precipitate was isolated by filtration, washed with DI H2O (20 mL) and ether (2×25 mL), and dried under vacuum to give the product (7.4 g) as a white fluffy powder.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=[CH:18][C:9]=1[N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:22][CH:23]=3)=[O:34])[CH2:6][CH:5]2[CH2:1]1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=C(c1ccccc1-c1ccc(C(F)(F)F)cc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 4′-trifluoromethyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C28H23F3N4O, 488.50; m/z found 489.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:7]=2[NH:6][C:5]1=[O:23].[CH3:24]I>O1CCCC1>[F:3][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:7]=2[N:6]([CH3:24])[C:5]1=[O:23]
Reactant: CI
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(F)N=C(c2ccccc2F)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A slurry of 0.17 g (0.007 mole) of sodium hydride in 10 ml of tetrahydrofuran was added to a solution of 1.8 g (0.005 mole) of 3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 10 ml methyl iodide in 100 ml tetrahydrofuran. The reaction mixture was stirred for 3 hr at 25° and then poured into 300 ml ice water. The aqueous mixture was extracted with methylene chloride, and the extracts were dried (MgSO4) and then evaporated to dryness under reduced pressure. The residue was recrystallized from heptane to give 0.91 g (50%) of cream-colored crystals: mp 127°-130° (with previous softening); 1H nmr (CDCl3) δ 3.49 ppm (s, 3H), 5.62 ppm (d, J = 57 Hz, 1H) and 6.9-7.9 ppm (m, 7H); 19F nmr (CDCl3) δ -111.9 ppm (m, 1F) and -162.4 ppm (d, J = 57 Hz, 1F).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]#[N:10])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N#CCc1ccccc1Br
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: [Na+]
Solvent: Cc1ccccc1
Product: N#CCc1ccccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
2-(2-bromophenyl)acetonitrile (5.00 g, 25.5 mmol), 4-chlorophenylboronic acid (4.30 g, 27.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.48 g 0.42 mmol) were mixed with toluene (57 ml) in a 250 ml 3-necked flask. A reflux condenser was attached and the flask was purged with nitrogen. Aqueous solution of Na2CO3 (2M, 29 ml, 58 mmol) was added by syringe, and the atmosphere was evacuated and replaced with nitrogen. The reaction mixture was heated at reflux overnight, and then allowed to cool at ambient temperature. The mixture was partitioned between saturated aq. NH4Cl and EtOAc (200 ml each). The organic phase was separated, dried (MgSO4), filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (ISCO, 120 g silica gel column, 0→20% EtOAc/hexanes) to give the tile compound (5.44 g, yield: 94%).