Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=[C:4]([NH:18][CH2:19][CH2:20][OH:21])[N:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:31][CH2:32][N:33]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:5]=[C:4]([NH:18][CH2:19][CH2:20][OH:21])[N:3]=3)[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCc1cccnc1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCc2cccnc2)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2-(2-hydroxy-ethyl-amino)-6-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile was treated with 4-(4-fluorophenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at 80° C. to yield the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethyl-amino)-6-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=448.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:27](OC)=[O:28]>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)=[CH:12][C:11]=1[CH2:27][OH:28]
Reactant: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Br
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Br
Temperature: -10 °C

Procedure:
A solution of lithium triethylborohydride (1.0M THF, 10.6 mL) was added dropwise to a THF solution (12 mL) of the intermediate from Step B (2.0 g, 5.33 mmol) cooled in an acetone/ice bath (−10° C.). The solution was stirred at −10° C. until no starting material remained by HPLC (approximately 3 hours). The reaction was quenched with methanol (ca. 10 mL) and concentrated. The residue was partitioned between water and ethyl acetate. The organic phase was washed with water (2×), brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.71 (d, J=2.0 Hz, 1H); 7.64-7.60 (m, 3H); 7.37 (dd, J=2.3, 8.2 Hz, 1H); 7.28-7.33 (m, 2H); 4.84 (s, 2H); 2.09 (s, 1H). LCMS1 3.77 min. (M−H2O)=329
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>O.[Ru](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:12][C@@H:11]([CH2:13][OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Agent: O=[Ru]=O
Solvent: O
Product: OC[C@H]1CC[C@@H](c2ccc(Cl)cc2)O1

Procedure:
The requisite [cis-5-(4-chlorophenyl)tetrahydrofuran-2-yl]methanol was prepared by hydrogenation of 5-(4-chlorophenyl)furan-2-carbaldehyde in the presence of ruthenium(IV) oxide hydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.COCCOCCOC>O1CCOCC1.[Cu]I.O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1cccnc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(COc2ccc(Oc3cccnc3)cc2)cc1
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
To a solution of p-benzyloxyphenol (550 mg, 2.754 mmol), Cs2CO3 (1.795 g, 5.509 mmol), 3-iodo pyridine (850 mg, 4.14 mmol) in anhydrous dioxane (15 ml) under N2 was added diglyme (38.42 mg, 0.275 mmol). After stirring for 10 min, CuI (19.38 mg, 0.102 mmol) was added and the reaction mixture was kept in a shaker at 85° C. overnight. The mixture was poured into EtOAc and water, the organic layer was dried over Na2SO4, and concentrated. Silica gel flash chromatography using EtOAc/Hexane gave the title compound (200 mg, 17%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:50][C:51]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=4)=[O:52])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][NH:27][C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([CH2:50][C:51]([O:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=3)=[O:52])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
8.0 ml of trifluoroacetic acid and 160 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a suspension of 1120 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(4-nitrobenzyloxycarbonylmethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 11) in 1.75 ml of anisole, and the resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, it was treated by a similar procedure to that described in Example 13(1), to give 1.58 g of the title compound as a powder.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C@@H:7]([CH3:11])[C:8](Cl)=[O:9].O.ClCCl>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:8](=[O:9])[C@@H:7]([Cl:6])[CH3:11])[CH3:2]
Reactant: C[C@H](Cl)C(=O)Cl
Reactant: CCNCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)[C@H](C)Cl
Temperature: 0 °C

Procedure:
Diethylamine (480 cc) is added to a solution of (S)-2-chloropropionyl chloride (175.2 g) in chloroform (900 cc), which is maintained at 0° C., in the course of 1 hour. Distilled water (400 cc) and dichloromethane (300 cc) are added to the reaction mixture. The organic phase is decanted and then washed with an aqueous 2N hydrochloric acid solution (300 cc) and then with distilled water (400 cc). The organic phase is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30° C. The residue obtained is distilled under reduced pressure (17 Pa). (S)-N,N-Diethyl-2-chloropropionamide (161.9 g) in the form of a colourless oil [b.p.17Pa =83°-85° C.; [α]D20 =+39.7°(c=10.4 ; CHCl3)] is thereby obtained.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:4]=2[O:3]1.ClC(OCC(C)C)=O.[BH4-].[Na+].Cl>C(N(CC)CC)C.O1CCCC1>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)O2
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OC(F)(F)O2
Reaction time: 1 h

Procedure:
Into 50 mL of tetrahydrofuran, 962 mg of 2,2-difluorobenzo[1,3]dioxol-5-carboxylic acid was suspended, 0.8 mL of triethylamine was added to the suspension, and after cooling with ice, thereto was added 0.75 mL of isobutyl chloroformate. The mixture was stirred for 1 hour, and then 662 mg of sodium borohydride was added thereto, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1 mol/L hydrochloric acid, the solvent was removed under reduced pressure, and ethyl acetate was added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 942 mg of a colorless oily substance, (2,2-difluorobenzo[1,3]dioxol-5-yl)methanol.
Reaction SMILES: [CH:1]1([N:4]([CH3:29])[C:5]2[C:6]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[CH:1]1([N:4]([CH3:29])[C:5]2[C:6]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C3CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C3CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of methyl 3-[cyclopropyl(methyl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate (74.7 mg, 0.19 mmol) in methanol (30 ml) was added NaOH (32 mg, 0.80 mmol), water (1 ml) with stirring overnight at room temperature. The resulting solution was extracted ethyl acetate (2×50 ml), and adjusted pH to 5 with AcOH. The resulting solution was extracted with ethyl acetate (3×30 ml), dried over anhydrous sodium sulfate, concentrated under vacuum to give a residue, which was purified via silica gel chromatography (20% methanol in ethyl acetate) to afford 3-[cyclopropyl(methyl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (13.6 mg, 19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@@H:4]([NH:8][C:9](=[O:37])[C@@H:10]([NH:14][C:15](=[O:36])[C@@H:16]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25]C=C)=[CH:20][CH:19]=1)[CH:11]([CH3:13])[CH3:12])[CH2:5][CH:6]=[CH2:7].CCOC(C)=O>ClC(Cl)CCl>[CH3:1][O:2][C:3]([C@H:4]1[NH:8][C:9](=[O:37])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH:14][C:15](=[O:36])[C@@H:16]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:17][C:18]2=[CH:23][CH:22]=[C:21]([CH:20]=[CH:19]2)[O:24][CH2:25][CH:7]=[CH:6][CH2:5]1)=[O:38]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC=C)C(=O)OC)C(C)C)cc1
Agent: COC(=O)[C@@H]1C/C=C/COc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1
Solvent: CCOC(C)=O
Solvent: ClCC(Cl)Cl
Product: COC(=O)[C@@H]1CC=CCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1

Procedure:
Diene 44 (1.80 g, 3.39 mmol) was dissolved in anhydrous 1,1,2-trichloroethane (0.01M) under an atmosphere of argon. GSGC (0.10 equiv) was added. The mixture was heated at reflux for one hour. Two further additions of GSGC (0.10 equiv) were added and after each the reaction mixture was subjected to one h and eighteen h of reflux respectively. This was then cooled and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a brown solid, 0.205 g, 12%. Rf=0.24 (1/1 EtOAc/(50/70) petroleum ether). m.p. 105-107° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[C:14]([C:15]3[O:16][C:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)=[CH:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]1([C:18]2[N:19]=[C:15]([C:14]3[CH:9]([CH2:8][C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=4)[O:1][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:10][CH2:11][CH2:12][CH:13]=3)[O:16][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
A suspension of 2-[6-[(3-hydroxyphenyl)methyl]-1-cyclohexen-1-yl]-4,5-diphenyloxazole (885 mg), ethyl bromoacetate (399 mg), and potassium carbonate (360 mg) in N,N-dimethylformamide was stirred at room temperature for 3 days and partitioned between ethyl acetate and water. The organic layer was separated, washed with water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (n-hexane--ethyl acetate (20:1)) to afford ethyl [3-[[2-(4,5-diphenyl-2-oxazolyl)-2-cyclohexen-1-yl]methyl]phenoxy]acetate (847 mg) as a solid.
Reaction SMILES: [CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][O:15][P:16]([O:19][P:20]([OH:23])([OH:22])=[O:21])([OH:18])=[O:17])[C@@H:11]([OH:24])[C@H:10]2[OH:25])[CH:2]=1.[OH:26][CH:27]1[O:34][C@H:33]([CH2:35]ON=[N+]=[N-])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:28]1[NH:40][C:41]([CH3:43])=[O:42]>CO.O.[Pd]>[CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][O:15][P:16]([O:19][P:20]([OH:22])([OH:23])=[O:21])([OH:18])=[O:17])[C@@H:11]([OH:24])[C@H:10]2[OH:25])[CH:2]=1.[OH:26][CH:27]1[O:34][C@H:33]([CH2:35][NH2:3])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:28]1[NH:40][C:41]([CH3:43])=[O:42]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CON=[N+]=[N-])[C@@H](O)[C@@H]1O
Agent: [Pd]
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: O
Solvent: CO
Product: CC(=O)N[C@H]1C(O)O[C@H](CN)[C@@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
UDP-GlcNAc6N3 (T5b-12 or F5-9) (100 mg, 0.16 mmol) was dissolved in MeOH—H2O (10 mL, 1:1, v/v) and 20 mg of Pd/C was added. The mixture was shaken under H2 gas (4 Bar) for 1 hr, filtered, and concentrated. The residue was purified by flash column chromatography (EtOAc:MeOH:H2O=3:2:1, by volume) to afford UDP-GlcNAc6NH2 F5-10 in 96% yield (93 mg). 1H NMR (600 MHz, D2O) δ 7.90 (d, J=8.4 Hz, 1H), 5.89-5.93 (m, 2H), 5.48 (dd, J=6.6, 3.0 Hz, 1H), 4.30-4.32 (m, 2H), 4.20-4.23 (m, 2H), 4.08-4.15 (m, 2H), 3.99 (d, J=10.8 Hz, 1H), 3.77 (t, J=9.6 Hz, 1H), 3.45 (d, J=13.2 Hz, 1H), 3.40 (t, J=9.6 Hz, 1H), 3.11 (t, J=12.6 Hz, 1H), 2.02 (s, 3H). 13C NMR (150 MHz, D2O) δ 174.94, 166.39, 151.96, 141.84, 102.79, 94.33, 88.82, 83.29 (J=9.0 Hz), 73.92, 71.82, 69.80, 69.28, 65.30, 53.64 (J=8.9 Hz), 40.70, 22.21. HRMS (ESI) m/z calcd for C17H28N4O16P2 (M+H)− 607.1054, found 607.1068.
Reaction SMILES: C(O)(=O)[C@H](C1C=CC=CC=1)O.[NH2:12][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[CH2:15][C@H:14]1[OH:25].[OH-].[Na+].[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[N+:22]([C:19]1[CH:20]=[C:21]2[C:16]([CH2:15][CH:14]([OH:25])[C@@H:13]2[NH:12][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:29][CH:30]=2)=[O:35])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2CC1O)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
Add 1(R)-amino-2(R)-hydroxy-6-nitroindane (S)-mandelate (0.64 kg, 1.85 mol) to a mixture of toluene (9.6 L) and aqueous 1 N NaOH (4.8 L, 4.8 mol, 2.6 equiv). After 1 h, add 4-biphenylcarbonyl chloride (0.44 kg, 2.0 mol, 1.1 equiv) in portions over 20-30 min. After 22 hours, filter the solids under vacuum and rinse sequentially with 0.5 L of toluene, 2 L of water, and 2 L of toluene. Dry the cake to afford 0.74 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2-hydroxyindan-1-yl)amide. Add 38.2 L of ethyl acetate to 1.914 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide prepared in a similar manner. Stir the slurry for 18 h, collect the solid by filtration, dry to afford 1.76 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH3:15])[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.O>O1CCCC1>[CH2:16]([C:9]1([CH3:15])[C:8]2[C:12](=[CH:13][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[NH:11][C:10]1=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C2(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC1(Cc2ccccc2)C(=O)Nc2cc(C(=O)O)ccc21

Procedure:
In a manner similar to that of Example 1C, by reacting 3-Benzyl-3-methyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (1.06 mmol) obtained in Example 19(B), sodium hydroxide (260 mg, 6.5 mmol), ethanol (10 ml) and water (1 ml) in tetrahydrofuran (10 ml), expected derivative was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]([Cl:23])=[O:20])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3ccc(C(=O)O)cc3s2)cn1
Reactant: O=S(Cl)Cl
Product: COc1ccc(-c2nc3ccc(C(=O)Cl)cc3s2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6-Methoxypyridin-3-yl)-1,3-benzothiazole-6-carboxylic acid (40 mg, 0.14 mmol) was mixed with thionyl chloride (1 mL) and stirred at r.t. for 3 h, then heated to 50° C. for 1 h. The solvent was evaporated in vacuo to give the intermediate, 2-(6-methoxypyridin-3-yl)-1,3-benzothiazole-6-carbonyl chloride as a crude product. This acid chloride was dissolved in DCM (3 mL) and added to pyrrolidine (0.5 mL) in CH2Cl2 (1.5 mL). The reaction was stirred at r.t. for 1 h. Water was added and the reaction mixture was extracted, twice, with DCM, dried (MgSO4), filtered and the solvent was evaporated. The solid was dried (in vacuo over P2O5) to give the title compound (45 mg) as an off-white solid. 1H NMR. δ 8.92 (d, 1 H) 8.39 (dd, 1 H) 8.35 (s, 1 H) 8.07 (d, 1 H) 7.67 (d, 1 H) 7.04 (d, 1 H) 3.97 (s, 3 H) 3.51 (t, 2 H) 3.45 (t, 2 H) 1.78-1.95 (m, 4 H); MS m/z (M+H) 340.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([O:20][CH3:21])[C:15]([N+:17]([O-])=O)=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].CO>[Pd]>[F:5][CH2:4][CH:3]([N:6]1[CH2:7][CH2:8][C:9]2[CH:16]=[C:15]([NH2:17])[C:14]([O:20][CH3:21])=[CH:13][C:10]=2[CH2:11][CH2:12]1)[CH2:2][F:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(C(CF)CF)CC2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Reaction time: 1 h
Yield: 100 %

Procedure:
3-(2-Fluoro-1-fluoromethyl-ethyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (670 mg, 2.23 mmol) was dissolved in methanol (40.0 mL, 987 mmol) and 10% Palladium on Carbon (50% Wet) (5:45:50, Palladium:carbon black:Water, 240 mg) was added. The reaction was hydrogenated at 35 psi. for 1 hour. The reaction was filtered through Celite and concentrated under reduced pressure to obtain 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine as a green oil (603 mg, 100%). LCMS (m/e) 271 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 6.58 (s, 1H), 6.51 (s, 1H), 4.75-4.66 (m, 2H), 4.64-4.54 (m, 2H), 3.84 (s, 3H), 3.67 (bs, 2H), 3.27-3.09 (m, 1H), 2.90-2.75 (m, 8H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.1 %

Procedure:
m-Nitroacetophenone (20 g) was dissolved in acetic acid (150 mL) under argon. Pyridinium tribromide (38.7 g) was added at once; the reaction was allowed to stir at room temperature for 1 hour and then quenched with water (250 mL). The product was filtered and air dried to give the title compound (25 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccccc1-c1ccc(N)cc1
Temperature: 25 °C
Yield: 107.6 %

Procedure:
A mixture of 52.4 g of 2-methoxy-4′-nitrobiphenyl and 76 g of ammonium formate in 640 mL of methanol was treated with 6.4 g of 10% Pd/C at 0° C. The reaction mixture was allowed to stir at the same temperature for half an hour. The reaction was then warmed to room temperature and the mixture was allowed to stir overnight. The reaction mixture was filtered through diatomaceous earth and the residue was rinsed with methanol. The methanol was evaporated in vacuo and the remaining mixture was dissolved in EtOAc and washed with water several times. The organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and yielded 49 g of 2-methoxy-4′-aminobiphenyl as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].Cl.Cl.[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][NH:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CC2CNC1CN2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)cc21
Yield: 43.4 %

Procedure:
A solution of 0.52 g (2.0 mmole) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.37 g (2.0 mmole) of 2,5-diazabicyclo(2.2.2)octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 0.90 ml (6.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 25 ml of acetonitrile was heated under reflux for 21 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from ethanol to give 0.30 g of the title compound, mp 270°-272°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1COCC1.O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of (6-methylpyridin-3-yl)methanol (1.08 g) in THF (15.0 mL) was added thionyl chloride (1.57 g) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and ethyl acetate, saturated aqueous sodium bicarbonate was added thereto, and the mixture was partitioned. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.81 g).