Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:53]([OH:55])=[O:54])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:61](=O)(O)[O-].[Na+]>CO>[CH3:61][O:54][C:53]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:51])([F:50])[F:52])=[CH:43][CH:42]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:55]
Reactant: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 18a (0.74 g, 0.95 mmol) in methanol (40 mL) was added concentrated sulphuric acid (0.75 mL, 13.8 mmol) at 0° C. The mixture was warmed up to room temperature and stirred for 12 hours, and then adjusted with saturated aqueous sodium bicarbonate to pH 8 and concentrated in vacuo to remove most of the solvent. To the residue was added water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (80 mL), dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated in vacuo to give the title compound 18b as orange-yellow oil (0.6 g, 81.1%). This material was not further purified. The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ(ppm): 7.45 (d, 1H), 7.41-7.35 (m, 2H), 7.34-7.27 (m, 6H), 7.24 (m, 4H), 7.20 (t, 1H), 7.15 (t, 2H), 7.08 (d, 2H), 6.85 (d, 2H), 6.76 (d, 2H), 4.82 (m, 2H), 4.77 (d, 1H), 4.61 (d, 1H), 4.51 (d, 1H), 4.25 (m, 3H), 4.17 (t, 2H), 4.07 (d, 1H), 3.99 (m, 2H), 3.84 (d, 1H), 3.72 (d, 1H), 3.69 (s, 3H).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].Cl[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C>ClCCl>[CH:10]([O:9][C:7](=[O:8])[NH:5][CH2:4][CH2:3][Br:2])([CH3:12])[CH3:11]
Reactant: CC(C)OC(=O)Cl
Reactant: NCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)NCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of bromoethylamine hydrobromide (5.0 g, 24.4 mmol), isopropyl chloroformate (1.0 M in tetrahydrofuran, 16.3 ml, 16.3 mmol), and anhydrous dichloromethane (100 ml) was treated with triethylamine (4.5 ml, 33 mmol) and stirred at ambient temperature for 18 hr. The mixture was diluted with dichloromethane (200 ml), washed with 1 M hydrochloric acid, 1 M sodium hydroxide, and brine, dried over sodium sulfate and evaporated to give (2-bromo-ethyl)-carbamic acid isopropyl ester clear oil. 1H-NMR δ(CDCl3) 5.01 (1H, br s), 4.92 (m, 1 H), 3.58 (m, 2 H), 3.48 (m, 2 H), 1.25 (m, 6 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:24]=1[CH2:25]Br.C(Cl)Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH2:25][C:24]1[CH:27]=[C:28]([Br:31])[CH:29]=[CH:30][C:23]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)CCNC(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)cc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CCNC(=O)OC(C)(C)C)COCc1cc(Br)ccc1F
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A stirred solution of 4-(t-butoxycarbonylamino)-2,2-dimethylbutan-1-ol (1.5 g, 6.90 mmol) in tetrahydrofuran (49 ml) at −45° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 7.59 ml, 7.59 mmol). The anion was stirred for 30 minutes at −45° C., then cooled to −78° C. and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.85 g, 6.90 mmol). The resulting yellow mixture was slowly warmed to ambient temperature and stirred for about 18 hours. The cloudy reaction mixture was diluted wtih methylene chloride and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.45 grams (52%) of the title intermediate as a colorless oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.OC1C=C(C=CC=1)CO.[OH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].C1C(C#N)=CN=C(Cl)C=1>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[CH:3][CH:4]=1)=[O:7]
Reactant: N#Cc1cccc(O)c1
Reactant: O=Cc1ccc(F)cc1
Agent: N#Cc1ccc(Cl)nc1
Agent: OCc1cccc(O)c1
Product: N#Cc1cccc(Oc2ccc(C=O)cc2)c1

Procedure:
The title compound is prepared essentially as described in Preparation 1 substituting 4-fluorobenzaldehyde (0.85 mL, 8.06 mmol) for 3-hydroxybenzyl alcohol and 3-hydroxybenzonitrile (1.06 g, 8.86 mmol) for 6-chloronicotinitrile. Yield (0.90 g, 50%); 1H NMR (CDCl3) 10.01 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.58-7.52 (m, 2H), 7.39-7.34 (m, 2H), 7.14 (d, J=8.5 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:46][C:47]1[C:55]2[CH2:54][CH2:53][CH2:52][CH2:51][C:50]=2[N:49]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:48]=1>CN(C=O)C.C1COCC1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH:3]1[CH2:46][C:47]1[C:55]2[CH2:54][CH2:53][CH2:52][CH2:51][C:50]=2[N:49]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:48]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: BrCc1nn(Cc2ccccc2)c2c1CCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4c3CCCC4)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
To a stirring solution of 164 mg (0.36 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of DMF at 0° C. is added 0.430 mL (0.78 mmol, 1.2 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and a solution of 120 mg (0.39 mmol, 1.1 equiv.) of 3-Bromomethyl-4,5,6,7-tetrahydro-1-benzyl-1H-indazole in 2 mL of DMF is added. The resulting solution is stirred for 3 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 175 mg of the title compound as a white solid: mp 173°-176° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-6.84 (m, 18H), 5.02 (s, 2H), 4.99 (m, 1H), 4.22 (s, br, 2H), 4.10 (dd, 1H, J=5.3, 8.7), 3.823 (s, 3H), 3.36 (dd, 1H, J=8.6, 15.6), 3.09 (dd, 1H, J=5.3, 15.6), 2.54-2.38 (m, 4H), 1.67 (m, 4H), 1.04 (d, 6H, J=6.6); low resolution MS (FAB)m/e 682 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][Si](C(C)(C)C)(C)C)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(OB(OC(C)C)OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[Cl:39][C:40]1[N:45]=[C:44](Cl)[C:43]([CH3:47])=[CH:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.ClCCl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:39][C:40]1[N:45]=[C:44]([C:5]2[S:1][C:2]3[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=3[CH:4]=2)[C:43]([CH3:47])=[CH:42][N:41]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2sccc12
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCc1ccccc1
Product: Cc1cnc(Cl)nc1-c1cc2c(O)cccc2s1
Temperature: -70 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
To a −65° C. solution of (benzo[b]thiophen-4-yloxy)(tert-butyl)dimethylsilane (6.25 g, 23.6 mmol) and triisopropylborate (4.89 g, 26.0 mmol) in THF (60 mL) is added lithium diisopropylamide (13.0 mL of a 2 M solution in heptane/THF/ethylbenzene, 26.0 mmol) dropwise over 5 minutes. The mixture is stirred for 2 hours at −70° C., whereupon the cold bath is removed and the mixture is allowed to warm to room temperature. After 2 hours, to the mixture is then added 2,4-dichloro-5-methylpyrimidine (3.85 g, 23.6 mmol), 2M Na2CO3 (23.6 mL, 47.2 mmol), 1,1′-bis(diphenylphosphino) ferrocene (655 mg, 1.18 mmol) and palladium(II) acetate (265 mg, 1.18 mmol) and the mixture is heated to reflux for 18 hours. Upon cooling to room temperature, the mixture is concentrated under reduced pressure, extracted from water (100 mL) with dichloromethane (3×150 mL) and the organic extracts are concentrated under reduced pressure. The crude material is subjected to chromatography on silica gel, eluting with dichloromethane in hexanes 50-100%, followed by CHCl3 in MeOH 0-100%, to obtain a dark solid. The crude material is extracted from 1 N NaOH (125 mL) with dichloromethane (3×100 mL). The aqueous layer is acidified with 5 N HCl, exhaustively extracted with 10% CHCl3/MeOH followed by 1:1 THF/dichloromethane and concentrated to yield a dark solid. Sonication of the solid in dichloromethane and filtration yielded the title compound as a brown solid (1.10 g, 12% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[O:43]1[C:47]2([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:46][NH:45][C:44]1=[O:53].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:50]1[CH2:49][CH2:48][C:47]2([O:43][C:44](=[O:53])[NH:45][CH2:46]2)[CH2:52][CH2:51]1)=[O:25]
Reactant: O=C1NCC2(CCNCC2)O1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C1NCC2(CCN(C(=O)CCC(Nc3ncnc4cc(C(=O)N5CCCC5)c(Cl)cc34)c3nc4cc(Cl)ccc4[nH]3)CC2)O1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 1-oxa-3,8-diaza-spiro[4.5]decan-2-one with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[P:22](=O)(O)(O)[OH:23]>>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:22]([O:9]3)([O:4]1)=[O:23])(=[O:13])[O:1]2)=[O:8]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [F-]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3

Procedure:
continuously introducing into a pre-reactor (i) phosphate rock containing 66-75% tricalcium phosphate comminuted to a size such that 90% passes a 100-mesh screen and 70-80% passes a 200-mesh screen, (ii) phosphoric acid containing 38-54% P2O5 in an amount sufficient to provide a ratio of P2O5 to CaO in the reaction mixture of 0.7 to 1.0, and (iii) water in an amount sufficient to dilute the phosphoric acid to 38-44% P2O5,
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[CH:13]=[CH:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([OH:10])=[O:9])=[CH:19][C:14]=2[CH:13]=[CH:12]1
Reactant: O=Cc1ccc2occc2c1
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1NCc1ccc2occc2c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 1-benzofuran-5-carbaldehyde (Maybridge). 13C-NMR (DMSO-d6) δ 169.9, 153.5, 150.6, 146.3, 134.3, 133.9, 131.6, 127.3, 123.6, 119.5, 114.4, 111.6, 111.2, 110.2, 106.6, 45.8.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.CN[C@H]1CCCC[C@@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]([N:13]2[N:14]=[CH:15][CH:16]=[N:12]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: c1c[nH]nn1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Temperature: 120 °C
Yield: 79.4 %

Procedure:
A mixture of 2-bromo-5-methylbenzoic acid (2.0 g, 9.30 mmol), 1,2,3-triazole (1.08 mL, 18.6 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (2.23 mL, 13.95 mmol), Cs2CO3 (4.55 g, 13.95 mmol) and CuI (124 mg, 0.65 mmol) in DMF (12 mL) was degassed and heated at 120° C. for 1 h in a microwave reactor. The reaction was cooled to rt, diluted with MeOH, and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% DCM/EtOAc) to yield the title compound as a yellow oil (1.5 g, 61%). MS (ESI) 204 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[I:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1>>[I:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(F)c(I)c1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(Nc2ccc([N+](=O)[O-])cc2I)CC1
Yield: 64 %

Procedure:
The desired compound was prepared according to the procedure of Example D83, step A, using 1-fluoro-2-iodo-4-nitrobenzene and benzyl 4-aminopiperidine-1-carboxylate as the starting materials in 64% yield. LCMS for C19H211N3O4 (M+H)+: m/z=482.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30](=[O:35])[NH:31][CH:32]([CH3:34])[CH3:33]>>[F:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)[CH:27]=[CH:28][C:29]=1[C:30](=[O:35])[NH:31][CH:32]([CH3:33])[CH3:34]
Reactant: CC(C)NC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CC(C)NC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cc1F
Yield: 17.8 %

Procedure:
Following the General Procedure-3, the titled compound (45 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 3-fluoro-4-(isopropylcarbamoyl)phenylboronic acid (120 mg, 0.54 mmol) as a grey solid. M.P.: 147-150° C. MS (m/z): 468.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:25]2[C@H:29]([CH2:30][OH:31])[CH2:28][O:27][C:26]2=[O:32])[CH:6]=[CH:7][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])#[N:2].[CH3:33]I>>[C:1]([C:3]1[CH:4]=[C:5]([N:25]2[C@H:29]([CH2:30][O:31][CH3:33])[CH2:28][O:27][C:26]2=[O:32])[CH:6]=[CH:7][C:8]=1[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])#[N:2]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3C#N)CC2)c(C)c1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(C#N)c1
Yield: 63.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{3-cyano-4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (566 mg) described in Example 349 and methyl iodide (221 mg), the title compound (371 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(Oc2ccc(N)cn2)cc1

Procedure:
Intermediate B-32 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and methyl 4-hydroxybenzoate as starting materials. MS (M+1): 245.
Reaction SMILES: C1(C(=[N:14][CH:15]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCOCC1>[NH2:14][CH:15]([C:21]1[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cnn(C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(N)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.7 %

Procedure:
To a solution of 228 mg of ethyl [(diphenylmethylene)amino](1-methyl-1H-pyrazol-4-yl)acetate in 2.8 ml of 1,4-dioxane was added 1.9 ml of 1 M hydrochloric acid, followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was washed with diethyl ether, and to the aqueous layer was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure to obtain 91 mg of ethyl amino(1-methyl-1H-pyrazol-4-yl)acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:7]1[N:8]([CH3:17])[C:9]3[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[C:14]=3[C:6]=1[CH2:5]2.[Li]CCCC.[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:7]1[N:8]([CH3:17])[C:9]3[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[C:14]=3[C:6]=1[CH:5]2[Si:27]([CH3:29])([CH3:28])[CH3:26]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(C)c2c3c(n(C)c2c1)-c1ccc(F)cc1C3
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(C)c2c3c(n(C)c2c1)-c1ccc(F)cc1C3[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A round bottom flask containing 48b (1.11g, 4.17 mmol) in dry ether (27 mL) was immersed in a 25° C. water bath. n-BuLi (1.5 M in THF, 3.33 mL, 5.00 mmol) was added via syringe pump over one hour, generating a brown solution. Following addition of base, the reaction mixture was stirred at 25° C. for an additional 30 minutes and then cooled to −78° C. TMSCl (1.11 mL, 8.76 mmol) was added rapidly via syringe and the solution was subsequently warmed to room temperature. The reaction was diluted with ether, filtered, and concentrated in vacuo. Crude product was purified by flash column chromatography (20:1 hexanes-ethyl acetate followed by a second column 40:1 to 26:1 hexanes-ethyl acetate) to yield 49b as an orange solid in 78% yield (1.09 g, 3.24 mmol). 1H NMR (400 MHz, CDCl3): δ 7.57-7.60 (dd, 1H, J=8.4, 5.2 Hz), 7.19-7.22 (dd, 1H, J=9.6, 2.4 Hz), 7.00-7.04 (m, 2H), 6.78 (s, 1H), 4.01 (s, 3H), 3.97 (s, 1H), 2.61 (s, 3H), 2.49 (s, 3H), −0.15 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 159.7 (d, J=289.5 117.2 (d, J=10.5 Hz), 111.7 (d, J=27.9 Hz), 111.6 (d, J=29.7 Hz), 107.0, 38.2, 31.0, 21.8, 20.1, −2.2; 19F NMR (CD3CD, 376 MHz): δ −118.6 (m) FTIR: cm−1 2952, 1583, 1445, 1357, 1248, 1198, 1037, 838. EI-HRMS: Calcd. for C21H24FNSi+ [M]+: 337.1662, found 337.1664.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH2Cl2(50 mL) at −78° C. was added m-CPBA (77%)(1.25 g, 7.23 mmol) portionwise. The mixture was allowed to slowly warm to RT (3 hrs). The reaction mixture was diluted with CH2Cl2 then neutralized with NaHCO3(sat.). The aqueous phase was extracted three times with CH2Cl2 then the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-10% CH2Cl2:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline (1.37 g, 94% yield) as a off-white foam. MH+=284.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[CH2:24][OH:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[CH2:24][OH:25])=[CH:13][CH:14]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(CO)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(Nc2ccc(O)cc2)c(CO)c1
Reaction time: 1.22 h
Yield: 73.8 %

Procedure:
To a solution of 2.41 g of 2-(4-benzyloxyphenylamino)-5-methoxybenzenemethanol in 200 ml of ethanol was added 60 mg of 10% palladium-on-carbon catalyst, and the mixture was hydrogenated on a Parr apparatus at room temperature and an initial pressure of 34 psi for 73 minutes. The reaction mixture was filtered and concentrated in vacuo to a volume of about 10 ml. Toluene (40 ml) was added and about half of the volume evaporated. The solution was cooled and crystallization induced. The solid product was collected and dried to give 1.3 g of 2-(4-hydroxyphenylamino)-5-methoxybenzenemethanol, pale lavender powder, m.p. 96.5°-97° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:14][CH:11]([CH3:13])[CH3:12])[CH:5]=1
Reactant: Clc1cc(Br)ccn1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To isopropanol (12 ml) under Ar was added 55% sodium hydride in oil (343 mg, 7.86 mmol) in two portions. After 30 min stirring at rt was added 4-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 1.01 g, 5.24 mmol) and the reaction mixture was heated with microwave irradiation to 150° C. for 30 min. The reaction mixture was concentrated, quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by MPLC (heptane/EtOAc 0% to 20%) to give the title compound as an oil. (HPLC: tR 3.58 min (Method A); M+H=216, 218 MS-ES)