Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[N:29][CH:30]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:26]=[N:27][CH:28]=[N:29][CH:30]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1cncnc1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: OC1(c2cncnc2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 60 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 5-bromopyrimidine, the title compound was formed in 60% yield as a white solid, mp 298°-300° C. (dec). free base: 1H NMR (CDCl3, 250 MHz) 9.12 (s, 1H), 8.86 (s, 2H), 7.26 (m, 2H), 7.18 (m, 2H), 6.94 (m, 4H), 4.29 (s, 1H), 3.49 (s, 2H), 2.96 (m, 2H), 2.70 (dt, J=2.5, 12.0 Hz, 2H), 2.61 (d, J=1.5 Hz, 2H), 2.10 (dt, J=4.6, 13.0 Hz, 2H), 1.89 (s, 1H), 1.76 (m, 2H) MS (CI, CH4) m/z 384 (M+1,100), 412 (M+29,20), 366 (13) hydrochloride salt:
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[NH:21]1[C:25]2=[N:26][CH:27]=[C:28](B(O)O)[CH:29]=[C:24]2[CH:23]=[CH:22]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:28]2[CH:29]=[C:24]3[CH:23]=[CH:22][NH:21][C:25]3=[N:26][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: OB(O)c1cnc2[nH]ccc2c1
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
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: CCO
Solvent: Cc1ccccc1
Product: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(-c2cnc3[nH]ccc3c2)n1
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol B-1-3 (0.312 g, 0.8 mmol) in toluene (15 mL) and EtOH (5 mL) were added 1H-pyrrolo[2,3-b]pyridin-5-ylboronic acid (0.40 g, 1.6 mmol) and 2 N aq. Na2CO3 (1.24 mL), and the resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.23 g, 0.2 mmol) was added and the mixture was degassed again. The resulting mixture was heated to reflux and stirred overnight. The organic layer was separated and concentrated, the residue was purified via prep HPLC to afford (2S)-1-(4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1) (0.260 g, 66.19%) as a yellow solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[O-2:10].[Zn+2:11].[OH-:12].[Ca+2:13].[OH-]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Zn+2:11].[OH:10][Ca:13][OH:12].[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: [O-2]
Reactant: [OH-]
Reactant: [Ca+2]
Agent: O=C(O)CC(O)C(=O)O
Agent: [Zn+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)[O-]
Product: O[Ca]O

Procedure:
An aqueous solution of malic acid was prepared by mixing 134.09 g of malic acid with 50 mL of water. An aqueous solution of zinc oxide was also prepared in a separate container by thoroughly mixing 81.38 g of zinc oxide in 25 mL of water. An aqueous solution of calcium hydroxide was also prepared in a separate container by thoroughly mixing 74.09 g of calcium hydroxide in 25 mL of water. The zinc oxide solution and the calcium hydroxide solution were then slowly added to the malic acid solution. The resulting solution was then spray dried to produce a powdered dihydroxycalcium zinc malate (or calciumhydroxy zinchydroxy malate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:5]=O.[N+:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-:19])=[O:18].C(N)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:20](/[N+:17]([O-:19])=[O:18])\[CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCCCC[N+](=O)[O-]
Reactant: O=Cc1ccc(OC2CCCCC2)c(Br)c1
Solvent: CCCCN
Solvent: Cc1ccccc1
Product: CCCC/C(=C\c1ccc(OC2CCCCC2)c(Br)c1)[N+](=O)[O-]
Yield: 70.4 %

Procedure:
3-bromo-4-cyclohexyloxy-benzaldehyde (13 mmol, 3.7 g), 1-nitro-pentane (19.6 mmol, 2.3 g) and n-butyl amine (2.6 mmol, 0.19 g) were dissolved in toluene (5 mL) and refluxed for 48 h. The reaction mixture was cooled, filtered and evaporated the solvent and purified by column chromatography using 2% ethyl acetate in hexane as an eluents to provide 2-bromo-1-cyclohexyloxy-4-((E)-2-nitro-hex-1-enyl)-benzene (3.5 g).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C:20]1[C:21]([OH:28])=[N:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[OH:28][C:21]1[C:20]([CH2:19][NH:18][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])=[CH:17][CH:16]=2)=[C:25]([CH3:26])[CH:24]=[C:23]([CH3:27])[N:22]=1
Reactant: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(S(=O)c3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.6 %

Procedure:
A mixture of 4-(phenylsulfinyl)benzoic acid (130 mg, 0.53 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.6 mmol), o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1.0 mmol) and triethylamine (0.1 mL) in dichloromethane (6 mL) was stirred at 25° C. for 12 hours. After the reaction, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(phenylsulfinyl)benzamide as a white solid (90 mg, 44%). LRMS (M+H+) m/z: calcd 380.12. found 380. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.47 (t, J=4.8 Hz, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.78-7.71 (m, 4H), 7.54-7.50 (m, 3H), 5.84 (s, 1H), 4.28 (d, J=4.8 Hz, 2H), 2.14 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.C(OP([CH2:20][C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(OCC)=O)C.[CH2:29]([O:32][C:33]1[C:34](/[C:47](/[CH2:52][CH3:53])=[C:48](/[F:51])\[CH:49]=O)=[CH:35][C:36]2[C:37]([CH3:46])([CH3:45])[CH2:38][CH2:39][C:40]([CH3:44])([CH3:43])[C:41]=2[CH:42]=1)[CH2:30][CH3:31]>C1COCC1.CN1CCCN(C)C1=O>[CH2:29]([O:32][C:33]1[C:34](/[C:47](/[CH2:52][CH3:53])=[C:48](/[F:51])\[CH:49]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:35][C:36]2[C:37]([CH3:46])([CH3:45])[CH2:38][CH2:39][C:40]([CH3:44])([CH3:43])[C:41]=2[CH:42]=1)[CH2:30][CH3:31]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CCCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Product: CCCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C\C(=O)OCC)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium and hexane (6.75 mL, 1.6 M, 10.8 mmol) was added over 20 minutes down the side of the flask into a stirring solution of ethyl 4-(diethoxyphosphoryl)-3-methylbut-2-enoate (2.86 g, 10.8 mmol) and THF (40 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.70 mL) at −78° C. After 30 min, the solution was treated with a solution of (E)-3-(3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enal (Intermediate 9, 1.80 g, 5.42 mmol) in THF (10 mL). The solution was stirred for 2 h at 0° C. and then cooled again to −78° C. The reaction was quenched at −78° C. by adding saturated aqueous ammonium chloride. The solution was warmed to room temperature, and the products were extracted three times with ether. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound after purification by silica gel chromatography using a 94:6 mixture of hexane:ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Crude dimethyl 4-bromo-2-nitrophenylmalonate was heated at 110° C. in 40 mL of 6 N hydrochloric acid for 24 hours and then cooled. The precipitate was collected by filtration, washed with water and dried to give 5.3 g (89% yield) of 4-bromo-2-nitrophenylacetic acid as an off white solid.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10](Br)[C@H:9]([O:13][C:14]([CH3:16])=[O:15])[C@@H:8]([O:17][C:18]([CH3:20])=[O:19])[C@@H:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([O-:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].[Na+].CC(C)=O.[OH-].[Na+]>O>[C:14]([O:13][C@@H:9]1[C@@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][C@H:10]1[O:34][C:31]1[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=1)(=[O:15])[CH3:16]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 18 h
Yield: 24.9 %

Procedure:
To a mixture of 15 g of acetobromoglucose, 7.92 g of sodium 4-nitrophenolate and 50 ml of acetone was added 300 mg of sodium hydroxide in 15 ml of water. This mixture was stirred for 18 hours, poured into 400 ml of water and the precipitate was filtered off. The residue was dissolved in 200 ml of methylene chloride, washed with 100 ml of aqueous sodium bicarbonate solution, dried and passed through a pad of hydrous magnesium silicate. Evaporation of the solvent and crystallization yielded 4.26 g of 4-nitrophenyl (2,3,4,6-tetra-O-acetyl)-β-D-glucopyranoside as white crystals, mp 173°-175° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O.C(C1C=CC=CC=1C(O)=O)=O.[C:29]([O:33][C:34](=[O:52])[CH2:35][C@H:36]([NH2:51])[CH:37]([OH:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:52])[CH2:35][C@H:36]([NH:51][C:13](=[O:15])[C@@H:12]([N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]1=[O:1])[CH2:16][CH3:17])[C:37](=[O:50])[CH2:38][O:39][C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[C:42]([F:48])[C:41]=1[F:49])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: CC[C@@H](C(=O)O)n1ccc2ccccc2c1=O
Agent: O=Cc1ccccc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2ccccc2c1=O

Procedure:
This compound was prepared using (S)-2-(1-oxo-1H-isoquinolin-2-yl)-butyric acid (prepared from 2-formylbenzoic acid using procedures similar to those described in methods A-E) and (3S)-3-Amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods H-J) using procedures similar to those described in methods F-G. This compound was isolated as a white solid This compound was prepared using methods similar to A-G and was isolated as a white solid 1H NMR (400 MHz CDCl3) δ 0.98 (3H, t), 1.30 (9H, s), 1.98-2.02 (1H, m), 2.26-2.32 (1H, m), 2.68 (1H, dd), 2.90 (1H, dd), 4.83-4.88 (1H, m), 5.06 (1H, d), 5.15 (1H, d), 5.50 (1H, t), 6.60 (1H, d), 6.75-6.82 (1H, m), 7.23 (1H, d), 7.33 (1H, d), 7.49-7.55 (1H, m), 7.68 (1H, t), 8.41 (1H, d); 19F NMR (376 MHz, CDCl3) (proton decoupled) δ −139.94, −139.97, −140.0, −140.02. −157/06, −157.09, −157.12, −157.14; ES(+) 565.3, ES(−) 563.3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2(C#Cc3ccncc3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C2(C#Cc3ccncc3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 85.6 %

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-1,1-(ethylenedioxy)cyclohexane (0.10 g, 0.24 mmol) and pyridinium p-toluenesulfonate (0.06 g, 0.24 mmol) in acetone (4 mL) and water (1 mL) was refluxed for 20 h., then was evaporated. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-one (0.08 g, 91%) as a white solid, mp 148°-149° C. Anal. (C25H27NO3.0.5 H2O) calcd: C, 75.29; H, 7.08; N, 3.51; found: C, 75.51; H, 6.95; N, 3.42.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:18](#N)[CH3:19].[CH2:21](I)[CH3:22]>O>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:18][CH3:19])=[O:6])[CH3:22]
Reactant: CCI
Reactant: CC#N
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1ccc(C)c(OCC)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-hydroxy-4-methyl benzoic acid (3.0 g), potassium carbonate (10.9 g), and acetonitrile (60 mL) was added ethyl iodide (4.8 mL) under ice-cooling, followed by stirring at 60° C. overnight. Thereafter, ethyl iodide (4.8 mL) was added thereto, followed by stirring at 70° C. for 3 days. In addition, ethyl iodide (4.8 mL) and potassium carbonate (5.5 g) were added thereto, followed by stirring overnight. To the reaction mixture was added water (100 mL), followed by extraction with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane:5/95) to obtain ethyl 3-ethoxy-4-methylbenzoate (4.0 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][CH:3]1[CH3:25].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH3:33][S:34]([O:1][CH:2]1[CH:3]([CH3:25])[CH2:4][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][CH:7]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])(=[O:36])=[O:35]
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of tert-butyl 6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) in DCM (0.09 M) was added triethylamine (1.5 equiv.) and the reaction was cooled to 0° C. MsCl (1.2 equiv.) was added to the reaction and stirred for 3 h. Another 1.0 equiv. of MsCl was added to the reaction and stirred for another 2 h. Worked up the reaction by adding water, the organic phase was dried with brine, sodium sulfate, and concentrated. The crude product was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to afford 2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate as a white foam in 65% yield. LC/MS=428.2 (M+H), LC: 3.542 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[C:18]([C:20]([O-])=[O:21])[S:19][C:12]=12.[Li+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][C:20]([C:18]2[S:19][C:12]3[C:13](=[N:14][CH:15]=[CH:16][C:11]=3[Cl:10])[CH:17]=2)=[O:21])[CH:2]=1
Reactant: NCCc1cccnc1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(NCCc1cccnc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-pyridine-3-yl-ethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 318/320 (MH+); HPLC Rf: 4.27 min.; HPLC purity 76%.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[F:21][C:22]1[C:27](I)=[CH:26][CH:25]=[CH:24][N:23]=1.[I:29][CH3:30]>C1COCC1>[F:21][C:22]1[C:27]([CH3:26])=[C:30]([I:29])[CH:25]=[CH:24][N:23]=1
Reactant: Fc1ncccc1I
Reactant: CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1c(I)ccnc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of LDA, freshly prepared from diisopropylamine (0.126 mL, 0.899 mmol) and n-BuLi (0.899 mmol), in THF (2 mL) at -78° C. is cannulated a solution of 2-fluoro-3-iodopyridine (200 mg, 0.897 mmol) in 0.4 mL of THF, and the mixture is stirred for 1 hour at -78° C. under nitrogen. Iodomethane (0.17 mL, 2.73 mmol) is added neat and the mixture is stirred for 30 min. at -78° C. The mixture is quenched with saturated sodium bicarbonate solution at -78° C. and then extracted with ether. Combined ether extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by radial plc (silica gel, hexanes) to give 154 mg (72%) of product as an off-white solid having amp of 90-91 ° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:34](=[O:37])[CH2:35][CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O:38]=[C:39]1[CH2:42][N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:40]1>C1COCC1>[OH:38][C:39]1([C@@H:35]([CH3:36])[C:34](=[O:37])[N:29]2[C@@H:28]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:32][O:31][C:30]2=[O:33])[CH2:42][N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:40]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a solution of diisopropylamine (6.5 mL, 46.3 mmol) in THF (200 mL) at −78° C. was added butyllithium (17 mL of a 2.5 M solution in hexanes, 42.5 mmol) over 5 min. The solution of lithium diisopropylamide was stirred for 15 min at −78° C. A solution of (S)-4-benzyl-3-propionyl-2-oxazolidinone (9.0 g, 38.6 mmol) in THF (100 mL) was added to the lithium diisopropylamide by addition funnel over 26 min. The reaction temperature was kept below −70° C. during the course of the addition. After the addition, the mixture was stirred for a further 30 min at −78° C. Then phenylmethyl 3-oxoazetidine-1-carboxylate (9.5 g, 46.3 mmol) was added by addition funnel over 25 minutes as a solution in THF (100 mL). Again, the reaction mixture was kept below −70° C. during the reagent addition. After stirring for an additional 1 hour at −78° C., the reaction mixture was quenched with saturated ammonium chloride solution and was then allowed to warm to rt. Water was added to dissolve any precipitated ammonium chloride, and ethyl acetate was added. The layers were partitioned, and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (50% ethyl acetate: 50% hexanes) to provide phenylmethyl 3-hydroxy-3-{(1R)-1-methyl-2-oxo-2-[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylate as a white crystalline solid (6.03 g, 13.8 mmol, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 8H), 7.20 (d, 2H), 5.12 (s, 2H), 4.66 (m, 1H), 4.27-4.20 (m, 2H), 4.10 (q, 1H), 4.03-3.93 (m, 3H), 3.28 (dd, 1H), 2.77 (dd, 1H), 1.29 (d, 3H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH:40]([CH2:44][OH:45])[CH2:39]1.C(OC(N1CCNCC1C(O)=O)=O)(C)(C)C.C(OC(N1CCNC[C@H]1C(O)=O)=O)(C)(C)C>ClCCl.O.C(N(CC)CC)C>[OH:45][CH2:44][CH:40]1[CH2:39][N:38]([CH3:37])[CH2:43][CH2:42][N:41]1[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CN1CCNC(CO)C1
Agent: CC(C)(C)OC(=O)N1CCNCC1C(=O)O
Agent: CC(C)(C)OC(=O)N1CCNC[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(C)CC4CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 270 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 130 mg of (4-methylpiperazin-2-yl)methanol (synthesized starting from commercially available 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid in one step in analogy to the synthesis of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid described in patent application WO2005/026152) in 10 ml dichloromethane is stirred at room temperature for 16 hours. 505 mg triethylamine is added and the reaction mixture is stirred additional 24 h at room temperature. Water (20 ml) is added to the mixture. After separation of the organic layer, the aqueous layer is extracted with dichloromethane (2×20 ml). The combined organic layers are dried over MgSO4. After filtration the solvent is removed under reduced pressure. The resulting residue is purified by flash chromatography [silica gel, eluent: ethyl acetate/methanol/aqueous solution of ammonia, 20/4/1 (v/v/v) and subsequently by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 65/35 to 15/85 (v/v)) to give the title product.