Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)(C)(C)C.C(N(CC)CC)C.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([S:36]([C:39]3[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=3)(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>ClCCl>[F:21][C:22]1[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][C:33]([S:36]([C:39]3[CH:40]=[C:41]([NH:45][S:2]([NH2:5])(=[O:4])=[O:3])[CH:42]=[CH:43][CH:44]=3)(=[O:38])=[O:37])=[CH:34][CH:35]=2)=[CH:26][CH:27]=1
Reactant: Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To dichloromethane (1 mL) at 0° C. was added chlorosulfonyl isocyanate (0.03 mL, 0.26 mmol) and tert-butanol (0.03 mL, 0.26 mmol). The mixture was stirred for 10 minutes then triethylamine (0.054 mL, 0.39 mmol) was added followed by [3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]amine hydrochloride (Example 212, 100 mg, 0.26 mmol). The reaction was allowed to warm to room temperature and stirred for 2 hours. The mixture was partitioned between ethyl acetate and water.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:40][O:41][CH2:42][C:43]1[N:48]([CH3:49])[C:47](=[O:50])[C:46]([OH:51])=[CH:45][N:44]=1.CS(O)(=O)=O>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH2:42][C:43]2[N:48]([CH3:49])[C:47](=[O:50])[C:46]([OH:51])=[CH:45][N:44]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cn1c(CON)ncc(O)c1=O
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Agent: CS(=O)(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4ncc(O)c(=O)n4C)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (65 mg) (0.11 mmol) are dissolved in 4 ml of absolute dimethylacetamide. 24 mg (0.14 mmol) of 2-[(aminooxy)methyl]-5-hydroxy-3-methyl-4(3H)-pyrimidinone and 14 mg (0.14 mmol) of methanesulphonic acid are added. After stirring at room temperature for 20 hours the dimethylacetamide is evaporated in a high vacuum and the residue is taken up in water and stirred for 15 minutes in order to precipitate the product completely. The product is filtered off, washed with water and diethyl ether and dried in a high vacuum at room temperature. There are obtained 48 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,6-dihydro-5-hydroxy-1-methyl-6-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[ [[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1>CCOC(C)=O>[NH2:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:37][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:31][CH2:32]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(F)ncc2Cl)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)c1
Temperature: 105 °C

Procedure:
To a scintillation vial containing 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (72 mg, 0.202 mmol) was added DMSO (3 ml) and trans-cyclohexane-1,4-diamine (230 mg, 2.018 mmol). The homogenous yellow reaction mixture was capped and heated to 105° C. in a oil bath for 3 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude solid was purified by Prep HPLC and the collected fractions were combined and diluted with EtOAc and neutralized with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to afford 2′-(trans-4-aminocyclohexylamino)-5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (73 mg, 80%). LCMS (m/z): 451.2 (MH+), retention time=0.70 min. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.34-1.48 (m, 2 H) 1.50-1.64 (m, 2 H) 2.06-2.22 (m, 4 H) 3.08-3.20 (m, 1 H) 3.63-3.74 (m, 1 H) 4.61 (s, 2H) 6.81 (s, 1 H) 6.87 (s, 1 H) 6.91-6.99 (m, 1 H) 7.02 (s, 1H) 7.04-7.10 (m, 1H) 7.12-7.18 (m, 1 H) 7.25-7.36 (m, 1 H) 8.00 (s, 1 H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH3:11]>CCOCC>[CH2:9]([N:12]([CH2:13][CH2:14][CH3:15])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH3:11]
Reactant: BrCc1ccccc1
Reactant: CCCNCCC
Solvent: CCOCC
Product: CCCN(CCC)Cc1ccccc1

Procedure:
An 11.9 ml portion of benzyl bromide and 41 ml of dipropylamine in ether were reacted as described in Example 3, giving 17.6 g of N,N-dipropylbenzenemethanamine as a clear liquid.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:29]1([CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCC.O1CCCC1>[C:29]1([CH2:35][CH2:36][CH2:37][C:38]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)CCCc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.17 h

Procedure:
tert-Butyl lithium (a 1.7M solution in pentane; 0.47 ml, 0.79 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (256.4 mg, 0.76 mmol), prepared as in Example 38, in tetrahydrofuran (5 ml) at -78 degrees under argon. After 10 minutes, a solution of 4-phenylbutyryl chloride (145 mg, 0.79 mmol) was added. Stirring was continued at room temperature for 2 days and the mixture was quenched with water. Extraction and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative thin-layer chromatography (20×20 cm, 1000 micron silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([O:29]C)=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([OH:29])=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)Cc3ccccn3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1ccccn1)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[methyl(pyridin-2-ylmethyl)amino]quinoxaline-6-carboxylate (120 mg, 0.30 mmol) in methanol (30 mL) was added sodium hydroxide (48 mg, 1.20 mmol), and the reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo, diluted with water (20 mL), and adjusted to pH 6 with HCl (2N). The solids were collected by filtration to give 2-(4-fluorophenyl)-3-[methyl(pyridin-2-ylmethyl)amino]quinoxaline-6-carboxylic acid as a yellow solid (66 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]4[O:26][C:25](=[O:27])[C:24]5[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=5[CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]([OH:26])[CH2:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:27])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1OC(c2cccc(/C=C/c3ccc4ccc(Cl)cc4n3)c2)CCc2ccccc21
Reactant: C1CCNC1
Product: O=C(c1ccccc1CCC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)N1CCCC1
Yield: 61.6 %

Procedure:
A stirred solution of lactone 49 (21.0 g, 49.0 mmol) in pyrrolidine (20 ml, 241 mmol) was heated at 90° C. for 3 hours. Excess pyrrolidine was distilled off and the residue was dissolved in dichloromethane (200 ml) followed by FC to give desired hydroxy pyrrolidinamide 50 (15.0 g, 61%) as a pale yellow solid.
Reaction SMILES: O1CCCC1.[O:6]([CH2:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[O:6]([CH2:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ccccc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 29.9 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (6-phenoxymethyl-pyridin-3-yl)-acetohydroximoyl chloride (89.0 mg, 0.322 mmol) described in Manufacturing Example 54-1-6 and 3-ethynyl-pyridin-2,6-diamine (25.0 mg, 0.188 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (78.6 μL, 0.564 mmol) at room temperature, which was stirred for 4.5 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=1:1→3:1) to obtain the title compound (21.0 mg, 29.9%).
Reaction SMILES: C1([SiH3])C=CC=CC=1.[F:8][C:9]1[C:10]([CH:15]=[CH2:16])=[N:11][CH:12]=[N:13][CH:14]=1.[Cl:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[O:20]>O1CCCC1.CN([C@@H]([C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1)C1C=CC=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C.[CH]1[CH][CH][CH][CH]1.[Fe]>[Cl:17][CH2:18][C@@:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[C@H:15]([C:10]1[C:9]([F:8])=[CH:14][N:13]=[CH:12][N:11]=1)[CH3:16]
Reactant: C=Cc1ncncc1F
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: [Fe]
Agent: CN(C)[C@@H]([C]1[CH][CH][CH][C]1P(c1ccccc1)c1ccccc1)c1cccc(P(c2ccccc2)c2ccccc2)c1
Agent: [CH]1[CH][CH][CH][CH]1
Solvent: C1CCOC1
Product: C[C@@H](c1ncncc1F)[C@](O)(CCl)c1ccc(F)cc1F
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To CuF(PPh3)3 methanol solvate (0.137 g) and (RP)-1-[(R)-α-(dimethylamino)-2-(diphenylphosphino)benzyl]-2-diphenylphosphinoferrocene (0.100 g) was added tetrahydrofuran (14 mL). The mixture was stirred at 0-5° C. (under argon) for 30 minutes until all solids were dissolved. To this solution was then added phenyl silane (0.789 g). After 10 minutes, a solution of 5-fluoro-4-vinylpyrimidine (0.903 g) and 2-chloro-1-(2,4-difluorophenyl)ethanone (1.68 g) in tetrahydrofuran (22 mL) was added over 30 minutes. The reaction mixture was stirred for 1 hour at 0-5° C. after which no further 5-fluoro-4-vinylpyrimidine was observable by HPLC. The reaction was quenched by addition of aqueous ammonium chloride (1 M, 15 mL), followed by methyl tert-butyl ether (30 mL). The organic layer was dried to a residue which was then subjected to purification by column chromatography (eluting with 5-40% ethyl acetate in cyclohexane) to give (2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)butan-2-ol as a white solid (1.70 g, 74% yield).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:5]=1[C:6]([NH2:8])=[NH:7].C1O[C:18]2([CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)OC1>>[ClH:1].[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([N:21]2[CH2:22][CH2:23][C:18]3([N:7]=[C:6]([NH2:8])[C:5]4[C:4](=[C:12]([F:13])[CH:11]=[CH:10][C:9]=4[F:14])[NH:3]3)[CH2:19][CH2:20]2)=[O:33])=[CH:30][CH:29]=1)#[N:32]
Reactant: N=C(N)c1c(F)ccc(F)c1N
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)N2CCC3(CC2)N=C(N)c2c(F)ccc(F)c2N3)cc1

Procedure:
This was prepared with 2-amino-3,6-difluorobenzamidine dihydrochloride (Example G) and 1-(4-cyanobenzoyl)-4-piperidone ethylene ketal by the method of Example 1 to give the title compound as a yellow solid, m.p >270° C., MS (+CI) 382 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:11]2[C:18](=[O:19])[N:17]3[C@@H:13]([C@@H:14]([O:20][Si](C(C)(C)C)(C)C)[CH2:15][CH2:16]3)[C@@:12]2([OH:32])[C:28]([F:31])([F:30])[F:29])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:11]2[C:18](=[O:19])[N:17]3[C@@H:13]([C@@H:14]([OH:20])[CH2:15][CH2:16]3)[C@@:12]2([OH:32])[C:28]([F:29])([F:30])[F:31])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(C2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@]2(O)C(F)(F)F)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(C2C(=O)N3CC[C@H](O)[C@H]3[C@@]2(O)C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a plastic vial containing compound 3B (20 mg, 0.041 mmol) in 0.2 mL of THF was added 100 μL of HF pyridine solution (Aldrich), and stirred at RT overnight. It was concentracted and purified on prepHPLC to give the title compound (10.2 mg). MS (ES) m/z 375 [M+H]+.
Reaction SMILES: C(O[CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(OC(=O)C)(=O)C.[BrH:44]>ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([NH:24][C:25](=[O:36])[C:26]2[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=2)[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]1[Br:44])(=[O:10])[CH3:9]
Reactant: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)OC(OC(C)=O)[C@@H]2OC(C)=O)c1
Reactant: Br
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)N[C@@H]2[C@@H](OC(C)=O)[C@@H](Br)O[C@H](COC(C)=O)[C@@H]2OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,2,4,6-Tetra-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-D-galactopyranose 4 (50 mg, 0.098 mmol) was dissolved in dichloromethane (1 ml) which had been dried over 4 Å molecular sieves. Acetic anhydride (18 μl, 0.20 mmol) and HBr (0.2 ml, 33% in AcOH) were added, and the mixture was stirred under N2 at room temperature. After 2 h 30 min, the reaction mixture was diluted with dichloromethane (30 ml) and poured into ice-water (30 ml). The organic phase was washed with NaHCO3 (30 ml of a saturated aqueous solution), dried (MgSO4), filtered and concentrated in vacuo to give 2,4,6-tri-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-α-D-galactopyranosyl bromide 9, which was used without further purification.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O:23]1[C:27]2([CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:51])[C:40]4[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=4[CH2:48][CH2:49]O)=[CH:34][C:33]=3[F:52])[CH2:28]2)[O:26][CH2:25][CH2:24]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[O:26]1[C:27]2([CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH:49]=[CH:48][C:41]5[C:40](=[CH:45][CH:44]=[C:43]([O:46][CH3:47])[CH:42]=5)[C:39]4=[O:51])=[CH:34][C:33]=3[F:52])[CH2:28]2)[O:23][CH2:24][CH2:25]1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCC4(C3)OCCO4)c(F)c2)c(CCO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(=O)n(-c3ccc(N4CCC5(C4)OCCO5)c(F)c3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (7 g) was added to a solution of N-[4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenyl]-2-(2-hydroxyethyl)-4-methoxy-benzamide (4.6 g) in methylene chloride (279 mL). The reaction mixture was stirred for 2 h at room temperature, then further Dess-Martin periodinane (1.4 g) was added, stirring for a further 4 h at room temperature. Then 5% Na2S2O3 solution was added to the reaction solution and the organic phase was then washed with water. The methylene chloride phase was dried over sodium sulfate and the solvent was removed in vacuum. The raw product was purified by preparative HPLC. In this way the product was obtained with molecular weight 396.15 (C22H21FN2O4); MS (ESI): 397 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:27])=[O:26])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([Li])CCC.IC>C1COCC1>[CH2:1]([N:8]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([CH:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH3:36])(=[O:27])=[O:26])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Cc1ccc(CS(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(C(C)S(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
A solution of 0.23 g (0.47 mmol) of 6 in 4 mL of THF was cooled to 0° C. and treated with 0.24 mL (0.59 mmol) of n-butyllithium (2.5M solution in hexanes) and allowed to reach room temperature for 20 min. After cooling the reaction to 0° C., 0.103 mL (1.66 mmol) of iodomethane was added as a solution in 2 mL of THF. The reaction was allowed to warm to room temperature for 30 min at which time the reaction was quenched with a few drops of saturated ammonium chloride. The reaction was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 80% hexanes/AcOEt to give 0.14 g (60%) of the title compound as a white solid. MS Calcd.: 499. Found: 500 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1Nc2cc(F)ccc2-n2cccc21
Product: COc1ccc(C(=O)N2c3cc(F)ccc3-n3cccc3C2C)cc1

Procedure:
7-Fluoro-5-(4-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 47 and p-anisoyl chloride according to the procedure of Example 106, Step 2. MS (ESI) m/z 337; Anal. Calcd for C20H17FN2O2: C, 71.42; H, 5.09; N, 8.33. Found: C, 70.89; H, 4.96; N, 8.01.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[N:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:27][C:8]1[N:9]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2=[N:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=[C:15]2[C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cn1cc(C2CCCCC2)c2ccc(C(=O)OCC)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OCC)nc21
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of ethyl 3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (463 mg, 1.34 mmol) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (287 mg, 1.61 mmol), and the mixture was heated under reflux for 4 hr. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate-5:1) to give ethyl 2-bromo-3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (457 mg, yield 64%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:20]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=[O:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:13][O:14][CH:15]([CH:34]([OH:35])[C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCCCCCCCCCCc1ccccc1C=O
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCCCc1ccccc1C(O)C(OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of di-i-propylamine (0.77 ml, 5 mmoles) in tetrahydrofuran (10 ml) at -78° C. was added n-butyl lithium (2.1 ml, 5.5 mmoles) under argon atmosphere. After 15 minutes, methyl methoxyacetate (0.52 g, 5 mmoles) in tetrahydrofuran (2 ml) was added dropwise, with stirring. The resulting enolate solution was stirrred at -78° C. for 45 minutes. A solution of 2-dodecylbenzaldehyde (1.65 g, 6 mmoles) in tetrahydrofuran (2 ml) was added. The resulting light-blue mixture became a suspension after 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with ether and ice-water. The aqueous phase was extracted with ether. The combined organic extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to give the product, which was purified by flash column chromatography (silica, 15% ethyl acetate/hexane). The fractions were pooled to give 620 mg (33%).