Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:8][C:2]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1CCNC1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)N1CCCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
Ethyl 2-bromo-2-methylpropanoate (0.6800 g, 3.4861 mmol) was taken up in pyrrolidine (4 mL) and heated to 70° C. The reaction was stirred for 18 h and then concentrated. The residue was taken up in EtOAc (100 mL) and washed with water (1×100 mL), dried over MgSO4, filtered and concentrated to afford 0.4754 g (2.5697 mmol, 74%) of the product. 1H NMR (CDCl3) δ 4.16 (q, 2H, J=7.1 Hz), 2.76 (bs, 4H), 1.76 (bs, 4H), 1.36 (s, 6H), 1.27 (t, 2H, J=7.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([CH2:15][N:16]([C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][N:16]([C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:18])[CH3:19])[C@H:11]([CH2:13][NH:39][CH:36]2[CH2:38][CH2:37]2)[CH2:12]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)cc1OCCCOC
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)cc1OCCCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4S)-3-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (described under step C in example 152) (6.9 g, 11.88 mmol) in dichloroethane (112 mL), cyclopropylamine (0.92 mL, 13.1 mmol) and NaBH(OAc)3 (3.52 g, 16.63 mmol) are added. The solution is stirred at RT overnight, then diluted with CH2Cl2. A saturated solution of NaHCO3 is added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluent: AcOEt/MeOH 100:0 to 85:15) to give the title compound. MS (LC-MS): 532.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.58 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:15][CH:12]1[CH2:13][CH2:14][N:9]([C:4]2[C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:26]
Reactant: NC1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=S(=O)(NC1CCN(c2ncccc2C(F)(F)F)CC1)c1ccccc1Cl
Yield: 41.4 %

Procedure:
1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (100 mg, 0.42 mmol) was reacted with 2-chlorobenzenesulfonyl chloride (106 mg, 0.50 mmol) to afford the title compound (73 mg), a white solid, in 41% yield.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(O)CCC>[N:29]1([CH2:28][CH2:27][CH2:26][NH:25][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:10]=3)=[O:7])=[C:4]([CH3:24])[N:3]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(NCCCn2ccnc2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 92 μL of 1-(3-aminopropyl)-imidazole in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield 6-(3-(1H-imidazol-1-yl)propylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. MS (Q1) 446.1 (M)+.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:10]=1[CH3:24])=[O:8])C.Cl>O1CCCC1.O>[C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:10]=1[CH3:24])([OH:8])=[O:6]
Reactant: CCOC(=O)c1ccn(-c2ccc3ccccc3n2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccn1-c1ccc2ccccc2n1
Yield: 111.1 %

Procedure:
3.9 g (93 mmol) of lithium hydroxide monohydrate, portionwise every 24 hours, are added at 20° C. to 1.9 g (6.78 mmol) of 3-ethoxycarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole dissolved in 50 mL of tetrahydrofuran and 50 mL of water. After stirring at reflux for 72 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue that is taken up in 75 mL of water. The pH of the aqueous phase is adjusted to 2 by addition of concentrated hydrochloric acid. After stirring for 1 hour, the aqueous phase is filtered and the solid residue is dried under reduced pressure (2.7 kPa) at 40° C. to give 1.9 g of 3-carboxy-2-methyl-1-(quinol-2-yl)-1H-pyrrole in the form of a beige-coloured solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:13]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[CH2:15][CH2:14]1)#N.[OH:25]S(O)(=O)=O>C1C=CC=CC=1.CCCCCCC>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2([CH:11]=[O:25])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1)[CH3:24]
Reactant: O=S(=O)(O)O
Reactant: CCOc1ccc(C2(C#N)CC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCOc1ccc(C2(C=O)CC2)cc1

Procedure:
1M Diisobutylaluminium hydride (14 ml) is added over 3 min. to a stirred solution of 1-cyano-1-(4-ethoxyphenyl)-cyclopropane (1.4 g) in dry benzene (35 ml) and dry n-heptane (14 ml) at 25° C. under an atmosphere of nitrogen. After 3 h the mixture is poured onto 2N H2SO4 (100 ml), extracted with diethyl ether (x3), dried and the solvent removed under reduced pressure. Yield 1 g, nD 1.5272.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)#[N:22]>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]#[N:22])[CH2:34][CH2:33]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: N#Cc1ccccc1N1CCNCC1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4C#N)CC3)c(OC)nc2c1
Yield: 97 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 97%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.28 (s, 4H), 3.86 (s, 3H), 4.08-4.19 (m, 4H), 7.01-7.08 (m, 3H), 7.17-7.37 (m, 1H), 7.49-7.61 (m, 4H)
Reaction SMILES: [ClH:1].C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:27][O:28][CH2:29][CH2:30][CH2:31][NH:32]C(OC(C)(C)C)=O)[C:11]([NH:13][CH:14]2[C:25](=[O:26])[N:16]3[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>>[ClH:21].[ClH:1].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:27][O:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:11]([NH:13][CH:14]2[C:25](=[O:26])[N:16]3[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Product: NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Conc.hydrochloric acid (0.4 ml.) was added to the solution of 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 0.6 g.) in methanil (20 ml.), and stirred at room temperature for 1.5 hours. After evaporating the solvent from the resultant mixture in vacuo, methanol was added to the residue. The mixture was evaporated in vacuo. The residue was dried over phosphorous pentoxide in vacuo to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 0.5 g.).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([CH2:24][CH2:25][N:26]=3)[C:10]3[C:15]([N+:16]=2[O-:17])=[CH:14][CH:13]=[C:12]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](O)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:27]([N:21]1[CH2:20][CH2:19][N:18]([C:12]2[CH:11]=[C:10]3[C:15]([N+:16]([O-:17])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]4[N:9]3[CH2:24][CH2:25][N:26]=4)=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCC(=O)O
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)N1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a stirred suspension of 1,2-dihydro-4-phenyl-8piperazinylimidazo [1,2-a]quinoxaline 5-oxide (1.5 g, 0.0043 mol) in dimethylformamide (20 ml) under an atmosphere of nitrogen and cooled in an ice-bath, was added octanoic acid (0.67 g, 0.0043 mol.) and diphenylphosphorylazide (1.29 g, 0.0047 mol). The reaction mixture was allowed to stand for 15 minutes. Triethylamine (0.95 g, 0.0047 mol) was added to the reaction mixture and the resulting mixture was allowed to stand for 1 hr, then warmed to room temperature over an additional 1 hr period. The solvent was removed in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and then water, dried over anhydrous magnesium sulphate and concentrated in vacuo to yield an orange solid. The orange solid was recrystallized from chloroform:ethyl acetate to yield 1,2-dihydro-8-(4-octanoylpiperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 5-oxide, (1.6 g) as yellow crystals, m.p. 212°-213° C. (Found: C,70.72; H,7.44; N,14.77%; C28H35N5O2 requires C,71.01; H,7.45; N,14.78%), represented by the structural formula: ##STR25##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[NH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][C:27]2[CH:32]=[C:31]([NH:33][C:34]([N:36]3[CH2:40][CH2:39][C@@H:38]([CH2:41][N:42]([CH3:44])[CH3:43])[CH2:37]3)=[O:35])[N:30]=[CH:29][N:28]=2)=[C:24]([F:47])[CH:23]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[CH3:44][N:42]([CH2:41][C@@H:38]1[CH2:39][CH2:40][N:36]([C:34]([NH:33][C:31]2[CH:32]=[C:27]([O:26][C:25]3[CH:45]=[CH:46][C:22]([NH:21][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:23][C:24]=3[F:47])[N:28]=[CH:29][N:30]=2)=[O:35])[CH2:37]1)[CH3:43]
Reactant: CN(C)C[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)C1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)C[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)C1
Reaction time: 1 h
Yield: 38 %

Procedure:
After adding a 2-(4-fluorophenyl)acetyl isothiocyanate-toluene (0.2 M, 2.2 ml) solution to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[(3S)-3-(dimethylaminomethyl)pyrrolidin-1-yl]carbonylamino}pyrimidine (105 mg) and (+)-10-camphorsulfonic acid (65 mg) in ethanol (2.5 ml) at room temperature, the mixture was stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=2:1, then ethyl acetate) to provide the title compound (60.5 mg, 38%) as white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(Cl)(=O)C>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:8](=[O:10])[CH3:9])=[CH:3][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccncc1
Solvent: CC(=O)Cl
Solvent: CCO
Product: CC(=O)Cc1ccncc1
Temperature: 50 °C
Reaction time: 0.12 h

Procedure:
To 10 g of 4-methylpyridine and 32.75 g acetic anhydride, maintained at room temperature, was added 1 ml of acetyl chloride, dropwise over 5-10 min. The solution was then warmed to 50° C. for 6-16 hours. The black reaction mixture was then cooled to 0° C. and 100 mls of ethanol, was added dropwise. The reaction mixture was stirred for 1 hour after the addition, then refluxed for 4-12 hours. The alcohol was removed under reduced pressure and the residue taken up in 100-150 ml methylene chloride. The methylene chloride was washed 2 times with saturated 50 ml portions of sodium carbonate solution then dried over sodium sulfate and evaporated under reduced pressure. Toluene was added to the residue and the excess 4-methylpyridine removed by azeotropic distillation under reduced pressure. Yield: 4.3 gm of 4-pyridinyl-2-propanone.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([OH:22])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(O)c2CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(OCc3ccc(F)cc3)c2CC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Prepare a slurry of sodium hydride (60% in mineral oil; 99 mg, 2.5 mmol) in DMF (4 mL) and heat to 65° C. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.84 mmol) in DMF (5 mL) dropwise and stir for 1 h. Add a solution of 4-fluorobenzyl bromide (191 mg, 1.0 mmol) in DMF (1 mL), stir at 65° C. for 1.5 h and cool to ambient temperature. Add water (1 mL) and concentrate the mixture to an oily residue. Partition the residue between EtOAc/hexane (1:1) and water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, wash with 2N aqueous NaOH, dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1 and 7:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=O)[C:5]([F:8])=[N:6][CH:7]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[N:12][OH:13])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: O=Cc1cc(Br)cnc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=Cc1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2) (20.0 g, 98.0 mmol) in 1:1 MeOH—H2O (250 mL) was added hydroxylamine hydrochloride (7.52 g, 108 mmol) and sodium carbonate (11.4 g, 108 mmol). The reaction mixture was stirred at rt for 1 hour. The solvent was evaporated in vacuo and the residue diluted with H2O (200 mL) and EtOAc (200 mL). The organic phase was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The product was obtained as a light pink solid (21.0 g, 93%); Rf: 0.4 (10% EtOAc-pet ether).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].[Si:34]([O:41][CH2:42][C@@H:43]1[C@@H:50]2[C@@H:46]([O:47][CH:48](O)[CH2:49]2)[CH2:45][C@H:44]1[O:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>O1CCCC1>[Si:34]([O:41][CH2:42][C@H:43]1[C@H:44]([O:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)[CH2:45][C@H:46]([OH:47])[C@@H:50]1[CH2:49]/[CH:48]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC1CCCCO1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 184.6 %

Procedure:
A suspension of (4-carboxy butyl) triphenyl phosphonium bromide (289.3 g, 652.6 mmol) in tetrahydrofuran (1000 ml) was cooled on ice. To the suspension, potassium t-butoxide (146.3 g, 1304 mmol) was added and the mixture was warmed to room temperature. A solution of (3aR,4S,5R,6aS)-4-(t-butyldimethylsilyloxymethyl)-5-(2-tetrahydropyranyloxy)hexahydrocyclopenta[b]furan-2-ol (23) (97.2 g, 261 mmol) in tetrahydrofuran (500 ml) was added, and the resulting solution was stirred for approximately 1.5 hours. Ice water (800 ml) was added to the reaction and the mixture was concentrated under reduced pressure. Then, ice-cooled 1N-hydrochloric acid (600 ml) and ethyl acetate (800 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (400 ml). The organic layers were combined, and washed with saturated aqueous sodium chloride (800 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, diethyl ether (1400 ml) was added to the residue and the mixture was stirred for 30 minutes. The resulting mixture was filtered, and the deposited white solid was eliminated. The filtrate was concentrated under reduced pressure to give crude (Z)-7-[(1R,2S,3R,5S)-2-(t-butyidimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenoic acid (24) (220 g) as white solid. The entire amount was used in the following step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[S:4][C:5]1[C:10]([Cl:11])=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:8]=[C:7]([Br:21])[C:6]=1[CH2:22][CH:23]=C.C1C[O:30]CC1.O>O=[Os](=O)(=O)=O>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[S:4][C:5]1[C:10]([Cl:11])=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:8]=[C:7]([Br:21])[C:6]=1[CH2:22][CH:23]=[O:30]
Reactant: C1CCOC1
Reactant: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1SC(=O)N(C)C
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: COc1ccc(Cc2cc(Br)c(CC=O)c(SC(=O)N(C)C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 218 (1.48 g, 3.25 mmol) in THF/water (15 mL/15 mL) were added NaIO4 (2.78 g, 13.02 mmol) and OsO4 (0.4 mL, 2.5% in isopropanol). After stirring at rt overnight, the reaction was quenched with saturated Na2SO3 solution (20 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product 219 was dried under high vacuum and used without further purification (1.57 g, 3.44 mmol, 106%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CC1C=CC=CC=1>[CH3:23][S:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1)(=[O:26])=[O:25]
Reactant: CCOC(=O)C1CCc2cc(N)ccc2O1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C1CCc2cc(NS(C)(=O)=O)ccc2O1
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a stirred and cooled (0° C.) solution of 40 parts of ethyl 6-amino-3,4-dihydro-2H-1-benzopyran-2-carboxylate, 86 parts of pyridine and 234 parts of methylbenzene was added dropwise a solution of 20.6 parts of methanesulfonyl chloride in 135 parts of methylbenzene. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated and the oily residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 210 parts of 2,2'-oxybispropane and 12 parts of acetonitrile, yielding 10.2 parts (18.9%) of ethyl 3,4-dihydro-6-[(methylsulfonyl)amino]-2H-1-benzopyran-2-carboxylate; mp. 111.1° C. (intermediate 25).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:15]1[NH:16]C=CN=1)=O.Cl.CN.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([NH:16][CH3:15])=[O:6]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CNc1ccc(C(=O)O)cc1Cl
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(NC)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-4-fluorobenzonitrile (1.0 g), methylamine (16 mL of a 2 M solution in methanol) and diisopropylethylamine was reacted in the microwave at 120° C. for min. The mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (30 mL), dried (MgSO4) and reduced in vacuo to give 3-chloro-4-methylamino-benzonitrile. A suspension of 3-chloro-4-methylamino-benzonitrile (900 mg) in 2 M aqueous sodium hydroxide solution (30 mL) was heated at reflux for 3 h. After cooling to room temperature, the solution was acidified with 2 M aqueous hydrochloric acid and the resulting solid collected by filtration and air-dried to give 3-chloro-4-methylamino-benzoic acid. To a solution of 3-chloro-4-methylamino-benzoic acid (860 mg) in DMF (20 mL) was added carbonyl diimidazole (630 mg) and the reaction stirred at room temperature for 1 h. Then, methylamine hydrochloride (262 mg) and triethylamine (1.62 mL) were added and the reaction stirred at room temperature for 16 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (3×40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-chloro-N-methyl-4-methylamino-benzamide.