Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH:7]([NH:8][C:9]2[C:14]([NH:15][C:16](=O)[C@H:17]([OH:19])[CH3:18])=[CH:13][N:12]=[C:11]3[CH:21]=[CH:22][S:23][C:10]=23)[CH2:6][CH2:5][N:4]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:3]1>C(O)(=O)C>[F:1][CH:2]1[CH:7]([N:8]2[C:9]3=[C:10]4[S:23][CH:22]=[CH:21][C:11]4=[N:12][CH:13]=[C:14]3[N:15]=[C:16]2[C@H:17]([OH:19])[CH3:18])[CH2:6][CH2:5][N:4]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:3]1
Reactant: C[C@@H](O)C(=O)Nc1cnc2ccsc2c1NC1CCN(C(=O)OC(C)(C)C)CC1F
Solvent: CC(=O)O
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(C(=O)OC(C)(C)C)CC1F
Yield: 10 %

Procedure:
To a mixture of tert-butyl 4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-3-fluoropiperidine-1-carboxylate (0.21 g, 0.57 mmol) and (R)-2-hydroxypropanoic acid (0.059 g, 0.65 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.23 g, 0.60 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water, concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give tert-butyl 3-fluoro-4-[(6-{[(2R)-2-hydroxypropanoyl]amino}thieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.155 g, 62%). LCMS calculated for C20H28FN4O4S (M+H)+: m/z=439.2. Found: 439.1. A solution of the amide intermediate in acetic acid (1 mL) was heated at reflux for 2 h. The resulting mixture was purified on silica gel (eluting with 0-10% MeOH in dichloromethane) to give tert-butyl 3-fluoro-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate (16 mg, 10%). LCMS calculated for C20H26FN4O3S (M+H)+: m/z=421.2. Found: 421.1. The Boc protected intermediate was treated with trifluoroacetic acid (0.1 mL, 1 mmol) in methylene chloride (0.2 mL) at room temperature for 1 h. The mixture was concentrated and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give two desired products. First peak retention time 0.253 min. LCMS calculated for C15H18FN4OS (M+H)+: m/z=321.1. Found: 321.1. Second peak retention time 0.514 min. LCMS calculated for C15H18FN4OS (M+H)+: m/z=321.1. Found: 321.1.
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:16]([F:25])[C:15]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[F:25][C:16]1[C:15]2[O:12][C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][N:2]=3)=[N:13][C:14]=2[CH:19]=[CH:18][C:17]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: O=Cc1nccc2ccccc12
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3nccc4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
In ethanol (13 ml), isoquinoline-1-carbaldehyde (500 mg, 3.18 mmol) and methyl 4-amino-2-fluoro-3-hydroxyphenylacetate (632 mg, 3.17 mmol) were stirred at room temperature for 2 days. Iodobenzene diacetate (1.23 g, 3.82 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (3:1, v/v) eluate fractions, methyl (7-fluoro-2-(1-isoquinolinyl)-6-benzoxazolyl)acetate (155 mg, 14%) was obtained as a red brown solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])C.Br[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]3[CH:37]=[CH:38][N:39]=[C:33]3[CH:32]=2)=[O:28])=[CH:22][CH:21]=1.BrC1C=CC(N)=CC=1>>[N:39]1[CH:38]=[CH:37][N:34]2[CH:35]=[CH:36][C:31]([CH2:30][NH:29][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([C:8]4[CH:7]=[N:6][N:5]([CH2:1][CH2:2][CH3:4])[CH:9]=4)=[CH:21][CH:22]=3)=[O:28])=[CH:32][C:33]=12
Reactant: O=C(NCc1ccn2ccnc2c1)Nc1ccc(Br)cc1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Nc1ccc(Br)cc1
Product: CCCn1cc(-c2ccc(NC(=O)NCc3ccn4ccnc4c3)cc2)cn1

Procedure:
The title compound was prepared as described in Example 51A, substituting 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1-(4-bromophenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.48 (dd, J=6.9, 0.9 Hz, 1H), 8.04 (d, J=0.8 Hz, 1H), 7.90-7.86 (m, 1H), 7.76 (d, J=0.8 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.46-7.35 (m, 5H), 6.84 (dd, J=7.0, 1.7 Hz, 1H), 6.69 (t, J=6.0 Hz, 1H), 4.34 (d, J=5.9 Hz, 2H), 4.04 (t, J=6.9 Hz, 2H), 1.91-1.73 (m, 2H), 1.26-1.05 (m, 1H), 0.85 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 375 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=2[OH:24])=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(C)=O>[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:23])[CH2:17][N:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=[CH:11][C:10]=2[O:24][CH2:16][C:13]1[CH:14]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2c(C(=O)CNC(C)(C)C)ccc(O)c2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1

Procedure:
53.6 g of 4-(N-tert-butylaminoacetyl)-7-hydroxyindole-2-carboxylic acid ethyl ester hydrochloride is combined with 59.3 g of potassium carbonate, 63.6 ml of benzyl bromide, and 1000 ml of acetone and heated under reflux for 6 hours. The mixture is then concentrated under vacuum and the residue combined with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed three times with sodium bicarbonate solution and once with water, dried over calcium sulfate, and concentrated. The residue is recrystallized twice from ethyl acetate/hexane, thus obtaining 47 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)indole-2-carboxylic acid ethyl ester, mp 155°-157° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Li]CCCC.CN([CH:20]=[O:21])C>O1CCCC1>[CH:20]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:21]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid (2.14 g, 10.0 mmol) in tetrahydrofuran (30 mL) under nitrogen at -78° C. was added n-BuLi (10 mL, 2.5 M in THF, 25 mmol) drop-wise. The mixture was stirred for 1 h below −70° C., then DMF (5 mL) was slowly added. The resulting solution was slowly warmed to room temperature and stirred for 1 h, then carefully quenched by slow addition of water (50 mL). The pH was adjusted to −3-4 using aqueous HCl (6 M) and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organics was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a yellow solid (1.6 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[C:6]([CH2:14][CH2:15][CH2:16][Cl:17])=[N:5]2.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:7]1[C:6]([CH2:14][CH2:15][CH2:16][Cl:17])=[N:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1CCCCl
Product: ClCCCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Yield: 21 %

Procedure:
6,7-Dichloro-3-(3-chloropropyl)-1H-quinoxalin-2-one (0.68 g, 2.33 mmol) was added to POCl3 (10 ml) and the resulting mixture was heated under reflux for 0.5 hours. The reaction mixture was poured onto ice and extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporate in vacuo. The resulting oil was purified by flash column chromatography (dichloromethane) to yield 21% of 2,6,7-trichloro-3-(3-chloropropyl)quinoxaline as a colourless oil.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22]C(=O)OCC5C=CC=CC=5)=[CH:18][CH:17]=4)=[CH:11][N:10]3[CH:33]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Ba+2].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>COCCOC>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]3[N:10]([CH:33]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[N:8]=3)[CH:11]=2)=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Ba+2]
Solvent: COCCOC
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Temperature: 90 °C
Reaction time: 36 h
Yield: 64003.6 %

Procedure:
To a solution of benzyl [4-({2[(cyclopropylcarbonyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]carbamate (500 mg, 1.13 mmol) in 1,2-dimethoxyethane (15 mL) was added 0.15 mol/L aqueous barium hydroxide solution (10 mL), and the mixture was stirred at 90° C. for 36 hr. After cooling to room temperature, the reaction mixture was adjusted to pH about 5 with citric acid, and to pH about 10 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate/tetrahydrofuran, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) to give the title compound (223 g, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:21](=[O:22])[O:23][CH:24]([CH3:26])[CH3:25])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)OC(C)C)ncc2c1
Yield: 74 %

Procedure:
A solution 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (52.0 mg, 206 mop in pyridine (1.0 mL) was treated dropwise with a solution isopropyl chloroformate (210μl, 1.0M, 210 μmol) at ambient temperature for 30 mins, and the mixture concentrated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a residue that was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white powder (51.6 mg, 74%). 1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 9.13 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.71 (dd, J=8.5, 1.6 Hz, 1H), 7.37 (dd, J=7, 6 Hz, 1H), 7.22-7.13 (m, 2H), 4.96 (septet, J=6.2 Hz, 1H), 2.25 (s, 3H), 1.29 (d, J=6.3 Hz, 6H). LCMS (Method E): RT=6.067 min, M+H+=339.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.CCN(P1(N(C)CCCN1C)=N[C:36]([CH3:39])([CH3:38])[CH3:37])CC.BrCC(C)=C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:38][C:36]([CH3:39])=[CH2:37]
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: C=C(C)CBr
Solvent: CN(C)C=O
Product: C=C(C)Cn1c(=O)[nH]c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
200 mg (0.531 mmol) of the compound from example 33 and 145 mg (0.531 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 72 mg (0.531 mmol) of 3-bromo-2-methylprop-1-ene 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 1 h. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 10:90→90:10). 88 mg of the title compound were obtained (37% of theory).
Reaction SMILES: C1(C(=[N:14][C:15]2[N:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>CO>[NH2:14][C:15]1[N:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N=C(c3ccccc3)c3ccccc3)cn2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)cn2)CC1
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 189c (2.5 g, 5.6 mmol) in methanol (25 mL) was added sodium acetate (0.56 g, 6.8 mmol) and hydroxylamine hydrochloride (0.7 g, 10 mmol). The reaction mixture was stirred for 0.5 h. It was then concentrated under reduced pressure and the residue was purified by column chromatography eluting with 15:1 dichloromethane/methanol to afford 189d (1.3 g, 71%). MS: [M+H]+ 280.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][SH:21])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[S:27][C:26]([NH:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)=[N:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:23]3[S:27][C:26]([NH:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[N:25][CH:24]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CS)c2CC1
Reactant: Brc1cnc(NCC2CC2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3cnc(NCC4CC4)s3)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.202 g, 0.617 mmol) and N-(5-bromothiazol-2-yl)-cyclopropylmethylamine (0.14 g, 0.62 mmol) in anhydrous DMF (6.2 mL) at room temperature add cesium carbonate (0.22 g, 0.68 mmol). Stir at room temperature overnight and partition the reaction mixture between saturated aqueous NaHCO3 (50 mL) and DCM (100 mL). Dry the organic extract over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to an Analogix® column (40 g) and purify the crude intermediate by preparative liquid chromatography (100:0 to 75:25 hexane/EtOAc over 30 min; 75:25 to 50:50 hexane/EtOAc over 33 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.129 g, 44%). MS (ES+) m/z: 480.2 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:8]=1[OH:9].CN([CH:18]=[O:19])C>[OH-].[Na+]>[OH:9][C:8]1[C:7]([CH3:6])=[C:13]([OH:14])[CH:12]=[CH:11][C:10]=1[CH:18]=[O:19]
Reactant: Cc1c(O)cccc1O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(O)ccc(C=O)c1O

Procedure:
Phosphorus oxychloride (8.0 mL, 86 mmol) was added dropwise with stirring to DMF (26 mL, 0.336 mol) the temperature being kept at 10-20° C. This reagent was slowly added to a solution of 2-methylresorcinol (4.84 g, 39 mmol) in 26 mL DMF at 20-30° C. After 30 min the reaction mixture was poured in 2 M aq. NaOH (200 ml), extracted with Et2O (2×100 mL), aqueous phase was neutralized with 5N aq. HCl, the product was extracted with Et2O (2×200 mL), dried and evaporated. The residue was separated on SiO2 (100 g) column, hexane-EtOAc (0 to 20% v/v). Yield 4.1 g (27 mmol, 69%) as white solid. 1H NMR (300 MHz, DMSO): δ 11.61 (s, 1H), 10.79 (s, 1H), 9.71 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.55 (d, J=8.5 Hz, 1H), 1.97 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)c(F)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Product: O=C1CCCc2cc(-c3ccc(F)cc3)c(F)cc21
Yield: 61.3 %

Procedure:
Using 1.50 g (4.80 mmol) of 3,4-dihydro-7-fluoro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone and 1.85 g (4.80 mmol) of 4-fluorophenyltributyltin, the same reaction as described in Reference Example 1 was carried out to obtain 0.76 g of the above-mentioned compound (yield 61%).
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:14])([CH2:6][C:7]1([CH3:13])[CH2:11][O:10][C:9](=[O:12])[NH:8]1)[CH2:4][CH3:5].C(O[Cl:20])(C)(C)C>CO>[Cl-:20].[Cl:1][N:8]1[C:7]([CH2:6][N+:3]([CH3:2])([CH3:14])[CH2:4][CH3:5])([CH3:13])[CH2:11][O:10][C:9]1=[O:12]
Reactant: CC[N+](C)(C)CC1(C)COC(=O)N1
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: CO
Product: CC[N+](C)(C)CC1(C)COC(=O)N1Cl
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To a solution of N,N-dimethyl-N-((4-methyl-2-oxooxazolidin-4-yl)methyl)ethanaminium chloride (6.76 mmol) in MeOH (10 ml) was added, dropwise, tert-butylhypochlorite (1.6 ml, 10 mmol). The solution was stirred for 2 h, evaporated, and purified by preparative HPLC (H2O/MeOH) to afford the title compound as a white foam (667 mg, 2.59 mmol, 38% over two steps). 1H NMR (D2O, 400 MHz) δ 1.44 (t, J=7.2 Hz, 3H), 1.65 (s, 3H), 3.22 (s, 3H), 3.25 (s, 3H), 3.57 (q, J=7.2 Hz, 2H), 3.76-3.80 (m, 2H), 4.61 (d, J=9.6 Hz, 1H), 4.90 (d, J=9.6 Hz, 1H). ESI/APCI expected for C9H18ClN2O2+: 221.11. Found: 221.
Reaction SMILES: ClP([N:5]=[C:6]=[O:7])(Cl)=O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1/[C:13](=[N:31]/[O:32][CH3:33])/[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].C([O-])(O)=O.[Na+].Cl.[OH-].[Na+]>C(#N)C.O.C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:33][O:32]/[N:31]=[C:13](\[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:6]([NH2:5])=[O:7])[CH2:22][S:23][C@H:18]12)=[O:15])/[C:9]1[O:8][CH:12]=[CH:11][CH:10]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: O=C=NP(=O)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Dichlorophosphinyl isocyanate (1.46 ml) was added to a stirred suspension of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in acetonitrile (50 ml) cooled to 5°. The reaction mixture was stirred at 5° for 15 minutes and then added to a solution of NaHCO3 (5.1 g) in water (100 ml). This mixture was stirred for 10 minutes when the pH was adjusted from 7.4 to 5.0 with hydrochloric acid. The pH fell to 3.0 after a further 10 minutes so it was readjusted to 5.0 with aqueous sodium hydroxide solution. The mixture was kept at ca. 20° overnight and then heated at 45° for 2 hours when TLC (chloroform:methanol:acetic acid=9:2:1) showed that reaction was essentially complete. The precipitated white solid was removed by filtration and the filtrate was washed with ethyl acetate. The aqueous phase was acidified to pH 1.9 with dilute hydrochloric acid in the presence of ethyl acetate. The aqueous phase was re-extracted with ethyl acetate, and the combined ethyl acetate extracts were washed with 25% aqueous sodium chloride solution and then evaporated. The solid residue was triturated with diethyl ether to give the title compound (3.18 g, 75.0%), purity by HPLC 95.4% and by TLC 91%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]([N:9]([CH3:11])[CH3:10])=O.[C:12]([C:14]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:15]=1[NH2:16])#[N:13]>C(Cl)(Cl)Cl>[CH3:10][N:9]([CH3:11])[C:7](=[N:16][C:15]1[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:14]=1[C:12]#[N:13])[CH3:6]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C#N)c(N=C(C)N(C)C)cc1OC
Reaction time: 0.08 h

Procedure:
Phosphorous oxychloride (1.0 ml) was added to a stirred solution of dimethylacetamide (2.8 ml) in chloroform (10 ml) at room temperature. The mixture was stirred for 5 minutes, 2-cyano-4,5-dimethoxyaniline (1.78 g) added and the reaction stirred under reflux for 4 hours. The mixture was cooled, poured onto ice and extracted with chloroform and the organic phase discarded. The aqueous layer was basified (solid NaOH) extracted with chloroform, the combined extracts washed with water, dried (Na2SO4) and evaporated in vacuo. A sample of the brown oily residue (2 g) was crystallised from diisopropylether to give N,N-dimethyl-N'-(2-cyano-4,5-dimethoxyphenyl)acetamidine, m.p. 94°-96°.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][CH2:8]2)[C:5]2[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:4]=2[NH:3]1.[OH-].[K+].CC(O)C>O>[NH:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5]3[CH:18]=[CH:19][C:20]([C:22]([F:24])([F:23])[F:25])=[CH:21][C:4]=3[NH:3][C:2]2=[O:1])[CH2:8][CH2:9]1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)ccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1C1CCNCC1

Procedure:
A mixture of 26 parts of ethyl 4-[1,3-dihydro-2-oxo-5-(trifluoromethyl)-2H-benzimidazol-1-yl]-1-piperidinecarboxylate, 30 parts of potassium hydroxide, 176 parts of 2-propanol and 4 parts of water is stirred and refluxed for 20 hours. The reaction mixture is evaporated. The residue is dissolved in water, acidified with a concentrated hydrochloric acid solution, while cooling, and alkalized with a concentrated ammonium hydroxide solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol. The product is filtered off and dried, yielding 1,3-dihydro-1-(4-piperidinyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one; mp. 198° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:4]=1[O:14][CH2:15][CH2:16][O:17][CH3:18].[C-:19]#[N:20].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:4]1[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:19]#[N:20]
Reactant: [C-]#N
Reactant: COCCOc1cccc(CCl)c1OCCOC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cccc(CC#N)c1OCCOC
Temperature: 70 °C
Reaction time: 17 h
Yield: 84.6 %

Procedure:
A mixture of 1-(chloromethyl)-2,3-bis{[2-(methyloxy)ethyl]oxy}benzene (1.15 g, 4.19 mmol) and potassium cyanide (0.82 g, 12.56 mmol) in DMF (10 mL) was stirred at 70° C. for 17 h. After cooling to rt, ethyl acetate (100 mL) was added, and the mixture was washed with sat. sodium bicarbonate (30 mL), 5% aqueous LiCl (2×30 mL), and brine (30 mL), dried with sodium sulfate, and concentrated. Column chromatography on silica (2:1 hexanes/ethyl acetate) afforded (2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.94 g, 85% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ7.02 (m, 2H), 6.88 (dd, 1H), 4.28 (m, 2H), 4.13 (m, 2H), 3.84 (s, 2H), 3.75 (m, 2H), 3.63 (m, 2H), 3.43 (s, 3H), 3.41 (s, 3H).