Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].CN(C1C=CC=CN=1)C.[C:23]([N:33]1[CH2:36][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][NH2:49])[O:45][C:44]3=[O:50])=[CH:39][C:38]=2[F:51])[CH2:34]1)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[F:51][C:38]1[CH:39]=[C:40]([N:43]2[CH2:47][C@H:46]([CH2:48][NH:49][C:7](=[O:9])[CH3:8])[O:45][C:44]2=[O:50])[CH:41]=[CH:42][C:37]=1[CH:35]1[CH2:36][N:33]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:34]1
Reactant: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few crystals of 4 dimethylaminopyridine were added to a stirred solution of (S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in methylene chloride (30 mL), then stirred for 1 hr. The solvents were removed at 38°/0.75 mm and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 1-2% methanol-chloroform. The title compound was isolated as a white foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][O:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7](=[O:15])[CH:6]=1.Br[CH2:18][C:19](=[CH2:25])[C:20](OCC)=[O:21]>O1CCCC1.[Zn].C1(C=CC(O)=CC=1)O>[CH3:16][C:2]1([CH2:3][O:4][C:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7](=[O:15])[CH:6]=2)[CH2:25][C:19](=[CH2:18])[C:20](=[O:21])[O:1]1
Reactant: C=C(CBr)C(=O)OCC
Reactant: CC(=O)COc1cc(=O)oc2ccccc12
Agent: Oc1ccc(O)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CC(C)(COc2cc(=O)oc3ccccc23)OC1=O
Temperature: 0 °C
Reaction time: 36 h
Yield: 76.4 %

Procedure:
To a solution of 1a (0.655 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.255 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was reflued under nitrogen atmosphere for 36 h. (monitored by TLC). After cooling it was poured into an ice-cold 5% HCl solution (300 ml) and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with saline, dried over Na2SO4, and then evaporated to give a residual solid which was crystallized from ethyl acetate to afford the title compound (0.656 g, 76.4%) as a pale yellow crystal. mp: 161°-162° C.; IR(KBr) νmax : 1766, 1703, 1627; UV (CHCl3) λmax (log ε): 306 (3.79), 276 (4.01), 266 (4.05); 1H-NMR (CDCl3): δ1.64 (s, 3H, 5'-CH3), 2.88 (dt, 1H, 4'-H), 3.19 (dt, 1H, 4'-H), 4.08, 4.20 (two d, 2H, OCH2), 5.67 (s, 1H, 3-H), 5.75 (t, 1H, vinylic H), 6.38 (t, 1H, vinylic H), 7.12-7.33 (m, 2H, 6 and 8-H), 7.51-7.65 (m, 2H, 5 and 7-H). Anal. Calcd for C16H14O5 : C, 67.13; H, 4.93. Found: C, 67.14; H, 5.01.
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11](O)=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3].O=S(Cl)[Cl:20]>>[Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11]([Cl:20])=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3]
Reactant: Cc1cc(OCC(=O)O)cc(C)c1S(=O)(=O)Cl
Reactant: O=S(Cl)Cl
Product: Cc1cc(OCC(=O)Cl)cc(C)c1S(=O)(=O)Cl

Procedure:
Referring to FIG. 37, 2-(4-(Chlorosulfonyl)-3,5-dimethylphenoxy)acetic acid (6 g, 21.6 mmol) was dissolved in SOCl2 (50 mL) and the reaction mixture was refluxed overnight. Proton NMR analysis on a sample from the reaction mixture exhibited the conversion went completion. Concentration of the mixture under reduced pressure gave product as a white solid (6.4 g, quantitative); 1H NMR (CDCl3, 300 MHz): δ 6.71 (s, 2H), 5.03 (s, 2H), 2.80 (s, 6H).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH:5]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[BH4-]>O.CO>[CH:16]1[C:12]2[CH:13]=[CH:14][C:15]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH:10]([OH:20])[C:11]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC1c2ccccc2C=Cc2ccccc21
Reaction time: 0.75 h

Procedure:
In this preparation a solution containing 1.5 grams of sodium borohydride in 30 ml. of water containing 1.5 ml. of 3N aqueous sodium hydroxide is added to a solution containing 15.0 g. of dibenzo[a,d]cyclohepten-5-one in 200 ml. of methanol at room temperature, with stirring. The resulting mixture is stirred for 45 minutes and then an additional 0.5 g. of borohydride in 10 ml. of water is added and the mixture stirred at room temperatue for 60 hours. The reaction mixture is then cooled in an ice water bath while 300 ml. of water is slowly added with stirring. The resulting precipitate is collected by filtration and washed repeatedly with water and dried under vacuum affording a residue of 5H-dibenzo[a,d]cyclohepten-5-ol, which is sufficiently pure to use as starting material for subsequent preparations.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:14])[CH2:12]O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Br)(Br)[Br:16].O>C(OC(C)C)(C)C>[Br:16][CH2:12][C:11]([CH3:14])=[CH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=Cc1ccc(C(C)C)cc1)CO
Reactant: BrP(Br)Br
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(=Cc1ccc(C(C)C)cc1)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 136.4 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-2-methyl-2-propen-1-ol (6.30 g, 33.1 mmol) in isopropyl ether (50 ml) was added under ice cooling phosphorus tribromide (5.98 g, 22.1 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted with isopropyl ether. The organic layer was washed with water and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 7.63 g (91% yield) of the oily title compound.
Reaction SMILES: [C:1](C=P(CCCC)(CCCC)CCCC)#N.[C:17]([C:19]1[CH:50]=[CH:49][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:33][CH:32]3[O:34][CH:28]([CH2:29][N:30]([CH2:35][CH2:36][NH:37][S:38]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=4[F:48])(=[O:40])=[O:39])[CH2:31]3)[CH2:27]2)=[C:21]([F:51])[CH:20]=1)#[N:18].C1COCC1>CO>[C:17]([C:19]1[CH:50]=[CH:49][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:33][CH:32]3[O:34][CH:28]([CH2:29][N:30]([CH2:35][CH2:36][N:37]([CH3:1])[S:38]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=4[F:48])(=[O:40])=[O:39])[CH2:31]3)[CH2:27]2)=[C:21]([F:51])[CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(OCCN2CC3CN(CCNS(=O)(=O)c4ccc(F)cc4F)CC(C2)O3)c(F)c1
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCN1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2)S(=O)(=O)c1ccc(F)cc1F
Temperature: 160 °C
Yield: 52.4 %

Procedure:
Cyanomethylenetri-n-butylphosphorane (90%, 0.158 g, 0.59 mmol) was weighed into a microwave vial. N-(2-{7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-ethyl)-2,4-difluoro-benzenesulfonamide (100 mg, 0.2 mmol, from example 11 above) and THF (2 mL) were added. Methanol (16 μl, 0.39 mmol) was then added and the reaction was heated with microwave irradiation at 160° C. for 15 min. MeOH (1 mL) was added and the reaction was heated with microwave irradiation for a further 10 min in order to consume excess reagent. The reaction mixture was concentrated and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent. The product isolated could be purified further by recrystallisation from MeOH to give a solid (55 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:16][O:17][C:18]([C:20]1[C:21]([C:27]([F:30])([F:29])[F:28])=[N:22][C:23](Cl)=[N:24][CH:25]=1)=[O:19].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:16][O:17][C:18]([C:20]1[C:21]([C:27]([F:30])([F:28])[F:29])=[N:22][C:23]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH3:8])[C:6]=3[CH3:9])[CH2:11][CH2:12]2)=[N:24][CH:25]=1)=[O:19]
Reactant: Cc1c(Cl)nnc(N2CCNCC2)c1C
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a roundbottom flask is added 3-chloro-4,5-dimethyl-6-piperazin-1-yl-pyridazine (1 g, 4.41 mmol), 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (2.12 g, 8.82 mmol) and diisopropylethylamine (2.3 mL, 13.23 mmol) in a dioxane (9 mL) solution and stirred for 18 h at room temperature. Filter the reaction mixture and rinse with water and ethylacetate to give 1.35 g of 2-[4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (71%).
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>CO.N1CCCCC1>[I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH2:13][CH:12]([O:23][CH3:24])[O:11][CH3:10])[CH:16]=1
Reactant: Cc1cccc[n+]1C
Reactant: COC(COc1cccc(C=O)c1)OC
Agent: [I-]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(COc1cccc(C=Cc2cccc[n+]2C)c1)OC
Yield: 85.8 %

Procedure:
In 6 ml of methanol, 1.50 g of 1,2-dimethyl pyridinium iodide and 1.50 g of m-(2,2-dimethoxyethoxy)-benzaldehyde were dissolved. The resultant solution, with two drops of piperidine added thereto, was refluxed for five hours and thereafter cooled off. Consequently, crystals were deposited. When the crystals were collected and washed thoroughly with acetone, there was obtained 2.34 g of 1-methyl-2-[m-(2,2-dimethoxyethoxy)-styryl]pyridinium iodide. In water, this product showed the highest absorption at 336 nm (ε=2.13×104). The infrared absorption spectrum (KBr) showed peaks at 1620, 1600, 1580, 1268, 1137, 1068, 965, 840, 772 and 680 cm-1. The yield was 86%.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[P:9]([O-:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>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.O>[N:6]1[CH:7]=[CH:8][C:3]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccncc1

Procedure:
4-Bromopyridine hydrochloride (8 g, 41.1 mmol), diethyl phosphite (8.23 mL, 63.8 mmol), tetrakis(triphenylphosphine)palladium(0) (1.189 g, 1.029 mmol) and TEA (17.20 mL, 123 mmol) were stirred in refluxing toluene (160 mL) overnight. Room temperature was attained, water was added and the organic layer separated. The aqueous phase was extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (EtOAc) gave diethyl pyridin-4-ylphosphonate as a pale yellow oil. 1H NMR (DMSO-d6, 600 MHz) δ 8.75 (m, 2H), 7.61 (m, 2H), 4.03 (m, 4H), 1.21 (t, J=7.2 Hz, 6H). MS: cal'd 216 (MH+), exp 216 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)=[O:14])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:33]=[N:34][NH:35][N:23]=3)[CH:17]=2)=[O:14])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCc2cccc(C(=O)Nc3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
Heat a mixture of 3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-N-(3-cyano-phenyl)-benzamide, sodium azide (1.12 g, 17.3 mmol), and ammonium chloride in dimethylformamide at 110 C for 24 hours. Cool to room temperature and dilute with water. Filter and wash several times with water. Dry filtered material and dissolve in hot acetone. Purify the resulting solution via chromatography, eluting with hexanes:acetone with 1% acetic acid to afford the title compound. 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.52 (sextet, 2H), 2.58 (s, 3H), 2.62 (t, 2H), 5.37 (s, 2H), 6.76 (d, 1H), 7.57 (d, 1H), 7.61 (d, 1H), 7.68 (d, 1H), 7.74 (d, 1H), 7.82 (d, 1H), 7.97 (m, 2H), 8.09 (m, 1H), 8.59 (s, 1H), 10.56 (s, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 470 (100).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(#N)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:16][CH2:17][N:12]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]1
Reactant: c1ccc(C2CCNCC2)nc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(C2CCN(Cc3nc4cccnc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 38A (50 mg, 0.11 mmol), 2-(4-piperidinyl)pyridine (25 mg, 0.13 mmol), and DIEA (340 μL, 2.1 mmol) were combined in acetonitrile (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.13 (m, 4H), 3.13 (m, 4H), 3.61 (m, 3H), 7.38 (d, J=4.75 Hz, 1H), 7.76(dd, J=8.3 Hz, 4.6 Hz, 1H), 7.91 (m, 1H), 8.31 (m, 1H), 8.54 (m, 2H), 8.72 (dd, J=4.6 hz, 1.53 Hz, 1H); (ESI) m/z 311 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ccnc12
Yield: 89.9 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-3 using 4-chloro-8-nitroquinoline (Intermediate-11, step-2, 250 mg, 1.20 mmol), 4-fluoro-3-(trifluoromethyl)phenol (430 mg, 2.40 mmol), K2CO3 (479 mg, 3.60 mmol) in CH3CN (5 mL) to afford 380 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 10.75 (s, 1H), 8.82 (d, J=5.4 Hz, 1H), 7.92 (m, 1H), 7.86-7.81 (m, 3H), 7.31 (t, J=9.6 Hz, 1H), 6.90 (d, J=5.1 Hz, 1H); MS (m/z): 353.14 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([N+]([O-])=O)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1>O>[Br:16][C:17]1[CH:18]=[C:19]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 113.2 %

Procedure:
A flask was charged with 4-fluorophenol (44 g, 365 mmol) and DMF (500 mL). The reaction was cooled to 0° C. Sodium hydride (16.6 g, 414 mmol) was added and stirred for 10 minutes. 5-Bromo3-nitropicolinonitrile (90 g, 395 mmol) was added and the mixture stirred at ambient temperature for 30 minutes. The reaction was poured into a flask containing water (5000 mL) and stirred for 10 minutes. The pH was adjusted to 10 to give 5-Bromo-3-(4-fluorophenoxy)picolinonitrile (121 g, 413 mmol, 105% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:17])=[C:13]([F:16])[CH:14]=2)[C:9]([CH3:18])=[CH:8][C:7]1=[O:19].C(OCC)(=O)[C:25]([O:27]CC)=[O:26].[O-]CC.[K+]>C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:17])=[C:13]([F:16])[CH:14]=2)[C:9]([CH2:18][C:25]([OH:27])=[O:26])=[CH:8][C:7]1=[O:19]
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)c2cc(F)c(F)cc12
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)c2cc(F)c(F)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-6,7-difluoro-1,2-dihydro-4-methyl-2-oxoquinoline (5 g.) in benzene (15 ml.) was added with stirring at ambient temperature to a mixture of diethyl oxalate (2.3 g.), benzene (2 ml.) and a 6N-solution of potassium ethoxide in ethanol (6 ml.). The mixture was allowed to stand overnight at ambient temperature under dry nitrogen. The yellow solid was filtered off, washed with benzene (5 ml.) and dried by suction on the filter. The dried solid (5.7 g.) was mixed with 2.77 N-aqueous sodium hydroxide (21 ml.) at 0° C. and kept at 0° C. overnight. Ice (11.5 g.) and then 100 vol. hydrogen peroxide (4.04 ml.) were added to the mixture and it was again kept overnight at 0° C. A further quantity of 100 vol. hydrogen peroxide (1.7 ml.) was added and the mixture kept at 0° C. for 72 hours. The mixture was then treated with manganese dioxide (1 g.). When the effervescence had ceased the mixture was warmed to 50° C. and filtered. The filter cake was washed with warm 2.77 N-aqueous sodium hydroxide (20 ml.) and the total filtrate acidified with concentrated hydrochloric acid. The precipitate was collected and recrystallised first from a mixture (1/2 v/v) of ethyl acetate and cyclohexane, and then from ethanol to give 1-(3,4-dichlorobenzyl)-6,7-difluoro-1,2-dihydro-2-oxoquinol-4-ylacetic acid m.p. 185°-7° C. (dec.), in 10% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)[CH:38]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[N:36][N:37]([CH:39]5[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]5)[CH:38]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate. LCMS (M+H)+: m/z=574.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1.[N:17]1[NH:18][C:19](=[O:23])[CH:20]=[CH:21][CH:22]=1>>[CH2:13]([N:12]([CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:18]2[C:19](=[O:23])[CH:20]=[CH:21][CH:22]=[N:17]2)=[CH:3][CH:4]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCN(CC)C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: O=c1cccn[nH]1
Product: CCN(CC)C[C@H]1C[C@@H]1c1ccc(-n2ncccc2=O)cc1

Procedure:
Following the general procedure, reaction of 7c (2.87 g assayed, 10.2 mmol) with 3(2H)-pyridazinone (1.27 g, 13.2 mmol) afforded a solution of the free base of 8c in an assayed yield of 2.55 g (84% assay yield, 93% peak area).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:2]([Cl:1])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cc2Cl)CC1

Procedure:
5,6-Dichloro-nicotinic acid (5.0 g, 0.026 mol, Aldrich) reacted with piperazine-1-carboxylic acid tert-butyl ester (4.87 g, 0.026 mol, Aldrich) under the conditions of Example 3a to give the title compound as yellow semi-solid, which was used in the next step without further purification. MS (ESI, neg. ion) m/z: 340 (M-1).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH:14][C:15](=[O:17])[CH3:16].[OH-].[K+].[CH3:20]S(C)=O.CI>O>[CH3:20][N:12]1[C:13]2[CH2:1][CH:2]([NH:14][C:15](=[O:17])[CH3:16])[CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(=O)NC1CCc2c([nH]c3ccccc23)C1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CC(=O)NC1CCc2c(n(C)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 mol of N-(1,3,4,9-tetrahydro-2H-carbazol-2-yl)acetamide, 0.15 mol of powdered KOH, and 75 ml of DMSO was stirred under nitrogen for 2 hr at room temperature. Methyl iodide (0.15 mol) was added in one portion, and, after brief cooling to moderate the exothermic reaction, the mixture was stirred at room temperature for 2 hr. The precipitate obtained by pouring the reaction mixture into excess water, was filtered, washed with water, and recrystallized from ethyl acetate to give the title compound, mp 171°-172°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26](S(C)(=O)=O)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.N1(C(N)=O)CCNCC1.[CH:43]1([C:46]([OH:48])=O)[CH2:45][CH2:44]1>>[CH:43]1([C:46]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)=[O:11])=[CH:20][CH:19]=4)=[O:22])[CH2:24][CH2:25]2)=[O:48])[CH2:45][CH2:44]1
Reactant: O=C(O)C1CC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Agent: Cl
Agent: NC(=O)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b), and cyclopropylcarboxylic acid 1-piperazineamide hydrochloride to afford the desired product as a light-brown foam (89%). MS (ISP): 452.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:12]=[C:11]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[O:10][N:9]=3)=[CH:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: NC(=O)OCc1cc(-c2ccc(N)cc2)no1
Reactant: O=Cc1ccc(F)cc1
Product: NC(=O)OCc1cc(-c2ccc(NCc3ccc(F)cc3)cc2)no1

Procedure:
An experiment was performed using the above-obtained carbamic acid 3-(4-amino-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.64 mmol) as a starting material and 4-fluorobenzaldehyde (82 μl, 0.77 mmol) in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(4-fluoro-benzylamino)-phenyl]-isoxazol-5-ylmethyl ester.