Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[S:5][C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[N:3][C:2]=1[CH2:10][S:11][CH2:12][CH2:13][C:14]([NH:16][S:17]([NH2:20])(=[O:19])=[O:18])=[NH:15].[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25]>ClCCl>[CH:1]1[S:5][C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[N:3][C:2]=1[CH2:10][S:11][CH2:12][CH2:13][C:14]([NH:16][S:17]([NH2:20])(=[O:19])=[O:18])=[NH:15].[NH2:21][C@H:22]([C:27]([O-:29])=[O:28])[CH2:23][C:24]([O-:26])=[O:25]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N=C(N)Nc1nc(CSCCC(=N)NS(N)(=O)=O)cs1
Solvent: ClCCl
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.56 g (0.166 cmole) of famotidine and 0.222 g (0.166 cmole) of aspartic acid was suspended in dichloromethane (10 ml). The mixture was stirred for 3 hours at room temperature, was filtered, washed with dichloromethane and dried. Weight: 0.782 g. Quantitative yield. Stereoscopically homogenous white microcrystalline solid, similar to milky quartz. Slightly bitter taste. M.P.: 165°-170° C. IR FIG. 2.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[CH2:11][C@:10]1([C:41]1[CH:46]=[C:45]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH3:55])=[CH:50][CH:49]=2)[CH:44]=[CH:43][C:42]=1[F:56])[OH:40])C1C=CC=CC=1>CO.C1COCC1.[OH-].[Pd+2].[OH-]>[CH2:54]([C:51]1[CH:50]=[CH:49][C:48]([CH2:47][C:45]2[CH:44]=[CH:43][C:42]([F:56])=[C:41]([C@:10]3([OH:40])[CH2:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]3[OH:8])[CH:46]=2)=[CH:53][CH:52]=1)[CH3:55]
Reactant: CCc1ccc(Cc2ccc(F)c([C@]3(O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(F)c([C@]3(O)C[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)cc1
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a mixture solution of (1R,2R,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethyl-1-[5-(4-ethylbenzyl)-2-fluorophenyl]cyclohexanol (271 mg, 0.361 mmol) in methanol-THF (1:1) mixed solvent (20 mL), a 20% palladium hydroxide catalyst (40 mg) was added thereto. The mixture was stirred under a hydrogen atmosphere for 30 minutes, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=methanol:methylene chloride (1:10)] to obtain the title compound (44.6 mg, 31.6%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>>[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH:30][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: COCCOc1cccc(CN)c1
Reactant: Cc1ccc(CN)o1
Product: COCCOc1cccc(CNc2cccc3nc(NCc4ccc(C)o4)ccc23)c1

Procedure:
The title compound, MS: m/e=418.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3-(2-methoxy-ethoxy)-benzylamine.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].O>C(#N)C>[C:1]1([CH2:7][C:8]([N:13]=[C:12]=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ccccc1)N=C=S
Temperature: 80 °C

Procedure:
According to the descrition of technical literature, commercially available 2-phenylethanoyl chloride (80 mg) was dissolved in acetonitrile (20 ml). Potassium thiocyanate (300 mg) was added to the solution, and the mixture was heated at 80° C. for 2 hr. Water was added to the reaction solution, and the organic layer was extracted and was concentrated to give 2-phenylethanoyl isothiocyanate. 2-Phenylethanoyl isothiocyanate thus obtained was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 85%) (Referenc: Elmore, D. T. et al., Journal of chemical Society 1956, 4458).
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:25])[C:19](=[CH:23][CH:24]=1)[C:20](O)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH2:1]([C:16]1[CH:17]=[C:18]([OH:25])[C:19](=[CH:23][CH:24]=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1ccc(C(=O)O)c(O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCc1ccc(CO)c(O)c1

Procedure:
4-Pentadecylsalicylic acid (5.3 g) in dry tetrahydrofuran (60 cm3) is slowly added to stirred lithium aluminium hydride (2.5 g) in dry tetrahydrofuran (25 cm3) and the mixture then stirred and refluxed for five hours to complete the reduction. Work-up by recovery of the tetrahydrofuran, addition of a little ethyl acetate to the cooled residual material, followed by acidifiction and ethereal extraction yields the crude product which is crystallised from light petroleum (40°-60°) to give 4-pentadecylsalicyl alcohol as pale cream prisms, m.p. 94°-95°, (4.05 g).
Reaction SMILES: [CH:1]1([CH:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1.C(=O)=O.CC(O)C>>[CH:1]1([C@@H:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(O)C1CC1
Agent: O=C=O
Solvent: CC(C)O
Product: COc1cc([N+](=O)[O-])ccc1OC[C@H](O)C1CC1

Procedure:
Racemic 1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol (45.1 g, mmol) in 2/1 MeCN/1-PrOH (451 mL) was resolved by chiral chromatography resolution using a CHIRALPAK® AD-H (3×25 cm, 5 μm) column under the Chiral-SFC conditions. The chromatographic conditions employed an 85/15 mixture of CO2/i-PrOH as the mobile solvent with a flow rate of 130 mL/min at 35° C. with the BPR pressure maintained at 100 bar and detector wavelength at 234 nM. Each 0.7 mL injection required a run time of 7 min. The chiral purity of the R enantiomer was determined to be greater than 99.9% at 234 nm based on SFC/UV area % using analytical SFC conditions. Concentration of the resultant eluant under vacuum using a rotary evaporator yielded (R)-1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol as yellow oil. Subsequent dissolution in 150 ml EtOH and reconcentration yielded the title compound in the form of a yellow oil, which solidified to form a light yellow solid (20.9 g) upon drying under high vacuum overnight. M.P. 77° C. 1H NMR (400 MHz, CDCl3): δ ppm 0.30-0.37 (m, 1H), 0.42-0.50 (m, 1H), 0.55-0.69 (m, 2H), 0.97-1.08 (m, 1H), 2.40-2.70 (bs, 1H), 3.41 (ddd, J=8.3, 8.3, 2.7 Hz, 1H), 3.93 (s, 3H), 4.10 (dd, J=9.3, 8.0 Hz, 1H), 4.23 (dd, J=9.3, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.89 (dd, J=8.8, 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ ppm 153.7, 149.2, 141.7, 117.6, 111.5, 106.7, 74.4, 73.5, 56.2, 13.4, 2.7, 2.0. HPLC: 6.26 min retention time, 98.7% API; ZORBAX® column SB C18 4.6×75 mm; flow rate 2.5 ml/min; Gradient solvent system: from 100% A:0% B to 0% A:100% B for 8 min (Solvent A: 10% MeOH-90% H2O=0.2% H3PO4; Solvent B: 90% MeOH-10% H2O+0.2% H3PO4) Detection at 220 nm. LC/MS: m/e=254.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][CH2:32]Cl.Cl.[NH:35]1[CH2:38][CH2:37][CH2:36]1>>[N:35]1([CH2:31][CH2:32][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])[CH2:38][CH2:37][CH2:36]1
Reactant: ClCCBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C1CNC1
Agent: Cl
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCC1

Procedure:
(5Z)-3-(2-Azetidin-1-ylethyl)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1), 1-bromo-2-chloroethane and azetidine hydrochloride following General Procedure G.
Reaction SMILES: [C:1]([C:9]([O:11]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]I.[CH2:17]([O:24][CH2:25][C:26](Cl)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li+].[CH3:30]C([N-]C(C)C)C.Cl>C1COCC1.CCOCC>[OH:11][C:9]1[C:1]([CH3:30])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:8][C:26](=[O:27])[C:25]=1[O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: C[Mg]I
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(c2ccccc2)OC(=O)C(OCc2ccccc2)=C1O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 20 %

Procedure:
To a 2-necked flask flame dried under argon with septum and charged with a solution of 3.6 g (20 mmol) of ethyl benzoylformate in 50 mL of anhydrous THF at -30° C. was slowly added 7 mL (21 mmol) of a 3.0 M solution of methylmagnesium iodide. The reaction mixture was stirred at 0° C. for 45 minutes, then at room temperature for 30 minutes and again cooled to 0° C. Benzyloxyacetyl chloride (3.4 mL, 21 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour, cooled to -78° C. and 33 mL of a 1.5 M solution of LDA in THF was added with rapid stirring. The mixture was worked up after 1 hour by the addition of 100 mL of aqueous 10% HCl solution and 300 mL of ether. The layers were separated and the organic phase was washed with 50 mL aqueous 10% HCl solution, 30 mL of H2O, and extracted with 3×40 mL of saturated NaHCO3 solution. The bicarbonate extracts were combined and washed with 40 mL of ether, acidified to pH 1 with 10% aqueous HCl solution, and extracted with 2×80 mL of ether. The organic fractions were combined, washed with 25 mL of H2O, 25 mL of brine, dried (MgSO4), and concentrated leaving 1.2 g (20% yield) of 4-hydroxy-5-methyl-5-phenyl-3-phenylmethoxy-2-(5H)-furanone as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-methoxypyridin-4-ylboronic acid (0.308 g, 2.0 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 19.7 h to give 4-chloro-5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methylquinoline as an off white solid. Mass Spectrum (ESI) m/e=321.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[NH2:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:27][NH:26][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1ccncc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1ccncc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) and EtOAc (10.0 mL). 4-Hydrazinylpyridine hydrochloride (0.16 g, 1.2 eq.) was added at −40° C. followed by the simultaneous addition of T3P (50% in EtOAc, 0.85 mL, 2.0 eq.) and DIPEA (0.49 mL, 4.0 eq.). The reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.35 g of crude material. Purification by column chromatography using MeOH:CH2Cl2 as a mobile phase (compound was eluted with 4% MeOH in CH2Cl2) afforded 80 mg (yield: 29.85%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-4-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.53 (br s, NH exchangeable, 1H), 9.58 (s, 1H), 8.88 (br s, NH exchangeable, 1H), 8.84 (s, 2H), 8.29 (s, 1H), 8.09-8.11 (d, 2H), 7.52-7.54 (d, J=10.4 Hz, 1H), 6.66-6.69 (m, 2H), 6.06-6.10 (d, J=14.4 Hz, H); LCMS for C18H13F6N6O [M+H]+ 443.33. found 443.24 (RT 2.241 min, purity: 90.17%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].C(O[O:14][C:15]([CH3:18])(C)C)(C)(C)C.[C]=O.[CH2:21]([OH:23])C>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][C:21]([O:14][CH2:15][CH3:18])=[O:23]
Reactant: CCO
Reactant: Cc1ccccc1C
Reactant: CC(C)(C)OOC(C)(C)C
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1C
Temperature: 120 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
o-Xylene (1.59 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 81 mg ethyl o-methylphenylacetate was obtained by column chromatography, in a yield of 91%. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 2.32 (s, 3H), 3.63 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.15-7.21 (m, 4H); 13CNMR (100 MHz, CDCl3) δ 14.2, 19.6, 39.3, 60.8, 126.1, 127.3, 130.1, 130.3, 132.9, 136.8, 171.5; HRMS (ESI) calcd. for C11H14NaO2 [M+Na]: 201.0886. found: 201.0882. The ethyl o-methylphenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 66 mg product o-methylphenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 97%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1C.Cl[S:19]([OH:22])(=[O:21])=[O:20].S(=O)(=O)([O-])N.[C:28](=O)([O-])[O-].[Na+:32].[Na+]>N1C=CC=CC=1C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:19](=[O:20])(=[O:21])[O-:22])=[CH:7][C:6]=1[CH3:28].[Na+:32]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(-c2nc3ccccc3s2)ccc1N
Agent: NS(=O)(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccn1
Product: Cc1cc(NS(=O)(=O)[O-])ccc1-c1nc2ccccc2s1
Yield: 82 %

Procedure:
2-(4'-amino-3'-methylphenyl)benzothiazole was treated with chlorsulphonic acid in 2-picoline and sodium carbonate according to the above-described general procedure for preparation of sulphamate salts. A yellow powder was obtained in 82% yield, m.p. 169.5° C. (dec).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[NH:31]1[CH2:35][CH:34]=[CH:33][C@@H:32]1[C:36]([NH2:38])=[O:37].C(N(CC)C(C)C)(C)C.CN(C)C(=O)C>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:31]5[CH2:35][CH:34]=[CH:33][C@@H:32]5[C:36]([NH2:38])=[O:37])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:25])[CH3:26]
Reactant: NC(=O)[C@H]1C=CCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC=C[C@@H]3C(N)=O)cc1OCC2
Temperature: 80 °C

Procedure:
A mixture of 134 mg (0.30 mmol) of 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate, (R)-2,5-dihydro-1H-pyrrole-2-carboxamide (84.1 mg, 0.750 mmol) and N,N-diisopropylethylamine (61.0 uL, 0.350 mmol) in N,N-Dimethylacetamide (3.0 mL, 32 mmol) was heated for 18 hours at 80° C. The mixture was concentrated in high vacuum, the residue triturated with 5% aqueous citric acid. The precipitate was filtered out, washed with aq. citric acid, water, dried in vacuum and purified by RP HPLC (acetonitrile gradient) to give 388. Yield 28 mg. M/z 407.2, calc. 406.19. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 6.98 (s, 1H), 6.13 (dd, J=6.2, 1.9, 1H), 6.02-5.88 (m, 3H), 4.97 (s, 1H), 4.52 (dd, J=9.3, 7.1, 4H), 4.39-4.18 (m, 2H), 1.48 (dd, J=6.6, 2.5, 6H)
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(O)(O)=O>C(#N)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=1)=[N:3]2
Reactant: O=Cc1cc2c(Cl)cccc2nc1Cl
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: O=Cc1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.0000 g, 4.424 mmol), 3-fluorophenylboronic acid (0.6808 g, 4.866 mmol), tetrakis(triphenylphosphine)-palladium (0.2556 g, 0.2212 mmol), and sodium carbonate anhydrous (2.344 g, 22.12 mmol) in acetonitrile-water (3:1) (0.04000 mL) was stirred at 100° C. After 3 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-2-(3-fluorophenyl)-quinoline-3-carbaldehyde as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.14 (1 H, s), 9.06 (1 H, d, J=0.8 Hz), 8.13-8.18 (1 H, m), 7.92-8.00 (2 H, m), 7.59-7.67 (2 H, m), 7.53-7.58 (1 H, m), 7.39-7.47 (1 H, m); LC-MS (ESI) m/z 286.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]/[C:7]([O-:9])=O)[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Cl.[CH3:25][N:26]([CH3:35])[CH2:27][CH2:28][CH2:29]N=C=NCC>C(Cl)Cl>[CH2:27]([N:26]1[CH2:25][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH:6]([C:7]([N:21]2[CH2:20][CH2:19][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)[CH2:23][CH2:22]2)=[O:9])[CH2:35]1)[C:28]1[CH:29]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1C(=O)N1CCC(c2ccc(F)cc2)CC1
Yield: 100.3 %

Procedure:
A solution of 2.87 g (20 mmol) of mono-ethylfumarate (Aldrich), 3.24 g (20 mmol of 4-(4-fluorophenyl)piperidine, 2.93 g (24 mmol) of 4-dimethylaminopyridinie, and 7.67 g (40 mmol) of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in 40 mL of CH2Cl2 at rt was stirred for 2.5 h. The reaction mixture was diluted with CH2Cl2, washed with NaHCO3, dried over Na2SO4, filtered. The filtrate was concentrated and the residue was purified by chromatography (silica, acetone: hexanes, 1:3) to give 4.4 g of the title compound 1H NMR (CDCl3) δ 7.44 (d, 1H, J=15.5 Hz), 7.14-7.16 (m, 2H), 7.00 (t, 2H, J=8.5 Hz), 6.77 (d, 1H, J=15.5 Hz), 4.26 (q, 2H, J=7 Hz), 1.33 (t, 3H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl.[Cu]I>[C:23]([C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8])#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C#CCCCCCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 72.3 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (425 mg, 1.1 mmol), 1-octyne (0.2 mL, 1.4 mmol), Pd(PPh)3Cl2 (20 mg), CuI (catalytic amount) and triethylamine (0.5 mL) in methylene chloride (8 mL) was heated at reflux for 16 hours. Heating was continued until no starting material remained. The solvent was removed, and the residue was washed with 10% NaOH then extracted with methylene chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:ether 100:6-100:15 to afford to give the title compound (335 mg, 72% yield). MS (DCI/NH3) m/z 421 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.90 (m, 3H), 1.32 (m, 4H), 1.48 (s, 9H), 1.49 (m, 2H), 1.62 (m, 2H), 1.88 (m, 2H), 2.00 (m, 2H), 2.48 (m, 2H), 3.34 (m, 2H), 3.90 (m, 1H), 4.12 (m, 2H), 7.30 (br s, 1H), 7.98 (m, 1H).
Reaction SMILES: [Cl-:1].[Mg+2].[Cl-].[O:4]=[C:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1C=CC=CC=1.Cl[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>O1CCCC1>[Cl:1][C:30]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([CH:6]([C:5](=[O:4])[CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:25]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: [Cl-]
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a suspension of magnesium chloride (3.01 g) in tetrahydrofuran (30 mL) was added tert-butyl 3-oxobutanoate (5.00 g). The mixture was cooled under an ice-bath. Then, pyridine (5.00 g) was added over 15 minutes. After stirring for 1 hour at room temperature, the resulting mixture was cooled under the ice-bath. A solution of 2-chlorobenzoyl chloride (4.98 g) in tetrahydrofuran (30 mL) was added over 15 minutes. The mixture was stirred for 1 hour at room temperature. The reaction was quenched by adding 1N hydrochloric acid (65 mL). The mixture was filtered, and the solvent was evaporated off. The residue was extracted with ethyl acetate (150 mL). The extract was washed with water (100 mL), saturated sodium bicarbonate (100 mL), and brine, dried over magnesium sulfate, and evaporated to give tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate as an yellow oil (8.82 g).