Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:15][C:16]([OH:18])=O)[CH2:7][CH2:8][C:9]1[O:10][C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:5])[CH3:2].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][C:16](=[O:18])[C:13]2[CH:12]=[C:11]([CH3:14])[O:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CCc1ccc(C)o1)CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)N1CCc2oc(C)cc2C(=O)C1
Temperature: 0 °C
Yield: 44.3 %

Procedure:
[Ethoxycarbonyl[2-(5-methylfuran-2-yl)ethyl]amino]-acetic acid (0.17 g) prepared in the step 5 was dissolved in 3.5 mL of methylene chloride, then 0.12 g of thionyl chloride and 1 drop of DMF were added thereto and the mixture was heated to reflux for 2 hours. After the reaction solution was cooled, it was diluted with 5 mL of methylene chloride, then 0.18 g of aluminum chloride was added thereto and the mixture was heated to reflux again for 30 minutes. After the reaction solution was cooled, it was poured over 50 mL of ice water, the organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.07 g of the objective compound as yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=O)[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3[CH:22]=[CH:21]N=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:27]N(C)C=O.C(N)C#C>O>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][CH2:22][C:21]#[CH:27])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: C#CCN
Solvent: O
Product: C#CCNC(=O)c1ncn2c1[C@@H]1CCCN1Cc1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 54.7 g (148.7 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 100 ml of N,N-dimethylformamide and 8.60 g (156.1 mmol) of propargylamine is stirred at room temperature overnight. The solution obtained is then poured into 500 ml of water, the resulting suspension is filtered under suction and the filter residue is dried. By recrystallization from methylene chloride and ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-N-(2-propynyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide of melting point 233°-235°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[O:18]C)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[OH:18])[C:3]=12
Reactant: COc1cc(F)ccc1-c1nn(C(C)c2oc3ccccc3c(=O)c2-c2cccc(F)c2)c2ncnc(N)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(F)cc2O)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
To a solution of Example 90 (0.080 g, 0.152 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 0.8 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.027 g, 35% yield). MP: 235-237° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.66 (s, 1H), 8.04 (d, J=9.8 Hz, 1H), 8.02 (s, 1H), 7.84 (t, J=7.0 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.35 (t, J=7.2 Hz, 2H), 7.10 (t, J=8.4 Hz, 1H), 6.96 (br s, 2H), 6.79 (m, 2H), 5.98 (q, J=7.0 Hz, 1H), 1.88 (d, J=7.1 Hz, 3H). Mass: 512.22 (M++1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[CH:11][O:10][C:6]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CCN1Cc2ccoc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CCN1Cc2ccoc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: FC1C=CC(S([N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][CH2:29][C@@H:28](O)[C:27]3=[O:32])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[CH2:68][CH2:67][NH:66][CH2:65]2)=[CH:60][C:59]=1[CH3:69].N1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[CH2:68][CH2:67][N:66]([C@H:28]3[CH2:29][CH2:30][N:26]([C:23]4[CH:22]=[CH:21][C:20]([S:17]([NH:11][C:12]5[S:13][CH:14]=[CH:15][N:16]=5)(=[O:19])=[O:18])=[CH:25][CH:24]=4)[C:27]3=[O:32])[CH2:65]2)=[CH:60][C:59]=1[CH3:69]
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Reactant: Cc1cc(C2CCNC2)ccc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C2CCN([C@H]3CCN(c4ccc(S(=O)(=O)Nc5nccs5)cc4)C3=O)C2)ccc1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
Synthesized according to General Procedure 9. To a stirred suspension of [(R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl]-N-(thiazol-2-yl)benzenesulfonamide (500 mg, 1.01 mmol) in anhydrous DCM (10 mL) under nitrogen at −20° C. was added DIEA (0.88 mL, 5.03 mmol) followed by the dropwise addition of triflic anhydride (0.22 mL, 1.31 mmol) over 5 min. After stirring for 15 minutes at −20° C. a solution of 3-(4-chloro-3-methylphenyl)pyrrolidine (197 mg, 1.01 mmol) in anhydrous DCM (1 mL) was added dropwise over 5 minutes. The reaction mixture was continued to stir at −20° C. for 1 hour. Morpholine (0.35 mL, 4.02 mmol) was added and the reaction mixture was stirred at −20° C. for 1.5 hours. The reaction mixture was then poured into saturated aqueous NaHCO3 (10 mL), DCM (5 mL) was added and the phases were separated. The aqueous phase was extracted with DCM (5 mL). The organic portions were combined and washed with saturated aqueous NaHCO3 (5×5 ml). The organic layer was washed with brine (5 mL), dried over MgSO4 and absorbed onto Celite. Purification by silica gel column chromatography (1-5% MeOH in DCM) afforded 4-[(3′S)-3-(4-chloro-3-methylphenyl]-2′-oxo-1,3′-bipyrrolidin-1′-yl)-N-(thiazol-2-yl)benzenesulfonamide as a white solid (385 mg, 0.74 mmol, 74% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=517.0; tR=1.11
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13](I)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([P:27](=[O:28])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1I
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-tert-butyldimethylsilyloxy-2-methylphenyliodide 1-2 (250 mg, 0.72 mmol) in 5 mL of THF, chilled to −78 was added 0.85 mL of a 1.7 M solution of t-butyllithium in pentane (1.44 mmol). The resulting pale yellow solution was stirred at −78° C. for 30 min. Then diethyl chlorophosphate (0.13 mL, 0.86 mmol) in 2 mL THF was added via a cannula needle. The resulting mixture was stirred at −78° C. for 30 min, then diluted with aqueous NH4Cl and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The resulting residue was subjected to MPLC on a 12 g column of SiO2 eluting with 15% EtOAc in hexanes (10 min) to provide diethyl 5-tert-butyldimethylsilyloxy-2-methylphenylphosphonate 1-3 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 0.18 (s, 6H), 0.95 (s, 9H), 1.22 (t, 6H, J=6 Hz), 2.40 (d, 3H, J=1.5 Hz), 3.9-4.0 (m, 4H), 6.99 (dd, 1H, J=8, 2 Hz), 7.19 (m, 1H), 7.24 (m, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH:11]=O)=[C:9](Cl)[N:8]=[CH:7][N:6]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:4][C:5]1[N:6]=[CH:7][N:8]=[C:9]2[NH:2][N:3]=[CH:11][C:10]=12
Reactant: NN
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 830.2 %

Procedure:
Hydrazine hydrate (11.5 mL, 23.7 mmol) was slowly added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (40.0 g, 22.6 mmol) and triethylamine (30 mL, 22 mmol) in 1,4-dioxane (600 mL) with cooling to maintain an internal temperature below 20° C. After the addition was completed, the reaction was warmed to rt. After 1 hr, the reaction was filtered. The solvent was removed in vacuo to afford the title intermediate (29 g, 83%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ14.52 (br. s, 1H), 8.83 (s, 1H), 8.45 (s, 1H). MS m/z 155 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].[CH:11](OCC)(OCC)OCC>OS(O)(=O)=O>[Cl:10][C:3]1[C:2]2[N:1]=[CH:9][N:8]([CH3:11])[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: CNc1ccnc(Cl)c1N
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: Cn1cnc2c(Cl)nccc21
Reaction time: 0.38 h
Yield: 91.1 %

Procedure:
To a heterogeneous mixture of 3-amino-2-chloro-4-methylaminopyridine (5.9 g, 37 mmol) and triethyl orthoformate (12.92 mL, 87.2 mmol) was added 5 drops of conc. H2SO4. A short path distillation apparatus was attached. The reaction flask was lowered into a hot oil bath and stirred at 110° C. to 190° C. The time spent heating was 20-25 minutes. On cooling, the thick residue was dissolved in CH2Cl2 (40 mL) and was allowed to stir overnight with a little CaO. The solid was removed by filtration and the filtrate was concentrated. Flash chromatography on silica gel eluting with (CH2Cl2 /CH3OH, 95:5) gave 5.65 g (91%) of 4-chloro-1-methyl-1H-imidazo[4,5-c]pyridine as a light yellow solid: mp 127°-131° C.; MS 167 (M+).
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH2:19][C:13]2=[N:12][CH:11]=1)(=O)C1C=CC=CC=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.[CH3:29][OH:30]>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:29]([C:11]2[N:12]=[C:13]3[CH2:19][CH2:18][CH2:17][N:14]3[C:15](=[O:16])[C:10]=2[OH:9])=[O:30])=[CH:23][CH:22]=1
Reactant: O=C(Oc1cnc2n(c1=O)CCC2)c1ccccc1
Reactant: CO
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCC2

Procedure:
To a solution of crude mixture of Methyl 3-(benzoyloxy)-4-oxo-6,7,8,9-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxylate and 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl benzoate (ratio 6:1) in dry methanol, 3 eq. of 4-fluoro-benzylamine were added. The mixture was irradiated in a microwave apparatus (140° C., 500 sec). After cooling the solvent was removed under reduced pressure. The product was isolated by preparative RP-HPLC (Symmetry Column C18, 5 μm, 19×300 mm, gradient of CH3CN/H2O+0.01% TFA). The pooled product fractions were lyophilized to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Mg].[CH:14](=[O:18])[CH:15]([CH3:17])[CH3:16].S(=O)(=O)(O)O>C(OCC)C>[F:12][C:5]1[CH:4]=[CH:3][C:2]([CH:14]([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: CC(C)C=O
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A Grignard is prepared from 10 g (40 mmol) 5-bromo-2-fluorobenzotrifluoride, dissolved in 50 mL diethyl ether, and 0.97 g (40 mmol) magnesium. Then a solution of 3.63 mL (40 mmol) isobutyraldehyde and 30 mL diethyl ether is added dropwise at ambient temperature and the mixture is left overnight with stirring. The reaction mixture is poured onto ice water, combined with 30 mL 20% sulphuric acid and extracted with diethyl ether. The combined organic phases are washed successively with sodium hydrogen carbonate solution, water and sodium chloride solution, dried with sodium sulphate and evaporated down. The chromatographic purification of the residue yields the target compound in the form of a brown oil.
Reaction SMILES: S([N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1)(C1C=CC(C)=CC=1)(=O)=O.[C:17]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])O1>CN(C=O)C.C(#N)C.O>[NH:11]1[CH:15]=[C:14]([N:16]2[C:19](=[O:26])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]2=[O:27])[CH:13]=[N:12]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)n2cc(N)cn2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1c1cn[nH]c1
Yield: 92.3 %

Procedure:
1-tosyl-1H-pyrazol-4-amine (example 9-1b) (3 g, 12.7 mmol) and isobenzofuran-1,3-dione (1.9 g, 13 mmol) were stirred in DMF/Acetonitrile (1/1) (20 mL) at 100° C. for 1 hour. The mixture was cooled and diluted with H2O. The precipitate was collected by filtration, washed with additional water followed by ethyl acetate and hexanes. The solid product was dried under high vacuum to afford 2-(1H-pyrazol-4-yl)isoindoline-1,3-dione (2.5 g, 92%) as a yellow solid. MS M+H calculated 214.1; found 214.1. 1H NMR (CDCl3, 400 MHz) δ 7.93-8.10 (m, 6H), 13.03 (bs, 1H).
Reaction SMILES: C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][CH:13]([CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][C:15](O)=[O:16].C(OCC)(=O)C>O>[CH3:12][CH:13]([CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][CH2:15][OH:16]
Reactant: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CCC(C)CCO
Temperature: 10 °C

Procedure:
To 150 ml. of anhydrous diethyl ether there was added 1.9 g. of lithium aluminum hydride. To the mixture was dropwise added, under stirring and at 10° C., 11.9 g. of the carboxylic acid compound obtained in Example 3. The resulting mixture was then stirred at room temperature for 1 hour, and then 1 ml. of ethyl acetate and 1 ml. of water were added thereto. The mixture was subsequently washed with water and dried. The solvent was removed by evaporation and the resulting residual oil was purified by silica gel column chromatography to obtain 10.3 g. of the desired oily product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[S:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[S:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:35](=[O:37])[C@@H:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccccc2s1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
A solution of triphenylphosphine (274 mg, 1.04 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (211 mg, 1.18 mmol). The resulting brownish-purple mixture was stirred at 0° C. for 5 min until the reaction mixture was homogeneous. The reaction mixture was then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (200 mg, 0.70 mmol). The resulting reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzothiazole (157 mg, 1.04 mmol) and pyridine (0.17 mL, 2.09 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 85/15 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (221 mg, 76%) as a yellow foam: [α]23589=−42.4° (c=0.092, chloroform); EI-HRMS m/e calcd for C21H20Cl2N2OS (M+) 418.0673, found 418.0672.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([OH:35])=O)[CH:27]=4)[NH:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:35])[CH:27]=4)[NH:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(N2CCN(c3cncc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cncc(C4CC(C)(C)c5cc(C(=O)NS(C)(=O)=O)ccc5N4)c3)CC2)c(C)c1
Yield: 30 %

Procedure:
A mixture of 2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-methanesulfonamide (34.5 mg, 30%) as a light yellow solid: MS (ESI) M+1=548.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]([CH:19]1[CH2:24][CH2:23]O[C:20]1=[O:21])(=O)[CH3:17].P(Cl)(Cl)([Cl:27])=O>C1(C)C=CC=CC=1.C1CCCCC1>[Cl:27][CH2:23][CH2:24][C:19]1[C:20](=[O:21])[N:3]2[CH2:4][CH2:5][CH2:6][CH:7]([OH:8])[C:2]2=[N:1][C:16]=1[CH3:17]
Reactant: CC(=O)C1CCOC1=O
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-Amino-3-benzyloxypyridine (formula-2) (20 grams) in toluene (40 ml) added 2-acetyl gammabutyro lactone (formula-3) (16.6 grams), stirred for 15 min and added phosphorus oxychloride (0.27 ml). The reaction mixture was refluxed for 12 hours and water was removed azeotropically. Then the reaction mixture was cooled to 70-80° C., added phosphorus oxychloride (11.9 ml) and then heated to 90-95° C. and stirred for 8 hr. The solvent was distilled off under reduced pressure and concentrated hydrochloric acid (70 ml) was added to the reaction mixture followed by toluene (100 ml) and stirred at 65-70° C. for 9 hours. The reaction mixture was cooled to 0-5° C. and the solid formed was filtered, washed with toluene and acetic acid. The wet solid was taken in autoclave along with acetic acid (110 ml), added Pd/C and applied 3.0-3.5 kg/cm2 hydrogen pressure. The reaction mixture was heated to 50-60° C., stirred for 8 hrs, then cooled to 25° C. and quenched with water. The reaction mixture was filtered and the pH of the filtrate was adjusted to 11 using aqueous sodium hydroxide solution. Extracted the reaction mixture with ethyl acetate. The ethyl acetate layer was treated with basic carbon, filtered and distilled off under reduced pressure. The solid formed was taken in cyclohexane (45 ml) and stirred for 60 min at 25° C. The solid was filtered, washed with cyclohexane and dried to provide the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(F)c1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
2,3-Difluorophenol (4.55 g) was dissolved in DMF (25 mL) and was treated with powdered K2CO3 (6.0 grams) and the mixture was stirred at an ambient temperature for 10 minutes under nitrogen atmosphere. The mixture was treated with iodomethane (9.0 grams), and was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and was extracted with ether. The ether extract was washed with water, dried (Na2SO4) and concentrated to afford 3.8 grams of title compound as amber oil. 1HNMR(CDCl3): δ 6.97(m, 1H), 6.78(m, 2H), 3.90(s, 3H). Step 2: 2,3-Difluoro-4-methoxybenzaldehyde.
Reaction SMILES: C([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=CCC.C(#N)[CH:12]=[CH2:13].C(O)(=[O:17])C.O>C(#N)C>[CH2:12]([CH:7]([CH:6]=[O:17])[CH2:8][CH2:9][C:10]#[N:5])[CH3:13]
Reactant: CCC=CN1CCCCC1
Reactant: C=CC#N
Reactant: CC(=O)O
Solvent: O
Solvent: CC#N
Product: CCC(C=O)CCC#N
Yield: 42 %

Procedure:
A stirred solution of N-(1-buten-1-yl)piperidine [Mannich, D.; Ber. 1936, 69, 2106] (4.2 g, 29.9 mmol) and acrylonitrile (2.1 g, 38.8 mmol) in acetonitrile (25 mL) was heated at reflux for 18 hours. Acetic acid and water (10 mL, 1:1) was added and the reaction was heated an additional 4 hours. The acetonitrile was removed in vacuo and the residue was taken up in ether (60 mL). The ether was washed with water (2×40 mL), saturated sodium bicarbonate/water (40 mL), dried (magnesium sulfate), concentrated in vacuo and then distilled to afford the title compound (1.6 g, 42%) as a colorless liquid. bp 132° C. (18 mm);
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:17]1[CH:22]=[N:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>CN(C=O)C.CCOC(C)=O>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1cnc([N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (60%, 3.0 g, 75 mmol) in 100 mL of DMF was added tert-butyl ethyl propanedioate (14.1 g, 75 mmol) dropwise at 25° C. The mixture was stirred at 40° C. for 30 minutes and 2-bromo-5-nitropyrazine (10.2 g, 50 mmol) in 50 mL of DMF was added dropwise. The resulting suspension was stirred at 50° C. for 2 hours and diluted with 500 mL of EtOAc. The mixture was washed with water (100 mL*3), brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (petrol ether: EtOAc=5:1) to afford title compound.