Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17]>C(N(CC)CC)C.N1C=CC=CC=1.[Cu]I.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.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C#Cc1ccc(OCCCCC)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCCCOc1ccc(C#Cc2ccc(C(=O)OCC)cc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
To a suspension of ethyl 4-bromobenzoate (1.37 g), (4-n-pentyloxyphenyl)acetylene (565 mg), triphenylphosphine (16 mg) and copper(I) iodide (6 mg) in triethylamine (10 ml) and pyridine (4 ml) was added palladium(II) chloride bis(triphenylphosphine) (21 mg) and the reaction mixture was stirred for 24 hours at 80° C. After cooling, the precipitate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was taken up to dichloromethane, and the solution was washed successively with 1N HCl, water, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile, collected by filtration and dried under reduced pressure to give ethyl 4-(4-n-pentyloxyphenylethynyl)benzoate (355 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:20]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccncc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.014 gm (0.080 mMol) 4-pyridinecarbonyl chloride hydrochloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[C:16]1(=O)C2C(=CC=CC=2)CC1=O>>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]2[C:6]=1[C:11](=[O:12])[CH2:16][C:8]2=[O:10]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: O=C1Cc2ccccc2C1=O
Product: O=C1CC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21

Procedure:
Tetrachloro phthalic anhydride was converted to the indane dione by the method described in Example 8(a), decomposes on heating. (Found; C, 39.01; H, 0.75; Cl, 50.15; C9H2Cl4O2 requires: C, 38.07; H, 0.71; Cl, 49.60%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][S:5][CH2:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:1][CH2:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][S:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: O=C1CCSCC1CO
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1CSCCC1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To an ice-cooled solution of 1.26 g (0.0086 mol) of product from Step C and 1.44 g (0.0142 mol) of triethylamine in 25 ml of methylene chloride was added dropwise 0.75 g (0.0095 mol) of acetyl chloride. The solution was stirred for four hours at 0° C., after which time it was washed with water, a saturated solution of sodium bicarbonate, and water. The organic phase was dried (MgSO4), filtered, and evaporated to give 1.52 g (94%) of product.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N([O-])=[O:12].[Na+].[OH-].[Na+]>O.OS(O)(=O)=O>[S:8]1[C:4]2[CH:3]=[C:2]([OH:12])[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: O=N[O-]
Reactant: Nc1ccc2ncsc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc2ncsc2c1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-aminobenzothiazole (1.0 g, 6.66 mmol) in water (22 mL) and H2SO4 (16 mL) at 5° C. was added a solution of sodium nitrite (460 mg, 6.72 mmol) in water (13 mL) keeping the temperature below 5° C. The resulting solution was allowed to stir for 15 minutes. The reaction mixture was heated to 160° C. and a solution of H2SO4 (50 mL) and water (38 mL) was slowly added. The resulting mixture was allowed to stir for 1 h. The mixture was allowed to cool and an aqueous solution of 50% sodium hydroxide was added until the pH=7. The mixture was extracted with ethyl acetate and washed with brine. The combined organic was dried over MgSO4 and evaporated to yield a semi-solid. The semi-solid was purified by column chromatography (40% ethyl acetate/hexanes) to yield benzothiazo-6-ol 16 as an off-white solid. Synthesis of 6-(oxiran-2-ylmethoxy)benzothiazole (48):
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(O[C:16]([S-])=[S:17])C.[K+].C(O)C>O>[S:17]=[C:16]1[NH:1][C:2]2[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C#N)c1ccc2oc(=S)[nH]c2c1

Procedure:
A mixture of 2-(3-amino-4-hydroxyphenyl)propionitrile (4.86 g.), potassium ethylxanthate (5.3 g.), ethanol (30 ml.) and water (5.0 ml.) was heated under reflux for four hours. The mixture was filtered, diluted with water (15 ml.), acidified with acetic acid and then diluted with more water. The resulting brown precipitate was filtered off and recrystallised from aqueous ethanol to give 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl) propionitrile, m.p. 173°-6° C. Dry chlorine was passed into a suspension of the thione (8.0 g.) in freshly dried and distilled chloroform (200 ml.). After 20 hours, most of the solid had dissolved and the mixture was filtered. The filtrate was washed with water (100 ml.), 1N sodium hydroxide (50 ml.) and water (3 × 100 ml.) The dried (Na2SO4) organic solution was evaporated to yield 2-[2-chloro-5-benzoxazolyl]propionitrile as a brown oil which was shown to be a single compound by thin layer chromatography. The oil distilled at 128°-134° C./0.3 mm.Hg.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][C:7]([C:11]([F:14])([F:13])[F:12])([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[CH:30]=[C:31](I)[S:32][C:25]=12)[NH2:19]>>[NH2:19][C:18]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[C:31]([C:3]#[C:2][CH2:1][N:4]4[CH2:9][CH2:8][C:7]([C:11]([F:14])([F:12])[F:13])([OH:10])[CH2:6][CH2:5]4)[S:32][C:25]=23)=[C:16]([F:15])[CH:17]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCC(O)(C(F)(F)F)CC1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCC(O)(C(F)(F)F)CC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 39.7 %

Procedure:
Prepared from 1-(prop-2-ynyl)-4-(trifluoromethyl)piperidin-4-ol (40 mg, 0.19 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was partially purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (24 mg) and carried forward without further purification,
Reaction SMILES: C1(C(C2C=CC=CC=2)[O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:19]=[C:20]([C:25](=[O:27])[CH:26]=3)[C:21]([O:23]C)=[O:22])=[CH:13][CH:12]=2)=[O:10])C=CC=CC=1.O.C1C=CC=CC=1.C(O)(=O)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:19]=[C:20]([C:25](=[O:27])[CH:26]=2)[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1)([OH:10])=[O:8]
Reactant: COC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(C(=O)OC(c3ccccc3)c3ccccc3)cc2)cc1=O
Solvent: O
Solvent: c1ccccc1
Solvent: COc1ccccc1
Product: O=C(O)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Yield: 60.4 %

Procedure:
In a mixed solvent of 2.5 ml of anisole and 2.5 ml of trifluoroacetic acid was dissolved 0.25 g of methyl 6-(4-diphenylmethyloxycarbonylphenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate, and they were reacted at room temperature for 1.5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in a mixed solvent of 2.5 ml of ethanol and 2.5 ml of a 1N aqueous sodium hydroxide solution, and the resulting solution was subjected to reaction at room temperature for 3 hours. After completion of the reaction, 20 ml of water and 20 ml of benzene were added to the reaction mixture and the aqueous layer was separated. The aqueous solution thus obtained was adjusted to a pH of 5.5 with acetic acid and the precipitated crystals were collected by filtration, to obtain 0.10 g of 6-(4-carboxyphenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 280° C. or more.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:22]([N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl)[CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:31][CH2:30][N:26]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]1)=[O:21])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OCCC(C)C)cc1
Reactant: CCCCN(CCCl)CCCl
Product: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1

Procedure:
1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 =mol). Yield 7 g (79%); yellow oil; MS: 440 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.CN([CH:19]=[O:20])C1C=CC=CC=1>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH:19]=[O:20]
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CN(C=O)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc(F)c1

Procedure:
The 3,5-difluorobenzaledehyde used as a starting compound can be prepared as follows: 3,5-difluorophenylmagnesiumbromide can be prepared as described by A. Roe and W. F. Little: J.Org.Chem. 20 (1955) 1577. A solution of 3,5-difluorophenylmagnesiumbromide in diethylether is added dropwise to a solution of N-methylformanilide in tetrahydrofuran. By working up this reaction mixture, 3,5-difluorobenzaldehyde is obtained. b55 =86°-88° C.
Reaction SMILES: [Li].N.[CH2:3]1[CH2:29][O:28][C:5]([C@@H:7]2[C@:24]3([CH3:25])[C@H:10]([C@H:11]4[C@H:21]([CH2:22][CH2:23]3)[C@:19]3([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[C@@H:17]5[O:26][C@@H:18]53)[CH:13]=[CH:12]4)[CH2:9][CH2:8]2)([CH3:6])[O:4]1.C=CC(=C)C.[Cl-].[NH4+]>CCOCC.O1CCCC1.CCOCC>[CH2:29]1[CH2:3][O:4][C:5]([C@@H:7]2[C@:24]3([CH3:25])[C@H:10]([C@H:11]4[C@H:21]([CH2:22][CH2:23]3)[C@:19]3([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:27])[CH2:17][C@@H:18]3[OH:26])=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)([CH3:6])[O:28]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4C=CC5=CC(=O)[C@@H]6O[C@@H]6[C@]5(C)[C@H]4CC[C@]23C)OCCO1
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C=CC(=C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](O)C[C@H](O)[C@]5(C)[C@H]4CC[C@]23C)OCCO1
Reaction time: 0.08 h
Yield: 84.9 %

Procedure:
A mixture of 0.594 g (0.0856 g-atom) of lithium in 500 ml of dry liquid ammonia of -31° C. to -33° C. is prepared and stirred for 5 minutes. Then, a solution of 4.535 g (0.0122 mol) of 20,20-ethylenedioxy-1α,2α-epoxy-pregna-4,6-dien-3-one in 300 ml of ether/tetrahydrofuran (2:1) is added to the mixture dropwise under argon during 40 minutes. The resulting deep blue mixture (at -33° C.) is stirred for a further 15 minutes and treated with 2 ml of isoprene until the colour changes to yellow. A total of 4.579 g (0.0856 mol) of ammonium chloride are added in portions with stirring. To the mixture is then added 0.654 g (0.0122 mol) of ammonium chloride and subsequently 0.0849 g (0.0122 g-atom) of lithium. As soon as the lithium has dissolved, this procedure, i.e. the addition of 0.0122 mol of ammonium chloride followed by the amount of lithium equivalent thereto is repeated a further fifteen times, for which a total of 9.81 g (0.183 mol) of ammonium chloride and 1.273 g (0.183 g-atom) of lithium are required. As soon as the lithium of the last addition has dissolved, 9.5 g (0.17 mol) of ammonium chloride and then 500 ml of ether are added. Ammonia is evaporated with stirring until an internal temperature of 0° C. has been reached and the remaining suspension is treated with 500 ml of water and 500 ml of ether. The organic phase is separated and the aqueous phase is back-extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated at 40° C. in a water-jet vacuum. The residue yields, by chromatography on 150 g of silica gel with ether/tetrahydrofuran (19.1) and (4:1), 3.9 g (85%) of uniform 20,20-ethylenedioxy-1α,3β-dihydroxy-pregn-5-ene. The analytical sample is obtained by recrystallisation from methanol; melting point 203°-207° C.; [α]D25 =-47° (c=0.5 in chloroform).
Reaction SMILES: [C:1]1([C:7]([N:9]=[C:10]=[S:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([CH3:34])[C:28]=1[CH3:35].C1(C)C=CC=CC=1>C(O)C>[C:7]([NH:9][C:10]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[C:28]([CH3:35])[C:29]=1[CH3:34])=[S:11])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Comercially available 1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (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 (50 mg, yield 67%).
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[CH2:15][C:14]([O:18][CH3:19])([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.N>>[SH:4][CH2:5][C:6]([N:8]1[CH2:15][C:14]([O:18][CH3:19])([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CSC(C)=O)C1
Agent: N
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CS)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to yield 1-(2-mercapto-1-oxoethyl)-4,4-dimethoxy-L-proline.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>[Pd].CCO>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1c([N+](=O)[O-])ccc2ncccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2ncccc2c1N
Reaction time: 8 h

Procedure:
A mixture of 5-Amino-6-nitroquinoline (650 mg, 3.44 mmol), Pd/C (70 mg) and 15 mL of EtOH was stirred under H2 (balloon) overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated to give 5,6-diaminoquinoline.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.[Cu](C#N)[C:18]#[N:19]>CN(C)C=O.Cl.[Fe](Cl)Cl>[C:18]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)#[N:19]
Reactant: Brc1ccsc1-c1sccc1-c1cccs1
Reactant: N#C[Cu]C#N
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1ccsc1-c1sccc1-c1cccs1
Temperature: 25 °C

Procedure:
10 mmol of 3-bromoterthiophene was refluxed in anhydrous dimethylformamide (10 ml) containing 15 mmol of copper cyanide for 4 hours. After the dark mixture was allowed to cool to room temperature it was mixed with iron chloride (10 g) in hydrochloric acid solution (20 ml, 2.0M) and maintained at 60˜70° C. for 30 minutes. The organic extract was washed with hydrochloric acid solution (20 ml, 6M), distilled water, saturated sodium bicarbonate solution and aqueous sodium chloride solution to obtain a dark yellowish solid. The obtained solid was recrystallized from an organic solvent. The product has a melting point of 83° C. and a molecular weight of 272.9736 g/mol as measured using a mass spectrometer. The structure of the product was identified through 13C NMR, 1H NMR, and IR spectrometer.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH2:16])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]([F:26])([F:25])[C:19]([OH:24])([CH3:23])[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CO>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:20](=[O:21])[C:19]([OH:24])([CH3:23])[C:18]([F:26])([F:25])[F:17])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(O)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Temperature: 0 °C

Procedure:
A cooled (0° C.) solution of 3-amino-6-bromo-5-(trifluoromethyl)picolinohydrazide (Intermediate H) (15 g, 50.2 mmol) in dry NMP (50 ml) was treated with 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (8.72 g, 55.2 mmol), HATU (20.98 g, 55.2 mmol) followed by dropwise addition of TEA (15.38 ml, 110 mmol) over 10 minutes. The orange solution was stirred at 0° C. and allowed to warm to RT and stirred for 3 days. The reaction mixture was partitioned between EtOAc (200 mL) and 1M NaOH (200 mL), shaken and separated. The organic portion washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to give an orange oil. The oil was taken up in methanol (50 mL) and triturated with water (300 mL) to afford the title compound as a yellow solid;
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]([NH2:14])[CH3:13].[C:15]([NH:22][CH2:23][CH2:24][C:25](O)=[O:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:18]([O:17][C:15](=[O:16])[NH:22][CH2:23][CH2:24][C:25](=[O:26])[NH:14][CH:12]([C:4]1[NH:3][C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)[CH3:13])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(N)c1cc2ccncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)CCNC(=O)OC(C)(C)C)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.9 %

Procedure:
A mixture of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethylamine dihydrochloride (Example 75) (108 mg, 0.46 mmol), N-Boc-β-alanine (71 mg, 0.37 mmol), diisopropylethylamine (0.31 mL, 1.85 mmol), EDCI (78 mg, 0.41 mmol) and HOBt (catalytic amount) in methylene chloride (2.2 mL) was stirred at room temperature under a nitrogen atmosphere overnight (22 h). The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in CH2Cl2, washed with water and saturated NaHCO3, and dried over Na2SO4. Filtration and concentration provided tert-butyl[2-[N-[1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl]carbamoyl]ethyl]carbamate (70 mg, 58%) as a tan solid: 1H NMR (500 MHz, CD3OD) δ1.45 (9H, s), 1.63 (3H, d), 2.37-2.51 (2H, m), 3.30-3.42 (2H, m), 5.26-5.35 (1H, m), 6.43 (1H, s), 7.48-7.51 (1H, m), 7.99-8.05 (1H, m), 8.60 (1H, s); ESI MS m/z 333 [C17H24N4O3+H]+; HPLC (Method A) 95.9% (AUC), tR=14.39 min.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.Cl.O1CCOC[CH2:13]1>CO>[ClH:1].[CH3:13][O:9][C:8](=[O:10])[CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: C1COCCO1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1c[nH]cn1

Procedure:
A mixture of 4.9 g (29.4 mmol) of (1H-imidazol-4-yl)-acetic acid hydrochloride, 4 N HCl in dioxane (22.5 mL) and methanol (70 mL) was refluxed overnight. Evaporation of the solvents gave (1H-imidazol-4-yl)-acetic acid methyl ester hydrochloride. LCMS: 141 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]2[NH:18][C:6]([C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:19][C:14]=2[CH:13]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc3cc(C)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
4-Methylbenzoyl chloride (2.17 mL, 2.54 g, 16.4 mmol) in dichloromethane (25 mL) was added dropwise to a stirred, cooled (0° C.) solution of 4-methyl-1,2-benzenediamine (2.0 g, 16.4 mmol) and triethylamine (4.57 mL, 3.32 g, 33 mmol) in dichloromethane (25 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, acetic acid (40 mL) was added and the mixture was stirred at 100° C. for 24 h. The solvent was evaporated under reduced pressure, water (100 mL) was added and the pH was adjusted to 7.0 with aqueous sodium carbonate (10%). Ethyl acetate (50 mL) was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (4×35 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, heated to reflux and allowed to cool. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (1.17 g, 32%). 1H NMR (360 MHz, CDCl3) δ 7.92 (2H, d, J 8.2 Hz), 7.52 (1H, d, J 8.1 Hz), 7.38 (1H, d, J 1.0 Hz), 7.27 (2H, d, J 8.2 Hz), 7.08 (1H, dd, J 8.1, 1.0 Hz), 2.47 (3H, s), and 2.40 (3H, s). m/z (ES+) 223 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH3:45])([CH3:44])[C:35]([NH:37][S:38]([CH:41]2[CH2:43][CH2:42]2)(=[O:40])=[O:39])=[O:36])=[C:6]([CH:8]2[CH2:13][C:12](=O)[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:47]>C1COCC1.C1(C)C=CC=CC=1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:33][C:34]([CH3:45])([CH3:44])[C:35]([NH:37][S:38]([CH:41]4[CH2:42][CH2:43]4)(=[O:39])=[O:40])=[O:36])[CH2:13][C:12](=[S:47])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(=O)(=O)C2CC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=S)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(=O)(=O)C2CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 88.5 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-4′-[5-chloro-2-(2-cyclopropanesulfonylamino-1,1-dimethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (12 mg, 0.018 mmol) and P2S5 (12 mg, 0.054 mmol) in THF (1 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM layers were combined and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (11 mg).