Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[OH:7])([CH3:3])[CH3:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.[NH4+].[Cl-]>C1COCC1.O>[CH3:16][C@@H:8]([C@@H:6]([OH:7])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:15])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)[C@@H](C)[C@@H](O)C(=O)OC(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a cold (−78° C.) solution of diisopropyl-(S)-(−)-malate (4.72 mL, 22.9 mmol, 1 eq.) in anhydrous THF (8.50 mL) was added slowly a solution (1 M) of lithium bis(trimethylsilyl)amide (48.1 mL, 48.1 mmol, 2.10 eq.) in THF. The temperature was raised to 20° C. over 30 minutes, than lowered again to −78° C. Iodomethane (1.7 mL, 28 mmol, 1.20 eq.) was added and the mixture stirred at RT for 16 hours. The reaction mixture was then cooled to 0° C. and a saturated solution of NH4Cl was added. The resulting mixture was diluted with water, extracted three times with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was then purified by chromatography (SiO2, 20/80 EtOAc/c-hex) to give the product (mixture of diastereoisomers) as a colourless oil (3.77 g, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Cl-].[CH:16](=[N+:23]([CH3:25])[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:16]([N:23]([CH3:25])[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1H-indole-2-carboxylic acid ethyl ester and benzylidene-dimethyl-ammonium chloride. For characterization, an ESI-MS was recorded:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([OH:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CC>[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:21]3[CH:22]=[CH:23][C:18]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=3)[CH:3]=2)[CH:8]=1)([OH:14])=[O:13]
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an 100 mL three-necked RB flask equipped with a magnetic bar, a condenser and a nitrogen gas inlet, 6-bromo-2-naphthoic acid (2.51 g, 10 mmol), 4-carboxybenzene boronic acid (1.66 g, 10 mmol) and 20 mL of 1-propanol were mixed and stirred at room temperature for about 30 min. Palladium acetate (0.007 g, 0.003 equiv., 0.03 mmol), triphenylphosphine (0.024 g, 0.009 equiv., 0.9 mmol), Na2CO3 solution (2 M, 8 mL, 1.20 equiv., 12 mmol) and water (4 mL) were added and the mixture was refluxed for 1.5 h. When the mixture was still hot, 20 mL of water was added and the mixture was stirred and cooled to room temperature. The solid was separated by filtration and refluxed with 2 mL of 1 M HCl and 25 mL of acetic acid. A white solid was obtained after filtration. No melting point was detected up to 350° C. 1H NMR (500 MHz, DMSO) δ 7.9-8.7 (m, 10H), 13.1 (s, 2H). IR (KBr) ν (cm−1): Anal. Calcd for C18H12O4: C, 73.97; H, 4.14. Found: C, 73.59; H, 4.05.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH2:20]>C(O)C>[CH3:19][NH:20][CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN
Reactant: ClCC[C@@H](Oc1ccccc1Br)c1ccccc1
Solvent: CCO
Product: CNCC[C@@H](Oc1ccccc1Br)c1ccccc1
Yield: 99.2 %

Procedure:
Compound 1-B (1.31 g, 4.02 mmole) was dissolved in an aqueous solution of ethanol (40 ml) and methylamine (80 ml), and heated to reflux for 30 h. After cooling, the solution was extracted with chloroform (100 ml, twice), and an organic layer was decanted. The organic layer was dried over anhydrous sodium sulfate, and dried by evaporation under vacuum, to obtain the product as oil (1.28 g, 99.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[CH:10]([C:12]1[N:13]=[CH:14][N:15](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=1)[OH:11].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[OH:11]
Reactant: CCc1cccc(Cl)c1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cccc(Cl)c1C(O)c1c[nH]cn1

Procedure:
Prepared in analogy to Example 57(e) from rac-(2-chloro-6-ethyl-phenyl)-(1-trityl-1H-imidazol-4-yl)-methanol, triethylsilane and trifluoroacetic acid in dichloromethane at room temperature, with the title compound being obtained as a by-product resulting from deprotection of trityl group without concomitant reduction of the benzylic alcohol moiety. Yellow oil. MS (ISP): 238.9 ([{37Cl}M+H]+), 236.8 ([{35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I.O>CN(C)C=O.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH3:29])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
Under ice cooling, a solution of the 2-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-5-methylpyridine (52 mg, 0.132 mmol), which had been obtained in Example 137, in N,N-dimethylformamide (5 ml) was added dropwise to a suspension of sodium hydride (a 60% oil dispersion, 30 mg, 0.75 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred for 15 minutes under ice cooling, and then, methyl iodide (12 μl, 0.198 mmol) was added. After stirring at room temperature for 1 hour, water was added to the reaction mixture under ice cooling, followed by concentration under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column. A fraction obtained from the eluate with hexane:ethyl acetate (=8:1) was concentrated under reduced pressure. The residue thus obtained was solidified with hexane and collected by filtration, whereby the title compound (50 mg, 0.122 mmol, 93%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:24])(=[O:23])[NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][S:17]([C:4]1[S:3][CH:2]=[C:6]([C:7]2[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=2[CH3:16])[CH:5]=1)(=[O:23])=[O:24]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCO)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)NCCCO)c2)s1
Temperature: -70 °C

Procedure:
N-{5-[2-Bromo-5-(3-hydroxy-propylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (230 mg; 0.51 mmol; 1 eq), is dissolved in anhydrous THF (20 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (1.9 ml; 1.6 M; 3.04 mmol; 8 eq) is added dropwise. After 4 hours the reaction is quenched with water. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording Compound (32) as a white-off powder (80.2 mg; 32%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:11]2[C:15]3[C:16]([O:41][C@@H:42]([C@@H:44]4[CH2:48][C:47](=[O:49])[NH:46][CH2:45]4)[CH3:43])=[N:17][C:18]([C:20]4[CH:28]=[C:27]5[C:23]([C:24]6([CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]6)[C:25](=[O:30])[N:26]5[CH3:29])=[CH:22][CH:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:10][CH2:9]1>ClCCl.CO>[CH:8]1([N:11]2[C:15]3[C:16]([O:41][C@@H:42]([C@@H:44]4[CH2:48][C:47](=[O:49])[NH:46][CH2:45]4)[CH3:43])=[N:17][C:18]([C:20]4[CH:28]=[C:27]5[C:23]([C:24]6([CH2:31][NH:32][CH2:33]6)[C:25](=[O:30])[N:26]5[CH3:29])=[CH:22][CH:21]=4)=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:10][CH2:9]1
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CN(C(=O)OC(C)(C)C)C2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CNC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reaction time: 2 h
Yield: 21.2 %

Procedure:
TFA (1.3 mL) was added to a solution of tert-butyl 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-methyl-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 3.84 (53 mg, 0.09 mmol) in dichloromethane (5 mL). After two hours, reaction mixture was concentrated under reduced pressure and resulting residue was taken up in 1.5 mL methanol and loaded onto an Agilent StratoSpheres™ PL-HCO3 MP Resin neutralization column (pre-conditioned with methanol). Column was washed with methanol and collected liquids were concentrated under reduced pressure to yield 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-methylspiro[azetidine-3,3′-indolin]-2′-one 3.85 (9 mg).
Reaction SMILES: CNC1C=CC(C(N[C@H](C(OCC)=O)CCC(OCC)=O)=O)=CC=1.[O:25]=[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:36][N:37]([CH2:60]C#C)[C:38]3[CH:59]=[CH:58][C:41]([C:42]([NH:44][C@H:45]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[O:43])=[CH:40][CH:39]=3)[CH:34]=2)[N:29]=[CH:28][N:27]1[CH2:63][O:64][C:65](=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67]>>[O:25]=[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:36][N:37]([CH3:60])[C:38]3[CH:59]=[CH:58][C:41]([C:42]([NH:44][C@H:45]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[O:43])=[CH:40][CH:39]=3)[CH:34]=2)[N:29]=[CH:28][N:27]1[CH2:63][O:64][C:65](=[O:70])[C:66]([CH3:67])([CH3:69])[CH3:68]
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Agent: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)cc1)C(=O)OCC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(C)Cc2ccc3ncn(COC(=O)C(C)(C)C)c(=O)c3c2)cc1)C(=O)OCC

Procedure:
This compound was prepared from compound (11) in a manner similar to that described for the preparation of compound (5) using the reagent quantities and conditions set out in Table A.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)#[N:2].[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>>[C:23]([N:8]1[CH2:9][CH2:10][C:11]2[C:3]([C:1]#[N:2])=[C:4]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[S:5][C:6]=2[CH2:7]1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)Cl
Reactant: COc1cccc(C(=O)Nc2sc3c(c2C#N)CCNC3)c1
Product: CCCC(=O)N1CCc2c(sc(NC(=O)c3cccc(OC)c3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-methoxybenzamide (compound B3) and butyryl chloride.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH:21]=[CH:20][NH:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C2(C=CNCC2)N1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C1c2ccccc2C2(CCNCC2)N1Cc1ccccc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
10% Palladium on carbon (1 g) was added to a stirred solution of 2-benzyl-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one 2a (2 g, 6.9 mmol) and ammonium formate (8.7 g, 138 mmol) in ethanol (50 mL). The mixture was heated under reflux for 3 hr then cooled to room temperature. The solution was filtered through Celite and the filtrate was concentrated to give a white solid. The solid was washed with ethyl acetate (4×25 mL) and the washings were concentrated to give 2-benzylspiro[isoindoline-1,4′-piperidin]-3-one 2b as a yellow oil (2.0 g, 99%). FIA m/z [M+H]+ 293.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[N:6][C:7]=1Cl.[NH3:15]>O>[NH2:15][C:7]1[N:6]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[Cl:1]
Reactant: N
Reactant: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Solvent: O
Product: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Temperature: 80 °C

Procedure:
A mixture of 5,6-dichloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (i.e. the product of Step C1 or C2) (280 g, 1.2 mol), water (1.26 L) and aqueous ammonia (28%, 350 g, 5.76 mol) was heated at 80° C. for 5 h. The solution was concentrated at 50° C. and 70 torr (9.3 kPa) pressure to about half volume to remove most of the excess ammonia. The resulting slurry was stirred at 20° C., acidified to pH 1-2 with aqueous hydrochloric acid, cooled to 5° C. and filtered. The isolated solid was dried in a vacuum oven to afford the title product (270 g), a compound of the present invention.
Reaction SMILES: [CH2:1]([CH:3]([C:7]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:8]=1[C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=O)[C:4]([CH3:6])=O)[CH3:2].S(=O)(=O)(O)O.O.[NH2:37][NH2:38].C([O-])(O)=O.[Na+].C>C(O)(C)C>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[C:8]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:7]=3[CH:3]([CH2:1][CH3:2])[C:4]([CH3:6])=[N:38][N:37]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: CCC(C(C)=O)c1cc(OC)c(OC)cc1C(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: NN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCC1C(C)=NN=C(c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
1.40 g (3.36 mmoles) of 2-(1-ethylacetonyl)-3',4,4',5,5'-pentamethoxybenzophenone are dissolved in 5.4 ml of isopropanol, and 0.175 ml of concentrated sulfuric acid are added dropwise to the solution. The reaction mixture is heated to boiling, stirred at this temperature for one hour, thereafter the mixture is cooled to 60° C. and 0.41 ml (8 mmoles) of 98% hydrazine hydrate are added. The resulting mixture is stirred for a further hour. 0.154 g of sodium hydrocarbonate are added in portions to the mixture, the mixture is heated to boiling, decolorized with charcoal, filtered, the filtrate is evaporated, and the residue is passed onto a filter with a total amount of 25 ml of water. 0.835 g (60.5%) of the title compound are obtained; m.p.: 152°-155° C. When recrystallized from a small amount of isopropanol the product melts at 160°-162° C. C23H28N2O5 =412.5.
Reaction SMILES: C[O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[C:14]4[NH:17][C:18]([NH:20][C:21](=[O:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:19][C:13]4=[CH:12][C:11]=3[C:10]([CH3:30])([CH3:29])[C:9]2=[O:31])=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[C:14]4[NH:17][C:18]([NH:20][C:21](=[O:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:19][C:13]4=[CH:12][C:11]=3[C:10]([CH3:29])([CH3:30])[C:9]2=[O:31])=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2C(=O)C(C)(C)c3cc4nc(NC(=O)c5ccccc5)[nH]c4cc32)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC1(C)C(=O)N(Cc2ccc(O)cc2)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
N-[5-(4-Methoxy-benzyl)-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (10 mg; 0.02 mmol) is suspended in a BBr3 solution in CH2Cl2 (1 M; 100 μl) and stirred at RT for 18 h. After addition of hydrochloric acid (200 μl; 1 N) the mixture is stirred at RT for another 1 h and then evaporated to dryness. The crude material is purified by preparative RP-HPLC, eluted with MeCN/water to yield the desired compound (5 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:18]([O-])=O.[Na+]>C(O)(=O)C.Cl.CN1CCCC1=O.O>[CH2:16]([C:12]1[CH:11]=[C:10]([C:3]2[C:2]3[N:1]=[N:18][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:17]
Reactant: O=N[O-]
Reactant: CCc1cccc(-c2nsc(C(N)=O)c2N)c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cccc(-c2nsc3c(=O)[nH]nnc23)c1
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
496 mg of 4-amino-3-(3-ethylphenyl)-5-isothiazolecarboxamide in 7 ml of glacial acetic acid, 4 ml of concentrated hydrochloric acid and 4 ml of N-methyl-pyrrolidone was stirred at 0° C. during the addition of 165 mg of sodium nitrite in 1 ml of water. The mixture was held at 0° C. for 1.5 hours then filtered and the solid residue was recrystallized from ethanol to give 400 mg of 7-(3-ethylphenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one, m.p. 156°-157° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:24]([O:26][CH3:27])=[O:25])[CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]>CO.O1CCCC1.[Pd]>[CH3:28][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:24]([O:26][CH3:27])=[O:25])[CH:18]=3)[NH:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N(C)C)c1)=N2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N(C)C)c1)N2
Yield: 79.5 %

Procedure:
A mixture of methyl 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (100 mg, 0.25 mmol) and 10% Pd/C (100 mg) in methanol (3 mL) and tetrahydrofuran (3 mL) was hydrogenated by a H2 balloon at 30° C. After filtration, the filtrated was concentrated and purified on preparative thin layer chromatography to afford 80 mg of methyl 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1COCC1.O>CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccco1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(-c3ccco3)cc2)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
The round-bottom flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), 2-furanylboronic acid (0.063 g, 0.56 mmol), aqueous 2 M Na2CO3, (0.06 g, 0.56 mmol), and THF/H2O mixture (4:1, 5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 10 h. Reaction mixture was cooled to room temperature, diluted with Et2O (10 mL) and filtered. The filtrate was diluted with EtOAc (30 mL), washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by silica gel chromatography using hexanes: EtOAc (19:1 to 4:1) as an eluent to give 0.0.42 g (44%) of compound 202 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.28 (s, 1H), 7.70 (br s, 1H), 7.59 (d, J=6.0 Hz, 2H), 7.12 (d, J=6.0 Hz, 2H), 6.91 (d, J=6.3 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.66 (d, J=6.3 Hz, 1H), 6.55 (br s, 1H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 343 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl-].[CH3:16][O:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH:20]=[N+:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[OH:1][C:2]1[C:3]([CH:20]([C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[O:17][CH3:16])[N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(O)ccc2c(C(=O)O)cccc12)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 6-hydroxy-1-naphthoic acid and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 28.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[C:5]=12.[I:12]N1C(=O)CCC1=O>ClCCl>[I:12][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[C:5]2=[N:1][CH:2]=1
Reactant: N#Cc1cccn2ccnc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: N#Cc1cccn2c(I)cnc12
Yield: 79.8 %

Procedure:
To a stirred solution of imidazo[1,2-a]pyridine-8-carbonitrile (1.2 g, 8.38 mmol) in dichloromethane (10 mL) was added N-iodosuccinimide (1.89 g, 8.38 mmol). LCMS monitored the reaction until the starting material consumed completely. The reaction mixture was diluted with dichloromethane and water. The separated organic layer was dried sodium sulfate, filtered and concentrated to give 3-iodoimidazo[1,2-a]pyridine-8-carbonitrile (1.8 g, 6.69 mmol, 80% yield) as a brown solid. MS (ES+) C8H8IN3 requires: 269. found: 270 [M+H]+.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:31]/[CH:32]=[CH:33]/[C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=1)[S:27]([CH3:30])(=[O:29])=[O:28])#[N:19]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:41][C:36]1[CH:35]=[C:34](/[CH:33]=[CH:32]/[CH2:31][N:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:18]2[NH:19][N:7]=[N:6][N:5]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:39]=[C:38]([Cl:40])[CH:37]=1
Reactant: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCc1nnn[nH]1
Yield: 53.4 %

Procedure:
Trimethylsilylazide (0.136 mL, 1.026 mmol) and dibutyltinoxide (38 mg, 0.15 mmol) were added to a solution of trans-N-(6-cyano-hexyl)-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide (59A) (199 mg, 0.52 mmol) in toluene (4 mL). The reaction was heated at reflux ovemight. The reaction was diluted with CH2Cl2 and the organic solution was washed sequentially with HCl (1×), water (1×), and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified via radial chromatography (CH2Cl2 to 5% MeOH/CH2Cl2) to afford the title compound (120 mg). 1H NMR (CDCl3 400 MHz) δ 7.26 (m, 3H), 6.50 (d, 1H), 6.22 (m, 1H), 4.00 (m, 2H), 3.23 (t, 2H), 3.02 (t, 2H), 2.90 (s, 3H), 1.83 (t, 2H), 1.62 (t, 2H), 1.38 (m, 4H); MS 132 (M+).