Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:35]=[CH:34][C:33]([C:29]2[N:28]([CH3:27])[CH:32]=[CH:31][N:30]=2)=[CH:40][CH:39]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: Cn1ccnc1-c1ccc(CN)cc1
Solvent: Cc1ccccc1
Product: Cn1ccnc1-c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 84.3 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (455 mg, 1.1 mmol) with 4-(1-methyl-1H-imidazol-2-yl)-benzylamine (240 mg, 1.3 mmol) in toluene (8 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to obtain 7-chloro-6-[4-(1-methyl-1H-imidazol-2-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (429 mg, 93%). MS (ES+) m/z: 463 (4+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[N+:30]([O-])=O)=[CH:9][CH:8]=1.[Cl-].[NH4+].O1CCCC1.O>C(O)C.[Fe]>[Cl:35][C:2]([Cl:1])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 95 %

Procedure:
A solution of the product of Example 100B (1.23 g, 2.0 mmol), iron powder (0.56 g, 10.0 mmol) and ammonium chloride (0.16 g, 3.0) in an ethanol (30 mL), tetrahydrofuran (30 mL), and water (10 mL) solution was heated to reflux for 6 hours. The resultant mixture was diluted with ethanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as a yellow powder (1.12 g, 95%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][C:12]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 19.9 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (100 mg) described in Preparation Example 4 and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (220 mg) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 4, the title compound (49 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:25][S:26]([CH2:29][C:30]#[N:31])(=[O:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C.N1CCCCC1.O>[CH2:18]([NH:25][S:26](/[C:29](=[CH:8]/[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)/[C:30]#[N:31])(=[O:28])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)NCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 100 °C

Procedure:
A mixture of 250 mg of 3,5-di-t-butyl-4-hydroxybenzaldehyde and 230 mg of N-benzyl cyanomethyl sulfonamide in 2 ml of ethanol with 2 drops of piperidine was heated at 100° C. for 3 hours. The cooled mixture was then diluted with 10 ml of water and extracted with 50 ml of ethyl acetate. The organic extract was then washed with brine, dried over sodium sulfate, filtered and concentrated, Crystallization of the crude with ethyl acetate and hexane yield 206 mg of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[CH:23]=[N:24][C:25]([N:29]4[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[CH3:35])=[C:26]([CH3:28])[CH:27]=3)[S:21][C:14]=12>>[CH3:34][C:33]1[N:29]([C:25]2[N:24]=[CH:23][C:22]([C:20]3[S:21][C:14]4[C:15](=[N:16][CH:17]=[CH:18][C:13]=4[NH:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)[CH:19]=3)=[CH:27][C:26]=2[CH3:28])[C:30]([CH3:35])=[CH:31][CH:32]=1
Reactant: Cc1cc(-c2cc3nccc(Cl)c3s2)cnc1-n1c(C)ccc1C
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cnc(-n6c(C)ccc6C)c(C)c5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-5-methyl-pyridin-3-yl]-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.71 (s, 1H), 8.17 (s, 1H), 8.08 (d, 1H), 7.77 (s, 1H), 7.30 (m, 2H), 6.95 (d, 1H), 6.58 (d, 1H), 6.11 (s, 1H), 5.84 (s, 2H), 2.40 (s, 3H), 1.99 (s, 3H), 1.91 (s, 6H); RP18-HPLC RT: 6.67 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:23]#[CH:24])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]>CCO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: C#Cc1c(C(=O)OCC)ncc2c1ccn2Cc1ccc(F)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CC
Reaction time: 18 h

Procedure:
To a solution of 4-ethynyl-1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (60 mg, 0.018 mmol, prepared in step 1 above) in EtOH (2 mL) was added Lindlar's catalyst (Aldrich, 20 mg). The atmosphere was vacuum degassed with hydrogen three times, and then a balloon of hydrogen was attached to the reaction. After stirring for 18 hours, the reaction was filtered through a fine filter to remove the palladium. The solvent was removed by rotary evaporation, and the crude oil was carried on without further purification. Yield 57 mg, 94%. MS (APCI): Calc: 326, Found: (M+H) 327.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH:16][NH2:17])(=[O:15])[CH3:14]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:17][NH:16][C:13](=[O:15])[CH3:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(=O)NN
Reactant: CCOC(=O)C(=NOC)C(C)=O
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(C)=NNC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl 2-methoxyiminoacetoactate (a mixture of syn and anti isomer) (226.6 g.) and acetohydrazide (78.5 g.) in ethanol (500 ml.) was stirred for 1.5 hours at ambient temperature. Precipitates were collected by filtration, washed with ethanol and ether and dried to give ethyl 2-methoxyimino-3-acetylhydrazonobutyrate (a mixture of syn and anti isomers) (155.7 g.), mp 190° to 191.5° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([OH:27])[CH2:20]C2CCOCC2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)[O:41][C:39](=O)[C:38]2[CH:37]=[CH:36][CH:35]=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](=[O:27])[CH2:20][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][O:41]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCOCC2)cc2cccnc21
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CC1CCCCO1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a solution of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol (2.1 g, 11 mmol) in dichloromethane (75 mL) was added Dess-Martin periodinane (8.3 g, 39 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h and then quenched with a saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with dichloromethane (50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-2-yl)-ethanone (2.0 g, 93%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C20H20N2O4S [M+H]+ 385.46, observed 385.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]([CH2:18][C:19]1[CH:27]=[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]3[N:20]=[C:19]([CH2:18][O:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:27]=[C:22]3[CH2:23]2)=[O:7])=[CH:4][CH:3]=1
Reactant: c1ccc(OCc2cc3n(n2)CCNC3)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
4-Fluorobenzoyl chloride (0.14 mL, 1.2 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.3 g, 1.0 mmol) and pyridine (0.16 mL, 2.0 mmol) in DCM (13 mL) under N2 at 0° C. The reaction was stirred at room temperature for 1 hour, diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo. The desired product was triturated with DIPE to yield 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.21 g, 59% yield) as a white solid. C20H18FN3O2 1H NMR (500 MHz, CDCl3) δ ppm 4.07 (br. s., 2H), 4.27 (br. s., 2H), 4.81 (br. s., 2H), 5.05 (s, 2H), 6.16 (br. s., 1H), 6.96 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 7.15 (t, J=8.5 Hz, 2H), 7.29 (dd, J=8.1, 7.8 Hz, 2H), 7.49 (dd, J=8.5, 5.3 Hz, 2H).
Reaction SMILES: Br[CH:2]=[C:3]([CH3:11])[CH:4]=[CH:5][O:6][Si](C)(C)C.C([Li])(C)(C)C.[CH2:17]1[CH2:25][O:24][C:19]([CH3:23])([CH2:20][CH:21]=O)[O:18]1.Cl>CCCCC.C(OCC)C.O>[CH2:17]1[CH2:25][O:24][C:19]([CH3:23])([CH2:20][CH:21]=[CH:2][C:3]([CH3:11])=[CH:4][CH:5]=[O:6])[O:18]1
Reactant: CC(C=CO[Si](C)(C)C)=CBr
Reactant: CC1(CC=O)OCCO1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: CCOCC
Product: CC(C=CCC1(C)OCCO1)=CC=O
Temperature: -70 °C
Reaction time: 1.67 h
Yield: 54.7 %

Procedure:
Anhydrous ethyl ether (11 cc) and 1-bromo-2-methyl-4-trimethylsilyloxy-1,3-butadiene (0.9 g) are introduced under an argon atmosphere into a 50-cc round-bottomed flask. This is cooled to -70° C. and then a solution (3.25 cc) of 1.65M tert-butyllithium in pentane is added over 10 minutes. The mixture is stirred at -70° C. for 100 minutes and 3,3-ethylenedioxybutanal (0.4 g) is then added in solution in anhydrous ethyl ether (4 cc). The temperature is allowed to rise to -30° C. and stirring is performed for 30 minutes. Further stirring is performed for 20 minutes at -20° C. and then the mixture is cooled to -60° C. N Hydrochloric acid (11.5 cc) is added over 20 minutes. The temperature is allowed to rise to about 20° C. After the reaction mixture has been taken up with ether and water and the organic phases have been dried over magnesium sulphate, and after flash chromatography, 7,7-ethylenedioxy-3-methyl-2,4-octadienal (0.33 g) is obtained, its characteristics being as follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5]1.C(N(CC)CC)C.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:38]([O:37][C:35]([CH2:34][NH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[N:5]1)=[O:36])[CH3:39]
Reactant: NCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 3-[2-(2-aminoethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (1.5 g), triethylamine (1.5 ml), and N,N-dimethylformamide (15 ml) was added ethyl 2-bromoacetate (0.60 ml), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, and the residue was partitioned between chloroform and water. The organic layer was separated, washed with sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated. Purification of the residue by column chromatography on silica gel (gradient elution, using 50:1 and 25:1 mixture of chloroform and methanol) gave 3-[2-{2-(ethoxycarbonylmethylamino)ethyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.90 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]([CH2:19]Cl)=[CH2:18].O>CN(C)C=O>[Cl:16][C:17](=[CH2:18])[CH2:19][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: C=C(Cl)CCl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cl)COc1ccc(C#N)cc1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
10.0 g of 4-cyanophenol and 11.6 g of potassium carbonate were suspended in 100 ml of dimethylformamide, and 9.4 g of 2,3-dichloropropene was added dropwise. The reaction solution was stirred at 80 oC for 3 hours, allowed to cool, and poured into 200 ml of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried. Ethyl acetate was evaporated under reduced pressure. The resulting oily product was purified by column chromatography (silica gel; developing solvent hexane/ethyl acetate (9:1)) to give 15.2 g of the desired 4-(2-chloro-2-propeneoxy)benzonitrile as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:31])[CH2:13][C@H:14]([N:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]([OH:17])=[O:16])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:39]=[N+:40]=[N-].[Na+]>CC(C)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:31])[CH2:13][C@H:14]([N:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]([OH:17])=[O:16])=[O:7])=[CH:32][CH:33]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(C(=O)OCCOC(=O)C[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C(=O)OCCOC(=O)C[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a stiffed solution of 19 (0.115 g, 0.260 mmol) in acetone (6 mL) was added 5% HCl (6 mL) at 0° C. and the solution was stiffing for 5 min NaNO2 (0.020 g, 0.28 mmol) in 1 mL water was added dropwise to the above solution causing an immediate color change from colorless to orange. After 20 min of stirring at 0° C., NaN3 (0.034 g, 0.52 mmol) in 1 mL water was added dropwise to the reaction mixture causing an immediate color changed from orange to colorless to pale yellow. The reaction mixture was stiffed for additional 20 min and extracted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL). The final organic layer was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to obtain (S)-4-(2-(4-azidobenzoyloxy)ethoxy)-2-(9H-carbazol-9-yl)-4-oxobutanoic acid 20 (0.117 g, 96%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10][O:11][CH2:12][CH:13](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:14]>C1(C)C=CC=CC=1.CCOCC>[CH3:10][O:11][CH2:12][CH:13]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])[CH3:14]
Reactant: Cc1cccc(C)c1N
Reactant: COCC(C)OS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COCC(C)Nc1c(C)cccc1C

Procedure:
A solution of 484 g (4 mole) of 2,6-xylidine and 490 g (2 mole) of p-toluenesulphonic acid-(1-methoxyprop-2-yl)-ester in 1000 ml of toluene is refluxed for 25 hours. The reaction mixture is cooled, then made alkaline and diluted with ether. The organic phase is repeatedly washed with water and dried with magnesium sulphate. Evaporation of the solvent and subsequent distillation of the residue yields the desired N-(1-methoxyprop-2-yl)-2,6-xylidine with a boiling point of 70°-72°C/0.4 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:16])=[O:15])=[N:7][N:8]2[CH:11](C)C)=[CH:4][CH:3]=1.[CH3:17]OC(C1C2C(=CC=CC=2)NN=1)=O.CI.C(I)(C)C>>[CH3:17][O:16][C:14]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH3:11])[N:7]=1)=[O:15]
Reactant: CC(C)n1nc(C(=O)O)c2ccc(Br)cc21
Reactant: COC(=O)c1n[nH]c2ccccc12
Solvent: CC(C)I
Solvent: CI
Product: COC(=O)c1nn(C)c2cc(Br)ccc12

Procedure:
The title compound is prepared essentially as described in the synthesis of 6-bromo-1-isopropyl-1H-indazole-3-carboxylic acid substituting 6-bromo-1H-indazole-3-carboxylic acid methyl ester for 1H-indazole-3-carboxylic acid methyl ester and methyl iodide for isopropyl iodide ES/MS m/e 268.0 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].Cl[CH2:16][C:17]1[NH:18][C:19](=[O:27])[C:20]2[CH2:26][O:25][CH2:24][CH2:23][C:21]=2[N:22]=1>O1CCCC1>[C:8]([O:7][C:6](=[O:12])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:16][C:17]1[NH:18][C:19](=[O:27])[C:20]2[CH2:26][O:25][CH2:24][CH2:23][C:21]=2[N:22]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: COCCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 49.8 %

Procedure:
To a solution of tert-butyl 2-methoxyethylcarbamate (185 mg, 1.06 mmol) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (95%, 127 mg, 4.28 mmol) portion-wise slowly, followed by 2-(chloromethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (212 mg, 1.6 mmol). The reaction mixture was stirred for 48 h. The reaction was quenched with water (approximately 3 mL) and the solvent evaporated. The residue was re-dissolved in acetonitrile and purified by column chromatography (100% dichloromethane for 5 min, then slow gradient up to 15% methanol in dichloromethane). The resulting clear oil was dissolved with 0.5 mL of acetonitrile and heated in vacuo to give the title compound as a white solid (179 mg). 1H NMR (400 MHz, chloroform-d) 8 ppm 4.60 (s, 2H) 4.21-4.34 (m, 2H) 3.91-4.01 (m, 3H) 3.66-3.79 (m, 2H) 3.51-3.66 (m, 6H) 2.71-2.80 (m, 2H) 1.48 (s, 3H) 1.35 (s, 6H). MS (m/z, MH+): 340.4
Reaction SMILES: ClC1C2C(=C(N[C:13](=[O:22])C3C(Cl)=CC=CC=3Cl)C=CC=2)N=CC=1.C(NCCN)C1C=CC=CC=1.[CH2:34]([NH:41][CH2:42][CH2:43][NH:44][C:45]1[C:54]2[C:49](=[C:50]([NH:55][C:56](=[O:65])[C:57]3[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=3[Cl:64])[CH:51]=[CH:52][CH:53]=2)[N:48]=[CH:47][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:34]([N:41]1[CH2:42][CH2:43][N:44]([C:45]2[C:54]3[C:49](=[C:50]([NH:55][C:56](=[O:65])[C:57]4[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=4[Cl:64])[CH:51]=[CH:52][CH:53]=3)[N:48]=[CH:47][CH:46]=2)[C:13]1=[O:22])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Reactant: O=C(Nc1cccc2c(NCCNCc3ccccc3)ccnc12)c1c(Cl)cccc1Cl
Agent: NCCNCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c(N3CCN(Cc4ccccc4)C3=O)ccnc12)c1c(Cl)cccc1Cl
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (400 mg) and N-benzylethylenediamine (854 mg) was stirred for 6 hours at 130° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (methanol-dichloromethane) to give a residue containing 4-(2-benzylaminoethylamino)-8-(2,6-dichlorobenzoylamino)quinoline. A mixture of the obtained residue, 1,1'-carbonyldiimidazole (221 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (191 mg) in dimethylformamide was stirred for 4 hours at ambient temperature and for 2 hours at 130° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (methanol-dichloromethane) to give 4-(3-benzyl-2-oxoimidazolidin-1-yl)-8-(2,6-dichlorobenzoylamino)quinoline (150 mg).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][S:21][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: OCC(O)CS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCC(O)CO)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 3-mercapto-1,2-propanediol to provide 5-[2-[(2,3-dihydroxypropyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one; 1H NMR (CDCl3) δ1.66 and 1.68 (singlets, 3H), 1.83 (br s, 1H), 2.44 (br s with fine structure, 1H) and overlapping 2.45-2.58 (m, 2H), 3.10-3.28 (m, 2H), 3.47 (br s with fine structure, 1H), 3.55-3.78 (m, 2H), 4.50 (m, 1H), 5.39 and 5.40 (overlapping singlets, 1H), 7.05-7.20 (m, 2H), 7.27-7.43 (m, 6H); MS (HR-EI) m/z 390.0948 (M+ calcd. for C20H22O4S2 390.0959).