Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[CH:7]([C:11]([O:13]CC3C=CC([N+]([O-])=O)=CC=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[CH3:26][N:27]([CH3:39])[C:28]([C@@H:30]1[CH2:34][C@H:33]([SH:35])[CH2:32][N+:31]1([CH2:37][CH3:38])[CH3:36])=[O:29]>>[CH2:37]([N+:31]1([CH3:36])[CH2:32][C@@H:33]([S:35][C:8]2[CH2:9][C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:24](=[O:25])[N:6]3[C:7]=2[C:11]([O-:13])=[O:12])[CH2:34][C@H:30]1[C:28](=[O:29])[N:27]([CH3:26])[CH3:39])[CH3:38]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CC[N+]1(C)C[C@@H](S)C[C@H]1C(=O)N(C)C
Product: CC[N+]1(C)C[C@@H](SC2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C[C@H]1C(=O)N(C)C
Yield: 10.1 %

Procedure:
Following a procedure similar to that described in Example 6, but using 459 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate and 580 mg of the crude (2S, 4S)-2-(N,N-dimethylcarbamoyl)-1-ethyl-1-methyl-4-mercaptopyrrolidinium salt [prepared as described in Example 9-(2)], 55 mg of the title compound were obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:12][N:13]([CH3:37])[C:14](=[O:36])[C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[CH:19][C:18]([CH:28]([OH:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:28]([C:18]1[CH:19]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:15]([C:14]([N:13]([CH2:12][C:11]2[CH:10]=[C:9]([C:8]([F:45])([F:7])[F:46])[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=2)[CH3:37])=[O:36])=[CH:16][N:17]=1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1-c1cc(C(O)c2ccccc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(C(=O)c2ccccc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 0.018 ml (0.21 mmol) oxalyl chloride in 2.5 ml dichloromethane 0.03 ml (0.4 mmol) dimethylsulfoxide were added at −78° C. After 5 min a solution of 100 mg (0.179 mmol) (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(hydroxy-phenyl-methyl)-N-methyl-4-o-tolyl-nicotinamide (Example 76) in 2.5 ml dichloromethane were added dropwise at −78° C. After stirring for another 30 min at −78° C. 0.15 ml (0.90 mmol) triethylamine were added. The reaction mixture was allowed to warm to room temperature. Dilution with dichloromethane was followed by washing with three portions of 1 M aqueous hydrochloric acid solution and one portion of a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Column chromatography afforded 69 mg (70%) of the title compound as a light-yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29](O)=[O:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].Cl.[NH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([N:34]3[CH2:37][CH:36]([OH:38])[CH2:35]3)=[O:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32]
Reactant: Cc1cc(F)ccc1-c1nc(NCC(=O)O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CC(O)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 16 h
Yield: 49.1 %

Procedure:
A mixture of [8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid (100 mg, 0.23 mmol), azetidin-3-ol hydrochloride (37 mg, 0.34), o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (129 mg, 0.34 mmol) and N-methyl-morpholine (0.12 mL, 1.13 mmol) in DMF (2 mL) was stirred at 23° for 16 h to give the crude material, which was purified by preparative hplc to afford the title compound 56 mg (49%). LC-MS: 496.2 (MH+, m/z), 1.69 (Rt, min).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:41]=[CH:40][C:38](=S)[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1.[NH3:42]>>[C@@H:11]1([N:34]2[CH:41]=[CH:40][C:38]([NH2:42])=[N:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@@H](n2ccc(=S)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: N
Product: Nc1ccn([C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
Compound 19 (3.68 g, 6.42 mmol) was treated with 200 ml of methanolic ammonia in a bomb at 100° C. for 18 hours. After cooling to room temperature, the solvent was evaporated to dryness and the residue dissolved in water (200 ml). The aqueous solution was extracted successively with CHCl3 and CCl4 (3×100 ml) to remove benzamide and methyl benzoate. The aqueous layer was treated with active charcoal, filtered through Celite®, evaporated to dryness and coevaporated with EtOH. The solid obtained was recrystallized from MeOH to give pure compound 20 (1.36 g, 81%) as white solid: m.p. 206°-207° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([OH:14])[CH:8]=[CH:7]2)([O-])=O>CCO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2nc(O)ccc2c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc2[nH]c(=O)ccc2c1
Reaction time: 20 h
Yield: 92 %

Procedure:
A mixture of 6-nitroquinolin-2-ol and PtO2 (20 mg) in EtOH (30 mL) was stirred under H2 (1 atm) for 20 h. More PtO2 (10 mg) was added and was stirred under H2 (1 atm) for 2 days. The solution was filtered and washed with MeOH and CHCl3. The solvent was evaporated and the residue was dried under vacuum to obtain 6-aminoquinolin-2(1H)-one as a yellow solid (0.28 g, 92% yield). LC-MS (EI) m/z: 161.0 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C(#N)C>[C:30]([O:29][C:28]([NH:27][CH2:26][CH2:25][NH:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12)=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
To a mixture of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (500 mg, 1.971 mmol) and potassium carbonate (817 mg, 5.91 mmol) in acetonitrile (15 ml) was slowly added tert-butyl N-(2-aminoethyl)carbamate (1.248 ml, 7.88 mmol) via a syringe. The reaction mixture was stirred at room temperature for 3 hours. The solids were filtered off over a glass filter and washed with a 1:1 mixture of EtOH and DCM. The combined filtrates were concentrated under reduced pressure to give a white semisolid, which was purified by column chromatography (silica gel using a gradient of ethanol (0-5%) in DCM) to yield 658 mg of a white solid (1.743 mmol, 88%). MS (ESI) m/z=378.2 [M+1]+.
Reaction SMILES: [Br:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>>[Br:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([Cl:15])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Br)Cc1ccccc1
Product: O=C(Cl)C(Br)Cc1ccccc1

Procedure:
60.5g of 2-bromo-3-phenylpropionic acid was mixed with 100 ml of thionylchloride and the mixture was refluxed for 3 hours and, after the excess thionylchloride had been distilled off, was distilled under reduced pressure to give 46.2g of 2-bromo-3-phenylpropionylchloride. (b.p. 100°- 101°C/4 mmHg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([N:8]([CH2:19][CH:20](OC)OC)S(C1C=CC(C)=CC=1)(=O)=O)[CH3:7].O1CCOCC1.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:25]([CH:20]=[CH:19][N:8]=[C:6]2[CH3:7])=[CH:26][CH:27]=1
Reactant: COc1cccc(C(C)N(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ccnc(C)c2c1

Procedure:
A mixture of 39.3 g. (0.1 mole) of 3-methoxy-α-methyl-N-(2,2-dimethoxyethyl)-N-tosyl-benzylamine, one liter of dioxane and 80 ml. of 6 N hydrochloric acid is refluxed for six hours and allowed to stand for sixteen hours. The mixture is poured into two liters of water and extracted with ether. The aqueous phase is made alkaline with concentrated ammonium hydroxide and extracted with chloroform. The chloroform extract is washed, dried and evaporated to yield 7-methoxy-1-methylisoquinoline.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:8]([C:11]#[N:12])=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.[CH2:24]([N:31]([CH2:35][CH2:36]Cl)[CH2:32][CH2:33]Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([N:31]1[CH2:35][CH2:36][C:10]2([C:9]3[C:8]([C:11]#[N:12])=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2]2=[O:1])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#Cc1cccc2c1CC(=O)N2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc2c1C1(CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To a stirred solution of 2-oxoindoline-4-carbonitrile (2.97 g, 18.8 mmol; prepared as described in WO 00/21920) in THF (40 mL) was added dropwise a 1.0 M THF solution of NaHMDS (78.2 mL, 78.2 mmol) at about −78° C. under N2. After stirring at about −78° C. for about 30 min, N-benzylbis(2-chloroethyl)amine hydrochloride (4.20 g, 15.6 mmol) was added as a solid. The reaction mixture was stirred at about −78° C. for about 30 minutes and then allowed to warm to rt. The reaction mixture was then heated at reflux for 2 h. After cooling to about 0° C., the reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 60:1) to give 1′-benzyl-2-oxo spiro[indoline-3,4′-piperidine]-4-carbonitrile (2.10 g, 42%) as a solid. LCMS (APCI+) m/z 318 [M+H]+; Rt=2.42 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]/[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([O:24]/[N:23]=[C:19]1/[CH2:20][CH2:21][CH2:22][C:15]2[C:14]([S:11]([N:10]([CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:26])[CH3:25])(=[O:13])=[O:12])=[CH:18][S:17][C:16]/1=2)=[O:39]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/OC(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of the compound (30 mg) of Example 1 and triethylamine (18 μL) in dichloromethane (10 mL) was added dropwise pivaloyl chloride (13 mg) in dichloromethane (1 mL) on an ice bath. After stirring for 30 minutes, the solvent was removed at reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (35 mg) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH2:1]([N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN([CH:23]=[O:24])C.O=P(Cl)(Cl)Cl.CC([O-])=O.[Na+]>ClCCCl>[CH2:14]([N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH:23]=[O:24])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN(CCCCCC)c1ccccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCN(CCCCCC)c1ccccc1C=O
Reaction time: 8 h

Procedure:
To a solution of N,N-dihexylaniline (12.02 g, 4.60×10−2 mol) in anhydrous 1,2-dichloroethane (200 ml) at room temperature were successively added anhydrous DMF (3.60 ml, 4.65×10−2 mol) and POCl3 (5.20 ml, 5.58×10−2 mol), and the mixture was refluxed for 5.5 h. After cooling, 2M aqueous NaOAc solution (200 ml) was added and the reaction mixture was stirred overnight. The product was extracted three times with CHCl3 and the combined organic layers were dried over Na2SO4. The residue was chromatographed on silica gel with 1:1 hexane:CHCl3 as the eluent. Yield=10.793 g (81% based on 12.02 g of N,N-dihexylaniline). 1H NMR (250 MHz, CDCl3): δ 9.69 (s, 1H, —CHO), 7.70 (dd, 2H, J=8.9 Hz, Ph), 6.63 (d, 2H, J=9.0 Hz, Ph), 3.34 (t, 4H, J=7.8 Hz, —NCH2—), 1.48-1.70 (m, 4H, —NCH2CH2—), 1.19-1.41 (m, 12H, —CH2—), 0.91 (t, 6H, J=6.6 Hz, —CH3). CI MS m/z: 290.247 ((M+H)+) (calcd 290.248).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Yield: 95 %

Procedure:
A mixture of 7-hydroxy-2,2-dimethyl-4-phenylchroman (11.8g, 0.046 mole), anhydrous potassium carbonate (11.7g, 0.093 mole), epichlorohydrin (50ml) and dry acetone (50ml) was stirred and boiled under reflux for 6 hours, then cooled and filtered. The filtrate was evaporated in vacuo and the residual brown oil dissolved in ether, washed with water and dried (magnesium sulphate). Removal of the solvent gave 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman as a pale brown solid (13.56g, 95%), m.p. 82-85°, after crystallisation from ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[C:13]([CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29])[CH:14]=4)=[C:4]2[CH:3]=1.[C:31]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)(=[O:34])[CH:32]=[CH2:33]>>[N:35]1([C:31](=[O:34])/[CH:32]=[CH:33]/[C:2]2[CH:7]=[CH:6][C:5]3=[N:8][C:9]4[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[N:16]([CH3:23])[C:15]5[C:10]=4[C:11]([CH:12]=[C:13]([CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29])[CH:14]=5)=[C:4]3[CH:3]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C=CC(=O)N1CCOCC1
Reactant: CC(=O)OCCCc1cc2c3c(nc4ccc(Cl)cc4c3c1)-c1ccccc1N2C
Product: CC(=O)OCCCc1cc2c3c(nc4ccc(/C=C/C(=O)N5CCOCC5)cc4c3c1)-c1ccccc1N2C
Yield: 83 %

Procedure:
The general procedure (Method M) applied to acetic acid 3-(3-chloro-8-methyl-8H-quino[4,3,2-kl]acridin-6-yl)-propyl ester, 49 (100 mg, 0.247 mmol) and 4-acryloylmorpholine (70 mg, 63 μL, 2 eq) gave the title compound (104 mg, 0.2 mmol, 83%). Purity was checked by tlc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH2:24])=[S:23])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl[CH2:31][C:32](=O)[CH3:33]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[S:23][CH:31]=[C:32]([CH3:33])[N:24]=2)=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2nc(C)cs2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 16.3 %

Procedure:
A solution of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}-thioacetamide (0.44 g) and chloroacetone (0.30 g) in ethanol (30 ml) was heated under reflux for 7 hours and then evaporated. The residual oil was purified by chromatography on silica (t.l.c. grade, 10 g) using dichloromethane plus 0-10% v/v ethyl acetate as eluant. Appropriate fractions were combined and evaporated and the residue triturated with diisopropyl ether. The resulting solid was collected, washed with petroleum ether (b.p. 60°-80° C.) and dried to give the title compound (78 mg), m.p. 107°-110° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[Na+].[Na+].[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([N:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:26]6[C:21]([C:27]=5[CH:14]=4)=[CH:22][CH:23]=[CH:24][CH:25]=6)=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1

Procedure:
24.10 g (97.92 mmol) of 3-bromo-9H-carbazole 22, 30.93 g (107.71 mmol) of compound 25 and 11.56 g of sodium carbonate are suspended in 2500 ml of dioxane, 2500 ml of toluene and 1000 ml of water. 5.79 g (5.01 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 5 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene. The yield is 22.0 g (55%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2nccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2nccs2)cc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
A stirred solution of 2-[(4-nitrophenyl)sulfonyl]thiazole (1.50 g, 5.6 mmol) and stannous chloride dehydrate (6.26 g, 27.7 mmol) in absolute ethanol (25 mL) was heated at reflux for 1 hour. The reaction mixture was poured into ice water, and the aqueous solution basified with 15% NaOH and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed to yield a solid which on trituration with diethyl ether and filtration yielded the title thiazole (1.21 g, 89%) as a pale yellow solid, mp 148°-150° C. 1H--NMR (250 MHz, d6 --DMSO): 6.44 (br s, 2H, NH2), 6.66 (d, 2H, J=8.8 Hz, aromatic), 7.61 (d, 2H, J=8.7 Hz, aromatic), 8.03 (d, 1H, J=3.2 Hz, aromatic), 8.14 (d, 1H, J=3.2 Hz, aromatic). MS (CI, CH4): 241(M+1).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:23])=O>>[C:1]([N:5]1[C:11](=[O:12])[C:10]2[C:9](=[CH:17][C:16]([C:18]([Cl:23])=[O:20])=[CH:15][CH:14]=2)[S:6]1(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)(C)N1C(=O)c2ccc(C(=O)Cl)cc2S1(=O)=O

Procedure:
15.0 g of (0.05 mol) of tert-butylsulfamoylterephthalic acid in 95 ml of thionyl chloride were heated under reflux for 8 h. The mixture was concentrated and the residue was triturated with ethyl acetate. This gave 14.6 g (97% of theory) of 2-tert-butylsaccharin-6-carbonyl chloride of m.p. 185-186° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1.O.NN.Cl>C(O)C>[CH3:26][S:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][NH2:3])=[CH:17][CH:18]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(OCCCN)cc1
Reaction time: 1 h

Procedure:
A suspension of 5.5 g of N-[4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propoxy]phenyl]methanesulfonamide in 200 ml of ethanol is treated with 1.5 ml of hydrazine hydrate and the mixture stirred and refluxed for 6 hours. A precipitate forms in 1 hour. After 6 hours, 5 ml of HCl is added and the mixture refluxed for 1 hour and allowed to stand at room temperature for 18 hours. The precipitate is collected, stirred with 50 ml of hot water and the insolubles washed with 50 ml of water. The combined water washes are evaporated in vacuo to a dry residue. The residue is dissolved in 100 ml of saturated sodium bicarbonate, treated with activated carbon, filtered and the filtrate acidified with acetic acid and concentrated in vacuo to 100 ml. The precipitate is collected, washed with 25 ml of cold water and dried to give a solid, m.p. 200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][C:38]1[CH:42]=[CH:41][O:40][N:39]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[CH:42]=[CH:41][O:40][N:39]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: BrCc1ccon1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccon4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was stirred for 30 min at 0° C. 3-(Bromomethyl)isoxazole (29.4 mg, 181 μmol) was added and the mixture warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) gave 2-(6-chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (91 mg, 161 μmol, 97.5%) as a yellow powder. MS (M+Na)+=588 (88% purity); 1H NMR (CDCl3) δ: 9.27 (s, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.34-8.43 (m, 2H), 8.16 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 6.33 (d, J=1.5 Hz, 1H), 5.77 (s, 2H), 5.73 (s, 2H), 4.38-4.56 (m, 1H), 3.53-3.65 (m, 2H), 1.35-1.46 (m, 6H), 0.89-1.01 (m, 2H), −0.07-0.02 (m, 9H)