Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=2I)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:28]([O-])([O-])=[O:29].[K+].[K+]>C(#N)C.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.[Cu]I>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:28](=[O:29])[C:18]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(S(C)(=O)=O)cc2I)CC1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(S(C)(=O)=O)cc3c(=O)o2)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a stirring solution of 2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-methylsulfonyliodobenzene (1.89 g, 3.72 mmol) in acetonitrile (50 mL) was added K2CO3 (2.53 g, 18.6 mmol) followed by Pd(PPh3)4 (0.22 g, 0.19 mmol) and CuI (0.036 g, 0.19 mmol). The mixture was placed under an atmosphere of CO and heated to 75° C. After 2 h, the heat was removed and the mixture was diluted with ethyl acetate and washed with water, then brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a gradient of 10% to 20% ethyl acetate in dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 0.485 g (32%) of a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[C:25](Br)[CH:26]=[CH:27][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.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>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[C:25]([CH3:37])[CH:26]=[CH:27][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
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: [K+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](CCOCc3ccccc3)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Yield: 85.3 %

Procedure:
(S)-tert-Butyl (3-(benzyloxy)-1-(5-bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (0.6 g, 1.08 mmol) was dissolved in 36 mL anhydrous dimethylformamide in a pressure reactor vessel. 2,4,6-Trimethylboroxine (1.36 mL, 9.76 mmol), potassium carbonate (3 g, 21.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) were added under argon conditions. The reaction mixture was heated at 120° C. for 2 h and then cooled and filtered through a plug of Celite, washing several times with ethyl acetate. The combinated filtrates were washed with water, saturated ammonium chloride solution and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 20%, hexane-ethyl acetate) to give 0.45 g (85% yield) of the title compound as a white solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccn3)nc12

Procedure:
From 2-pyridylacetic acid hydrochloride, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: C(O)(=O)C.[N:5]([O-:7])=[O:6].[Na+].[Br:9][C:10]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[N+]([O-])(O)=O>O>[Br:9][C:10]1[CH:25]=[C:24]([N+:5]([O-:7])=[O:6])[C:23]([Br:26])=[CH:22][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=N[O-]
Reactant: O=S(=O)(Nc1cc(Br)ccc1Br)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c(NS(=O)(=O)c2ccccc2)cc1Br
Temperature: 90 °C

Procedure:
To 250 ml of acetic acid, diluted with 130 ml of water, are added: 1.5 g of sodium nitrite, 0.13 mole of 2,5-dibromo-N-benzenesulphonylaniline prepared in the previous stage and 0.78 mole (32.5 ml) of nitric acid (d=1.52). The reaction mixture is heated for 1 hour at 90° C. The reaction mixture, cooled beforehand, is poured onto 1 kg of ice and the expected product precipitates. It is filtered off, washed to neutrality and then recrystallized from acetic acid; it melts at 148° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.CN1CCOCC1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[F:38])[C:32](Cl)=[O:33].C(O)C(N)(CO)CO>CN(C)C=O>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:32]([C:31]3[CH:35]=[CH:36][C:37]([F:38])=[C:29]([F:28])[CH:30]=3)=[O:33])[CH2:2][CH2:3]2)[N:14]=1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccc(F)c(F)c4)CC3)cccc2n1
Reaction time: 2 h
Yield: 157.8 %

Procedure:
5-(Piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was shaken for 60 hours at room temperature in the presence of 3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and 3,4-difluorobenzoyl chloride (65.3 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated with 2 mL 1 N NaOH and ethanol (1:1). Solids were collected by filtration to yield [4-(2,4-diamino-quinazolin-5-yloxymethyl)-piperidin-1-yl]-(3,4-difluorophenyl)-methanone (117.4 mg; 76% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.51 (m, 2H), 7.35 (t, J=8.4 Hz, 1H), 7.26 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 5.94 (br s, 2H), 4.50 (br s, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.60 (br s, 1H), 3.11 (br s, 1H), 2.82 (br s, 1H), 2.22 (s, 1H), 1.87 (br s, 1H), 1.75 (br s, 1H), 1.31 (m, 2H). MS m/z (ESI) 414 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:20]([F:19])([F:29])[O:21][C:22]1[CH:23]=[C:24]([S:28][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: FC(F)(F)Oc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2cccc(OC(F)(F)F)c2)CC1
Yield: 74.1 %

Procedure:
A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.34 g, 4.79 mmol), 3-(trifluoromethoxy)benzenethiol (1.12 g, 5.75 mmol) and potassium carbonate (1.99 g, 14.4 mmol) in N,N-dimethylformamide (50 mL) at 90° C. for 20 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (20:1) to give 1.34 g (74%) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[C:12](C#N)[N:13]=[CH:14][C:8]=3[N:7](COCC[Si](C)(C)C)[C:6]=2[N:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][N:13]=[CH:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccnc2[nH]c3cnccc3c12

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1 eq.), the appropriate amine (5 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (0.1 eq.), and cesium carbonate (2 eq.) in 1,4-dioxane was heated between 100° C. to 110° C. until the reaction deemed complete. The reaction mixture was cooled then diluted with water and extracted with an appropriate solvent. The resultant residue was purified by flash chromatography on silica using either an ethyl acetate in heptane or methanol in dichoromethane gradient. The purified material was then deprotected using the conditions described below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([CH2:13][C:14]([O:16]CC)=O)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[CH3:21][CH:22]([CH3:37])[CH2:23][CH2:24][N:25]1[C:30]2[N:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28](=O)[O:27]C1=O.[H-].[Na+].C(O)(=O)C>C1COCC1>[OH:27][C:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:25]([CH2:24][CH2:23][CH:22]([CH3:37])[CH3:21])[C:14](=[O:16])[C:13]=1[C:8]1[NH:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:10](=[O:11])(=[O:12])[N:9]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(OC)ccc2N1
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 0 °C
Yield: 79.9 %

Procedure:
To a solution of the product of Example 183B (0.5 g, 1.6 mmol) and the product of Example 12A (0.375 g, 1.6 mmol) in anhydrous THF (16 mL) under nitrogen at 0° C. was added sodium hydride (95%, 0.162 g, 6.4 mmol). The reaction was heated at reflux for 4 hours, cooled to 0° C., and treated dropwise with glacial acetic acid (3 mL). The resulting mixture was heated at reflux for 2 hours, cooled to 25°, and diluted with ice water (150 mL). The resulting precipitate was collected by filtration, washed with water and recrystallized from dioxane/water to give the title compound (566 mg, 80%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. MS (ESI−) m/z 441 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.62 Hz, 6 H) 1.48 (m, 2 H) 1.64 (m, 1 H) 3.82 (s, 3 H) 4.29 (m, 2 H) 7.16 (m, 4 H) 8.36 (dd, J=7.54, 2.02 Hz, 1 H) 8.52 (dd, J=4.60, 2.02 Hz, 1 H) 15.86 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.O.[OH-].[K+].[C:19](=S)=[S:20]>CCO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:7][C:19]([SH:20])=[N:9][N:8]=2)=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1
Reactant: S=C=S
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(S)o1
Temperature: 90 °C

Procedure:
6-chloro-4-(isopropylamino)nicotinohydrazide (10) (1.5 g, 8.7 mmol) was taken in EtOH (10 mL): H2O (5 mL). Added KOH (13 mmol, 1.5 equiv.) followed by the addition of CS2 (87 mmol, 10 equiv.) to the reaction mixture and heated at 90° C., overnight. The reaction mass was concentrated under reduced pressure to remove solvents from the reaction mixture. The crude material obtained was taken to next step as such without purification. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.27 min; LCMS (ES-API), m/z 269.0 (M−H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)#[N:20]>CN(C)C=O.C1CCCCC1>[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[C:5]2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.9 g (0.06 mole) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° was added dropwise over 20 minutes a solution of 10.4 g (0.05 mole) of 3-methyl-2-(3-pyridyl)indole in 60 ml of dimethylformamide. The reaction mixture was stirred for 0.5 hour at 0°-5° followed by dropwise solution of 9.8 g (0.05 mole) of p-cyanobenzyl bromide in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture was poured into ice-water (600 ml). The resulting solid was collected, dried, washed with petroleum ether and redissolved in ether (500 ml). The ether solution was first washed with water, then with saturated sodium bicarbonate solution, dried over MgSO4, treated with charcoal and filtered. Evaporation of the ether extract to dryness yielded a yellow solid. This product was slurried in hot cyclohexane and collected by filtration to give 1-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)indole, m.p. 127°-9°.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([S:21]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cnc2[nH]cc(I)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of 3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (15, 4.30 g, 15.7 mmol) in 53.6 mL of N,N-dimethylformamide under nitrogen, sodium hydride (0.690 g, 60% in mineral oil, 17.2 mmol) was added. After 10 minutes, benzenesulfonyl chloride (11, 2.20 mL, 17.2 mmol) was added and the reaction was cooled in a water bath. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate purified by silica gel column chromatography, eluting with 30-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (16, 4.60 g).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16](=[S:23])[NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]=2[CH3:24])[CH2:5][C:4](=[O:25])[C:3]=1[C:26](=O)[CH2:27][CH3:28].Cl.[CH2:31]([O:33][NH2:34])[CH3:32]>>[CH2:31]([O:33][N:34]=[C:26]([C:3]1[C:4](=[O:25])[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16](=[S:23])[NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]=2[CH3:24])[CH2:7][C:2]=1[OH:1])[CH2:27][CH3:28])[CH3:32]
Reactant: CCON
Reactant: CCOC(=O)NC(=S)c1c(C)cc(C)c(C2CC(=O)C(C(=O)CC)=C(O)C2)c1C
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(C(=S)NC(=O)OCC)c2C)CC1=O

Procedure:
Reaction of 3-hydroxy-5-(3-ethoxycarbonylthiocarbamoyl-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one with ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1 part (v) gave 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(3-ethoxycarbonylthiocarbamoyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (23) as a yellow oil. the compound was characterized by its proton nuclear magnetic resonance spectrum and the data are recorded in Table 3, Example 11.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:5]2.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(#N)C.O>[OH:1][C@H:2]1[C@H:6]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])[CH2:3]1
Reactant: Oc1ccccc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2OC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1C[C@@H](O)[C@H](Oc2ccccc2)C1

Procedure:
2.6 g (0.01 mol) of the 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine described in Example 1 are heated together with 1.88 g (0.02 mol) of phenol and 10 ml of 1 N sodium hydroxide solution in 30 ml of acetonitrile for 5 hours under reflux. After cooling, the reaction mixture is diluted with water and extracted 3 times with methylene chloride, and the organic phase is washed twice with 2 N sodium hydroxide solution and then once with water, dried over sodium sulphate and evaporated under a water pump vacuum. The resulting oil crystallises from methylene chloride/hexane and gives trans-3-hydroxy-4-phenoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine with a melting point of 100°-103°.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16](O)=O)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([NH2:26])[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.[OH-].[K+]>O>[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]3[NH:26][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N:25]=3)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 0.83 h

Procedure:
To 73 parts of hot (70° C.) polyphosphoric acid were added 27 parts of 1-(phenylmethyl)-4-piperidineacetic acid hydrochloride: temperature rose to 100° C. When the addition was complete, there were added portionwise 14 parts of 1,2-benzenediamine and stirring and heating was continued for 50 minutes at 170° C. The hot reaction mixture was poured into 300 parts of warm water. The acid solution was alkalized with a potassium hydroxide solution. The precipitated free base was filtered off, washed with water and extracted with trichloromethane. The extract was dried and evaporated. The solid residue was recrystallized from a mixture of 2-propanone and methanol, yielding 17 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-benzimidazole; mp. 221.5°-222° C. (compound 1).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12](C(=O)C(F)(F)F)[CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 2-trifluoroacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid dimethylamide (prepared according to the method of Example 247, Step A, 337 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) in a 3:1 mixture of methanol/water (10 mL) was stirred at room temperature for 1 h and concentrated. The remaining aqueous residue was extracted with 10% isopropanol/chloroform (7×) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 214 mg (89%) of the title compound of Example 247, Step B as a white solid. 1H NMR (CD3OD, 300 MHz) δ 7.52 (d, 1H), 7.48 (s, 1H), 7.36 (d, 1H), 4.90 (s, 2H), 3.11 (t, 2H), 2.91 (t, 2H), 2.65 (s, 6H); MS (Cl/NH3) 241 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C[O-].[Na+].[CH2:13](N)[CH2:14][NH2:15]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:15][CH2:14][CH2:13][N:9]=2)[CH:3]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: NCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccnc(C2=NCCN2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-chloropyridine-2-carbonitrile (20.0 g, 121 nmuol, prepared as described by Sakamoto et al. Chem. Pharm. Bull. 1985, 33, 565-71) in MeOH (240 mL), was added sodium methoxide (0.655 g, 12.1 mmol). The reaction mixture was allowed to stir at rt under an atmosphere of argon for 2 h. Ethylene diamine (40.0 mL, 597 imol) was added and the mixture was allowed to stir at 50° C. for 20 h. The reaction mixture was allowed to cool to rt and then concentrated. The residue was dissolved in a mixture of water and DCM. The organic layer was separated, dried over MgSO4, filtered and concentrated to give 4-chloro-2-(4,5-dihydro-1H-imidazol-2-yl)pyridine as a light brown solid (21.9 g, >99%). LCMS: (FA) ES+ 182.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:13]2[N:14]=[CH:15][CH:16]=[N:12]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cn2nccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A 18-mL vial was charged with 1-(chloromethyl)-4-nitro-benzene (500 mg, 3 mmol, 1 eq.), triazole (310 mg, 4.5 mmol, 1.5 eq.), potassium carbonate (1.24 g, 9 mmol, 3 eq.) and DMF (5 ml). After the resulting mixture was stirred at rt overnight, water (20 ml) was added. The precipitate was collected by filtration and washed with small amount of water. After drying, 340 mg of the title compound was obtained as a mixture of two regioisomers (340 mg, 55% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH:13]O>[OH-].[Na+]>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:12])=[O:13]
Reactant: OO
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of the 6-bromoindoline-2,3-dione (e.g., 6-bromo-7-fluoroindoline-2,3-dione, 1 equiv) in 1 N NaOH (0.14 M) was added H2O2 (1.8 M) dropwise and the resulting mixture was stirred at room temperature until the reaction was complete (approximately 2 hours). The mixture was filtered and the filtrate was acidified to pH 2 with hydrochloric acid. The precipitate that formed was filtered, washed with water, and concentrated to provide the 2-amino-4-bromobenzoic acid (e.g., 2-amino-4-bromo-3-fluorobenzoic acid).