Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:13]2[N:12]=[C:11]3[N:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:24]4)[N:17]=[CH:18][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1
Temperature: 120 °C

Procedure:
A suspension of methyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.3 mmol), 4-aminophenylboronic acid pinacol ester (0.76 g, 3.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.27 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (2.5 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Gemini column, running a gradient elution of 20% acetonitrile/80% of 0.07% aqueous ammonium hydroxide to 95% acetonitrile over 10 minutes. After the concentration of fractions under reduced pressure, methyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate was obtained. MS (ES+): 464.6 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]([C:11]3([OH:24])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].O1CCOCC1>CO>[ClH:25].[F:1][C:2]1[C:10]2[O:9][CH:8]([C:11]3([OH:24])[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C2Cc3cccc(F)c3O2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: OC1(C2Cc3cccc(F)c3O2)CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(7-fluoro-2,3-dihydrobenzofuran-2-yl)-4-hydroxypiperidine-1-carboxylate (0.404 g, 1.197 mmol) in MeOH (7.04 mL) was added HCl in dioxane (4 M, 4.4 mL, 17.48 mmol). Upon completion of addition, the reaction mixture was stirred at room temperature for 5 hours. After this time, the solvent was removed under reduced pressure to afford Compound 1F as a light yellow solid (0.38 g, 100% yield). LC/MS (m/z)=238 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[CH3:15][N:16]=[C:17]=[O:18].CCOCC>C1C=CC=CC=1.CN(C)C>[CH3:15][NH:16][C:17](=[O:18])[O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=1
Reactant: COC(CSc1cccc(O)c1)OC
Reactant: CN=C=O
Agent: CN(C)C
Solvent: CCOCC
Solvent: c1ccccc1
Product: CNC(=O)Oc1cccc(SCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (1.80 grams) dissolved in benzene (5 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (12 ml) and trimethylamine (2 drops) were then added, and the resulting mixture was stirred at room temperature for a period of about 51/2 hours. The mixture was then allowed to stand overnight and was then stripped of excess methyl isocyanate and a portion of the benzene. The concentrated solution was then added to ether and cooled to -60° C., resulting in a precipitate. The precipitate was recrystallized from ether to yield the desired product O-[3-(2,2-dimethoxyethylthio)phenyl]-0 N-methylcarbamate having a melt point of 46° to 48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cc(F)cc(Cl)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 76.2 %

Procedure:
3-chloro-5-fluoroaniline (0.074 mL, 0.73 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.09 g, 0.18 mmol)) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-chloro-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.065 g, 75%) as a white solid. Mass Spectrum: M+H+ 474. NMR is Spectrum (CDCl3): 1.61 (d, 3H), 2.90 (bs, 3H), 3.09 (bs, 3H), 3.46-3.55 (m, 4H), 3.80-3.88 (m, 4H), 4.35 (d, 1H), 4.88-4.96 (m, 1H), 5.56 (s, 1H), 6.03 (ddd, 1H), 6.27 (dd, 1H), 6.39 (ddd, 1H), 7.70 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:25])[CH:7]=1.[Br:31]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>>[Br:31][C:7]1[C:8](=[O:25])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 3 (2.1 g, 5.06 mmol) and N methyl 2-pyrrolidine (10 mL). N-Bromo succinimide (1 g, 5.56 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica (1:1 hexanes; ethyl acetate) to give the title compound as an orange oil (0.77 g, 31%). 1H NMR (400 MHz, CD3OD) δ 8.16 (app qd, J=2.5 and 7.2 Hz, 1H), 7.84 (d, J=2.6 Hz, 1H), 7.64 (m, 1H), 7.30 (d, J=9.2 Hz, 1H), 7.04 (appt, J=8.4 Hz, 2H), 6.60 (s, 1H), 5.33 (s, 2H), 3.80 (s, 6H), 1.99 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.56 (1F), −116.00 (1F) ppm. ES-HRMS m/z 494.0398 (M+H calcd for C22H13BrF2NO5 requires 494.0409).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([N+:19]([O-])=O)[CH:11]=1>CCO.CCOC(C)=O.[Pd]>[NH2:19][C:12]1[CH:11]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:15]=[CH:14][C:13]=1[CH2:16][C:17]#[N:18]
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1N

Procedure:
A suspension of [4-(1,3-benzoxazol-2-yl)-2-nitrophenyl]acetonitrile (100 mg, 0.36 mmol) and Pd/C (20 mg) in EtOH/EtOAc (5:1, 60 mL) was hydrogenated (35 psi) over 2d. The resulting reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The yellow solid obtained was purified by flash chromatography on silica gel eluting with MeOH:CH2Cl2 (1:19) to afford [2-amino-4-(1,3-benzoxazol-2-yl)phenyl]acetonitrile as an orange solid (M.p. 198–199° C.). 1H NMR (CDCl3, 300 MHz) δ 7.77 (m, 1H), 7.71–7.66 (m, 2H), 7.58 (m, 1H), 7.40–7.34 (m, 3H), 3.88 (s, 2H), 3.66 (s, 2H). MS (ESI) 250 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[C:33]([O:34][CH3:35])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2ccccc2cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: COc1cc2ccccc2cc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3(b)] with 2-bromomethyl-3-methoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[3-methoxy-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a colourless resin; MS: 465 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]#[C:6][C:7]1([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:2]>[Pd].O.C(O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([OH:20])[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:11][CH2:12]1)[CH3:2]
Reactant: CCOC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
Palladium on carbon (5%, 1 g) in water (10 mL) was added to a solution of 1,1-dimethylethyl 4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate (Description 76, 14.6 g, 0.046 mol) in ethanol (200 mL) and the mixture was shaken under hydrogen (45 psi) for 90 minutes. The mixture was filtered through a glass fibre pad and the solvent was evaporated under reduced pressure to give the title compound. m/z (ES+) 302 (M+1).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:23][CH:24]=[C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:26]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([N-:40][S:41](N1C=CC(=[N+](C)C)C=C1)(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].O>ClCCl>[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:23][CH:24]=[C:25]([CH:27]3[CH2:32][CH2:31][N:30]([S:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])(=[O:42])=[O:43])[CH2:29][CH2:28]3)[N:26]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)cs2)cc1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCC(c2csc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
3-Phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(pyridin-2-ylthio)pyridin-2-amine (0.075 g, 0.162 mmol) and N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (0.0490 g, 0.162 mmol) were dissolved in dichloromethane (2 mL) and stirred at ambient temperature for 18 hours. Water was added and the reaction mixture was extracted with dichloromethane. The organic layer was dried, filtered and concentrated. The crude material was purified by silica gel chromatography (25-50% ethyl acetate in hexanes) provided tert-butyl 4(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-ylsulfonylcarbamate (0.0785 g, 75.4% yield).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2.[I-:18].[Na+]>CC(C)=O>[I:18]/[CH:2]=[CH:3]/[C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2
Reactant: O=C(/C=C/Cl)CCCCC1CCC2CCC1C2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)CCCCC1CCC2CCC1C2
Yield: 84.4 %

Procedure:
A solution of 3.2 g (13 mmol) of 1-chloro-7-(bicyclo-[3.2.1]oct-2-yl)-1E-hepten-3-one and 7.5 g (50 mmol) of sodium iodide in 25 ml of dry acetone (distilled from potassium carbonate) was refluxed for 18 hr under nitrogen. The solvent was removed in vacuo, and the residue was taken up in 50 ml of water and then extracted three times with 30 ml portions of ether. The combined ether extracts were washed with aqueous sodium thiosulfate, dried (MgSO4) and evaporated in vacuo to yield 3.8 g (88%) of 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1-E-hepten-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([NH:38][C:39]1[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:46])=[O:37]>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:12]([OH:19])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:35][C:36]([NH:38][C:39]3[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:46])=[O:37])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Nc1ccc2c(cnn2CC(O)(Cn2cncn2)c2ccc(F)cc2F)c1
Reactant: Cc1cccc(C)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc(C)c1NC(=O)CNc1ccc2c(cnn2CC(O)(Cn2cncn2)c2ccc(F)cc2F)c1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of (5-amino-1H-indazol-1-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.1 g, 0.27 mmol) in N,N-dimethylformaide (1 ml) was slowly added potassium carbonate (0.037 g, 0.27 mmol) at 0° C. and followed by stirring for 30 min. The addition of 2-bromo-N-(2,6-dimethylphenyl)acetamide (0.065 g, 0.27 mmol) to the solution was followed by stirring at room temperature for hours and concentrated by evaporation in a vacuum condition. The crude product was purified by chromatography on silica gel to give the title compound (Yield 50%).
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O>C(O)C>[N:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:2]=[C:1]([SH:3])[S:4][CH:8]=2)=[CH:12][CH:13]=1
Reactant: NC(=S)[S-]
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: [NH4+]
Solvent: CCO
Product: Sc1nc(-c2ccncc2)cs1
Reaction time: 18 h

Procedure:
Ammonium dithiocarbamate (0.444 g, 4.03 mmol) was added to 2-bromo-1-(4-pyridinyl)-1-ethanone hydrobromide (1.03 g, 3.67 mmol) in ethanol (10 ml and stirring continued at room temperature for 18 hr. The solid was filtered and re-crystallized from methanol to give 4-pyridin-4-yl-thiazole-2-thiol. This thiol (272 mg, 1.39 mmol) was then coupled with N1-3-chlorophenyl)-2-chloroacetamide (284 mg, 1.39 mmol) as described in earlier examples, in acetonitrile in the presence of triethylamine (0.580 ml, 4.2 mmol) to afford crude product. This was purified by reverse phase HPLC to afford N-(3-Chloro-phenyl)-2-(4-pyridin-4-yl-thiazol-2-ylsulfanyl)-acetamide. MS (ES) 363 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=N[CH2:25][CH2:26][CH2:27]N(C)C>C(O)(C)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH:26]([CH3:27])[CH3:25])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Solvent: CC(C)O
Product: CC(C)OC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reaction time: 16 h

Procedure:
2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid was mixed with EDCI and isopropanol and the reaction mixture was stirred for 16 h to obtain isopropyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [CH2:1]1[N:3]([CH2:4][CH:5]([OH:15])[CH2:6][N:7]2[C:11]([N+:12]([O-:14])=[O:13])=[N:10][CH:9]=[CH:8]2)[CH2:2]1.[ClH:16].C>CC(C)=O>[ClH:16].[N+:12]([C:11]1[N:7]([CH2:6][CH:5]([OH:15])[CH2:4][NH:3][CH2:2][CH2:1][Cl:16])[CH:8]=[CH:9][N:10]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1nccn1CC(O)CN1CC1
Agent: Cl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1nccn1CC(O)CNCCCl
Temperature: 0 °C
Yield: 66.3 %

Procedure:
A solution of 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol (2.12 g, 10.0 mmol) in acetone (20 cm3) prepared as described in Example 1(a) was stirred at 0°-5° C. using external ice-water cooling. Concentrated aqueous hydrochloric acid (38% w/w HCl, 2.0 cm3) was added in one portion. The mixture was treated with decolourising charcoal (0.3 g), filtered and chilled to give 1-(2-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanol hydrochloride (1.89 g, 66.3%) as a pale yellow microcrystalline solid, m.p. 152.5°-153.5° C. (dec.) after drying in vacuo.
Reaction SMILES: O.NN.[N+:4]([C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1)([O-])=O>CO.[Pd]>[NH2:4][C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2c(cc1N)OCCO2
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A solution of hydrazine monohydrate (1.0 mL, 21 mmol) in MeOH (3 mL) was added dropwise to a refluxing suspension of methyl 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (889 mg, 3.7 mmol) and palladium on carbon (10%, 220 mg) in MeOH (25 mL) under N2. After refluxing overnight, the resulting mixture was cooled to room temperature, filtered through celite and the filter cake was washed with MeOH. The combined filtrates were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 30% ethyl acetate in hexane to yield methyl 7-amino-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (390 mg, 50%). 1H NMR (CDCl3, 600 MHz) δ 7.19 (s, 1H), 6.17 (s, 1H), 4.24-4.22 (m, 2H), 4.17-4.15 (m, 2H), 3.82 (s, 3H); MS (ES+) m/z 210.1 (M+H)+
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[P:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[CH:1]([NH:4][P:6]([NH:4][CH:1]([CH3:3])[CH3:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: ClP(Cl)c1ccccc1
Reactant: CC(C)N
Solvent: CCOCC
Product: CC(C)NP(NC(C)C)c1ccccc1
Reaction time: 72 h
Yield: 33 %

Procedure:
To a stirred solution of isopropylamine (30 ml, 352 mmol) in diethylether (250 ml), dichlorophenylphosphine (9.63 ml, 71 mmol, dissolved in 50 ml diethylether) was added at 0° C. over a period of 30 min. After stirring for a total of 72 hrs the solution was filtrated. The residue was washed with diethylether and the solvent was removed in vacuum. The remaining oil was distilled at 0.2 Torr/76-78° C. to give a colorless liquid with 33% yield (5.3 g). 31P{H} NMR: 49.0 ppm.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH2:18][F:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH2:18][F:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCCCF)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCCCF)nc1Cl
Yield: 116.7 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-butoxypiperidine-1-carboxylate obtained in Example (127d) (0.84 g, 3.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.41 g, 2 mmol), WSC hydrochloride (0.77 g, 4 mmol), HOBt (0.41 g, 3 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 1.01 g of the title compound as a colorless solid (100%).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CC(N3CCOCC3)C2)cc1
Temperature: 25 °C
Yield: 693 %

Procedure:
A solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (Preparation 1(b)) (24.46 g, 7.72 mmol), potassium carbonate (32 g, 3 mol equiv) and morpholine (7.34 ml, 1.09 mol equiv) in acetonitrile (200 ml) was heated under reflux for 4 hours. The solution was then cooled to room temperature, water (50 ml) added and the mixture concentrated in vacuo. The residue was then partitioned between ethyl acetate (400 ml) and water (400 ml) and the organic phase washed with water (2×400 ml). The organic phase was dried over MgSO4, and the solvent removed in vacuo. The residue was chromatographed using silica gel eluting with hexane: diethyl ether (1:1) to give the title compound (16.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].ClCCl.[C:44](=O)(O)[O-:45].[Na+].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:13][C:12]1[C:2]([N:1]=[C:44]=[O:45])=[C:3]([CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:17]3=[N:18][CH:19]=2)[CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N=C=O)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a scintillation vial was combined 125 mg (0.224 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide, 2.0 mL dichloromethane, and 2.0 mL of a saturated aqueous solution of sodium bicarbonate. The vial was cooled to 0° C. in an ice bath and, under vigorous stirring, 601 μL (1.12 mmol) of a 20% phosgene in toluene solution was added. The reaction was stirred in the ice bath for 30 minutes and then stirred at room temperature for another 30 minutes. The layers were separated and organic layer was dried over sodium sulfate and concentrated to afford 3-fluoro-2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a brown foam.