Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[I-:15].[Na+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: [I-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)CCCCCCCCCCI

Procedure:
To 11-bromoundecanoic acid dissolved in acetonitrile (50 ml) were added sodium iodide (2 g) and tetra-n-butylammonium iodide (1 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 11-iodoundecanoic acid (0.89 g).
Reaction SMILES: [C:1]([S@:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([SiH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH:9]=[CH2:10]>C1COCC1.[Cl-].[Na+].O.[O-]CCC.[Ti+4].[O-]CCC.[O-]CCC.[O-]CCC>[CH2:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:7][S@@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])=[C:13]([SiH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH:9]=[CH2:10]
Reactant: CC(C)(C)[S@](N)=O
Reactant: C=CCc1ccc(C=O)c([SiH](C)C)c1
Agent: [Ti+4]
Agent: CCC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1ccc(C=N[S@](=O)C(C)(C)C)c([SiH](C)C)c1
Yield: 68.3 %

Procedure:
To a solution of (R)-(−)-tert-butanesulfinamide (3.7 g, 30 mmol) and 4-allyldimethylsilylbenzaldehyde (2 Scheme 1, 6.2 g, 30 mmol) in dry THF (15 mL) was added titanium(IV) propoxide (17 mL, 60 mmol). The mixture was refluxed for 1 h under a N2 atmosphere. The mixture was cooled immediately upon reaction completion, and poured into a brine (30 mL) with rapid stirring. The resulting white suspension was filtered through a pad of celite, which was then washed with ethyl acetate (100 mL). The filtrate was transferred to a separatory funnel where the organic layer was washed with brine (20 mL). The organic layer was dried (Na2SO4), concentrated. The crude oil was purified by column chromatography (1:5 ethyl acetate/hexanes) to afford a colorless oil (6.3 g, 68%); 1H NMR (300 MHz, CDCl3) δ 0.30 (s, 6 H), 1.26 (s, 9 H), 1.76 (d, J=7.92 Hz, 2 H), 4.83 (s, 1 H), 4.88 (d, J=4.41 Hz, 1 H), 5.74 (ddt, J=15.84, 9.27, 8.28 Hz, 1 H), 7.62 (d, J=7.92 Hz, 2 H), 7.82 (d, J=7.92 Hz, 2 H), 8.59 (s, 1 H); 13C NMR (75 MHz, CDCl3) −3.5 (2C), 22.6 (3C), 23.4, 57.8, 113.9, 128.4 (2C),134.0, 134.2 (2C), 134.4, 144.6, 162.8; HRMS (M+1) calcd for C16H26NOSSi 308.1505, found 308.1415.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:27]=[O:28].[Cl-].[NH4+]>O1CCCC1>[CH3:13][O:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:27]=[O:28])=[CH:3][CH:4]=1
Reactant: COCOCCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCCc1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Next, to a mixture of bromo-4-(2-methoxymethoxyethyl)benzene (12.0 g, 49.0 mmol) and tetrahydrofuran (75 ml), a 1.58 mol/L n-butyllithium n-hexane solution (34 ml, 53.7 mmol) was added dropwise at −78° C. over 10 minutes. After stirring at −78° C. for 1 hour, a solution of N,N-dimethylformamide (11.4 mL, 147 mmol) in tetrahydrofuran (5 mL) was added and stirred at −78° C. for 1.5 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to give 4-(2-methoxymethoxyethyl)benzaldehyde (7.0 g, 74%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH2:11]([O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N+:26]([C:29]1[N:30]=[CH:31][N:32]([CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:35](O)=[O:36])[CH:33]=1)([O-:28])=[O:27].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:35](=[O:36])[CH:34]([N:32]1[CH:33]=[C:29]([N+:26]([O-:28])=[O:27])[N:30]=[CH:31]1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCCCCCC(C(=O)O)n1cnc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)n1cnc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 30.4 %

Procedure:
Diisopropylethylamine (39.6 mmoles, 5.1 g) was added to a solution of L-proline benzyl ester hydrochloride (39.6 mmoles, 10.1 g) in 20 ml DMF at 0° and stirred for 1 hour. The solution was added to 2-(4-nitro-1H-imidazol-1-yl) octanoic acid (39.6 mmoles, 10.1 g) and hydroxybenzotriazole (43 mmoles, 5.8 g) in 10 ml DMF, and stirred for 30 minutes. Dicyclohexylcarbodiimide (43 mmoles, 8.97 g) was added portionwise over 2 hours. Ethyl acetate (50 ml) was added. The solution was filtered, dried over sodium sulfate and concentrated. The oil was chromatographed over silica gel eluted with 40% ethyl acetate in hexane to yield 5.32 g of 1-[1-oxo-2-(4-Nitro-1H-imidazol-1-yl)octyl]-L-proline benzyl ester.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH2:9].[CH:19]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([CH3:21])[CH3:20]
Reactant: O=C1CCNCC1
Reactant: CC(C)Oc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(CN2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-piperidone hydrochloride monohydrate (19.52 g, 127.12 mmol), 1-Bromomethyl-3-isopropoxy-benzene (19.41 g, 84.76 mmol) and K2CO3 in DMF (150 mL) is stirred at rt for 16 hr. Solvent is removed in vacco, the residue is extract (EtOAc/Brine), dried (Na2SO4), concentrated, and purified by chromatography (silica gel, EtoAc/hexanes, 2/3) to afford 14-4. (MH+, 266)
Reaction SMILES: CC1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH3:23])[N:9]=2)C(C)=CC=1.Cl.NO>C(O)C.O.O>[NH2:3][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH3:23])[N:9]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Cc1nc(N)nc(C)c1OCc1ccccc1

Procedure:
To a stirred solution containing 2.85 g (9.27 mmol) 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-benzyloxy-4,6-dimethylpyrimidine (6) in 30 mL of ethanol-water 1:1 were added 6.44 g (93 mmol) of hydroxylamine hydrochloride. The reaction mixture was stirred at reflux overnight under argon atmosphere. The pH of the solution was then brought to 10 and diluted with 20 mL of water. The mixture was extracted with two portions of 30 mL of dichloromethane. The combined organic solution was dried (MgSO4) and then concentrate under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with acetone-hexanes 1:2 gave the expected product as white solid. Yield: 2.1 g (98%). 1H-NMR (CDCl3) δ 7.39 (m, 5H), 4.80 (br. 2H), 4.74 (s, 2H), 2.29 (s, 6H). 13C-NMR (CDCl3) 160.05, 158.45, 141.50, 137.02, 37.27, 19.22.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.C1OC2C=CC(CC(O)=O)=CC=2O1>>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1cccc(I)c1
Agent: O=C(O)Cc1ccc2c(c1)OCO2
Product: OCCc1cccc(I)c1

Procedure:
This was prepared as described in Preparation 19 using 3-iodophenylacetic acid (commercially available) instead of 3,4-methylenedioxyphenylacetic acid. The title compound was obtained as a colourless oil (2.2 g, 58%), which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:19]([CH3:20])[C:18]4[NH:21][CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:19]([CH3:20])[C:18]4[N:21]([CH3:31])[CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc(=O)c2cc[nH]c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ccc2c(=O)nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c21
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
Under argon gas, 2-[4-(4-chlorobenzoyl) benzyl]thio-1-methyl-7H-pyrrolo(2,3-d]pyrimidin-4-one (103 mg) was dissolved in anhydrous DMSO (20 ml) with warming. Then, at room temperature, 60% sodium hydride-oil (11 mg) was added and the mixture was stirred for 20 minutes. Then, methyl iodide (42.6 mg) was added and the mixture was further stirred overnight. The reaction mixture was diluted with water (200 ml) and the resulting precipitate was collected by filtration, dried, and purified by flash column chromatography (silica gel; chloroform-ethanol: chloroform=1:49) to provide the title compound (47 mg).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:45])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:45])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
In a 10 mL pear-shaped flask, 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (130 mg, 0.20 mmol) was combined with CH2Cl2 (1 ml) to give a yellow solution. TFA (0.24 ml, 3.2 mmol) was added and the reaction was stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuo and redissolved in CH2Cl2. Ethylenediamine (0.33 ml, 5.0 mmol) was added dropwise and the reaction was stirred at room temperature for 20 min. The crude reaction mixture was concentrated in vacuo. The residue was suspended in cold water and filtered, washing with water then dried on high vacuum to give 70 mg (64%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow solid. MS: (M+H)+=520; 1H NMR (DMSO-d6) δ: 9.14 (s, 1H), 8.70 (d, J=7.0 Hz, 1H), 8.36-8.63 (m, 2H), 8.03 (s, 1H), 7.25 (d, J=6.6 Hz, 1H), 4.48-4.82 (m, 5H), 4.16-4.34 (m, 1H), 4.01-4.15 (m, 1H), 3.86 (d, J=5.1 Hz, 1H), 3.33 (br. s., 1H), 2.80 (t, J=6.1 Hz, 2H), 2.20 (s, 6H), 1.40 (t, J=6.4 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1O)[C:11]([O:13][CH3:14])=[O:12]>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[Cl:4])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(Cl)c([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
(I4B): Anhydrous DMF (242 ml) was cooled to −20° C. in a dry ice/acetone bath and the internal temperature was monitored carefully and maintained at or below this temperature. Neat oxalyl chloride (9.51 ml, 109 mmol) was then slowly added dropwise via addition funnel and the vessel was properly vented to allow the escape of gases generated. Following the addition, the cloudy-white suspension was stirred at −20° C. for 30 min. A solution containing methyl 3-bromo-4-hydroxy-5-nitrobenzoate (10 g, 36.2 mmol) in DMF (121 ml) was then added slowly, not allowing the internal temp to exceed −10° C. Following the addition, the suspension was warmed to room temperature and then heated to 100° C. for 2 h. The reaction was cooled to room temperature and stirred over weekend. The dark brown solution was poured into ice water and diluted with EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with water and brine, and then dried over anhydrous sodium sulfate. Filtration and concentration afforded methyl 3-bromo-4-chloro-5-nitrobenzoate (10 g) as a yellow solid that was dried in vacuo overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH:11]([C:13]([OH:15])=O)[N:10]([CH3:16])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[CH2:57][NH2:58]>ClCCl>[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[CH2:57][NH:58][C:13]([CH:11]1[CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)[C:9](=[O:17])[N:10]1[CH3:16])=[O:15]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CN1C(=O)N(c2ccnc(F)c2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(c2ccnc(F)c2)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
A solution of 1-(2-fluoro-4-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (200 mg, 0.521 mmol) and N-ethyl morpholine (0.400 ml, 3.13 mmol) in dichloromethane (10 ml) was treated with 1-hydroxybenzotriazole hydrate (80 mg, 0.521 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg, 0.521 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. [(2,4-Dichlorophenyl)methyl]amine (0.084 ml, 0.521 mmol) was then added and the reaction stirred overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine and separated through a hydrophobic frit. The organic layer was reduced under vacuum. The residue was purified mass-directed automated HPLC to give N-[(2,4-dichlorophenyl)methyl]-1-(2-fluoro-4-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxamide (64 mg, 30.3% yield). LC/MS [M+H]+=397, retention time=2.45 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH:7]=1
Reactant: O=c1[nH]nc2ccc(Br)cn12
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1n(-c2ccccn2)nc2ccc(Br)cn12
Temperature: 160 °C
Yield: 51 %

Procedure:
A mixture of 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.467 mmol), K2CO3 (129 mg, 0.94 mmol), and 2-fluoropyridine (1 mL) was placed in a sealed microwave vial and heated to 160° C. in a microwave reactor for 90 minutes. The reaction was cooled, diluted with water/EtOAC and the layers were separated. The organic layer was washed with NaHCO3 and brine. The organics were dried (MgSO4), filtered, concentrated and purified by flash chromatography (Rf=0.23, 1:2 hexanes:EtOAc) to afford 70 mg (51% y) 6-bromo-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one, which was used directly in the next reaction (M+1=292.1). Compound 34 was synthesized according to the procedure disclosed in Example 1, however the reaction was done in 24 hours (28% y). C18H11F3N4O2, m/z (ESI)=373.2 [M+H]+. 1H NMR (δ, d6-DMSO, 400 MHz) 8.54-8.57 (m, 1H), 8.22 (t, J=1.2 Hz, 2H), 7.98-8.07 (m, 2H), 7.88 (dt, J=2.0, 8.4 Hz, 2H), 7.72 (dd, J=2.0, 9.6 Hz, 1H), 7.43-7.47 (m, 3H), 7.36-7.40 (m, 1H)
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:13]=[C:5]3[C:3]([OH:4])=[O:2])[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 288 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid methyl ester in 10 ml THF, 3 ml water and 57.0 mg lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid. The resulting precipitate was collected by filtration and washed with 3 ml water. The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O[N:18]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N1C=C(C2C=C(C=CC=2)N)C=NC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:14]([NH2:18])=[O:16])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)c1cccc2c1[nH]c1ccccc12
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (422 mg) and 1-hydroxybenzotriazole (324 mg) in dichloromethane (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (575 mg), and the mixture was stirred for 15 minutes. After adding 3-(pyrimidin-5-yl)aniline (360 mg) and 4-dimethylaminopyridine (367 mg), the mixture was stirred for 48 hours. The residue was evaporated under reduced pressure and purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-i din-5-yl)-phenyl)-9H-carbazole-1-carboxamide (314 mg, 43.1%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:26])[C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(Nc2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N(C)c2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Yield: 76.8 %

Procedure:
Following general procedure F and using 4-[(3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 16, 0.12 g, 0.35 mmol), potassium carbonate (0.49 g, 3.5 mmol) and iodomethane (0.50 g, 3.5 mmol) in 2 mL of anhydrous N,N-dimethylacetamide, the title compound (0.095 g, 80%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 2H, J=9.1 Hz), 6.81 (d, 1H, J=2.3 Hz), 6.78 (d, 1H, J=2.3 Hz), 6.63 (d, 2H, J=9.1 Hz), 4.31 (q, 2H, J=7.1 Hz), 4.28 (s, 2H), 3.31 (s, 3H), 2.59 (q, 2H,J=7.6 Hz), 1.35 (t, 3H, J=7.1 Hz), 1.33 (s, 6H), 1.22 (t, 3H, J=7.6 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH3:16][S:17]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:5]=1)(=[O:19])=[O:18]
Reactant: O=C1OCCN1c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCc1cccc(N2CCOC2=O)c1
Yield: 93 %

Procedure:
The title compound was prepared in 93% yield according to the general procedure for the preparation of amides (Method B) starting from starting from 3-[3-(2-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one and methanesulfonyl chloride. The crude material was purified on SPE cartridge (Silica) using as eluent a gradient from cyclohexane (100%) to cyclohexane-ethyl acetate (8:2) affording the final compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[S:26]([CH3:25])(=[O:28])=[O:27])[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)c1cccc(NCc2cccnc2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 3.8 g. portion of 3-(3-trifluoromethylphenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane and to it was added 2.7 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature overnight, and at a gentle reflux for another day. Another 1.6 ml. of methanesulfonyl chloride was added, and the mixture was stirred under reflux for 3 days more. It was then cooled, and diluted with 20 ml. of aqueous sodium bicarbonate. The organic phase was separated, washed with water, dried and evaporated under vacuum. The residue was triturated with diethyl ether and petroleum ether, and dried to give 4.7 g. of the desired product, m.p. 106°-110°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:21])=[O:20].O>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[CH2:23][NH:22][S:19]([CH3:18])(=[O:21])=[O:20])[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)NCc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Temperature: 100 °C
Yield: 90.9 %

Procedure:
A mixture of 4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 (400 mg, 1 mmol), 3-methanesulphonylaminomethyl benzeneboronic acid (260 mg, 1.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.052 mmol) in 4 ml of acetonitrile and 4 mL of 1.0 M of sodium carbonate aqueous solution was heated to 100° C. in a microwave for 10 min. Water (5 mL) was added and the resulting solid was filtered and washed with water and ethyl acetate to yield crude N-[3-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-benzyl]-methanesulfonamide (400 mg).