Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16]O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16][Br:19])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Oc2ccccc2C=C1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1Oc2ccccc2C=C1CBr
Temperature: 0 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
To an ice-cooled mixture of 3-Hydroxymethyl-2H-chromene-2-carboxylic acid ethyl ester (1.73 g, 7.39 mmol) in methylene chloride (25 mL) was added commercially available carbon tetrabromide (2.70 g, 8.13 mmol) and commercially available triphenylphosphine (1.94 g, 7.39 mmol). After addition was complete the mixture was stirred at 0° C. for 6 hours. Upon completion of the reaction, the methylene chloride was removed under reduced pressure. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; (0% to 90% ethyl acetate/hexane) to afford 3-bromomethyl-2H-chromene-2-carboxylic acid ethyl ester as a yellow oil, 1.08 g (49% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([C:22]3[N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][C:23]=3[CH:37]=[O:38])[CH2:12][C:13]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][O:19][C:15]=4[CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(=O)(=O)([OH:41])N.Cl([O-])=O.[Na+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([C:22]3[N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:24][C:23]=3[C:37]([OH:41])=[O:38])[CH2:12][C:13]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][O:19][C:15]=4[CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCn1c(-c2ccccc2)nc(C=O)c1N(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: CCCCn1c(-c2ccccc2)nc(C(=O)O)c1N(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(bis-benzo[1,3]dioxol-5-ylmethyl-amino]-1-butyl-2-phenyl-1H-imidazol-4-carbaldehyde 213 (263 mg, 0.5 mmol) in actone (10 mL) and water (5 mL) is added sulfamic acid (107 mg, 1.11 mmol) at room temperature and the mixture is stirred for 30 min. Sodium chlorite (63 mg, 0.7 mmol) is added and the mixture is stirred for additional 30 min at room temperature. Evaporation of most actone and the residue is extracted with chloroform. The organic phase is washed with water, brine and dried over sodium sulfate. The solvent is removed and the product is dried in vacuo. Yield: 281 mg; LC-MS (MH+): 542.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1.[S:14](Cl)([OH:17])(=O)=[O:15].[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.O>[C:19]1([CH3:25])[CH:24]=[CH:23][C:22]([S:14]([O:1][CH2:2][CH2:3][CH:4]2[O:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][CH2:5]2)(=[O:17])=[O:15])=[CH:21][CH:20]=1
Reactant: OCCC1COc2ccccc2O1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
74 g of 2-(2-hydroxyethyl) (2,3-dihydro [4H] 1,4-benzodioxin) are dissolved in 150 ml pyridine and to this solution 76 g p toluene sulfochloride are added while maintaining the inner temperature beneath 25°. The whole mixture is kept under stirring at room temperature for 24 hours then poured in water and extracted with chloroform. The chloroformic solutions are united, washed with water, dried and evaporated off. The dry residue is further purified by recrystallizing it from a mixture isopropyl ether--petrol (50:50)
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]([NH:15][CH3:16])[C:13]#[N:14]>C1(C)C=CC=CC=1.O.[OH-].[Na+]>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]([N:15]([CH3:16])[C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[C:13]#[N:14]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CNC(C#N)c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(C#N)N(C)C(=O)C(Cl)Cl)cc1OC

Procedure:
A solution of 14.7 g of dichloroacetylchloride in 10 ml of toluene are added dropwise, while stirring at a temperature of -10° to 15° C. to another solution of 20.6 g of N-(3,4-dimethoxy-α-cyanobenzyl-N-methylamine (prepared according to J. Prakt. Chem. 285 (1961) p. 258) in 80 ml of toluene and 20 ml of water, in which was dissolved 4 g of solid NaOH. A solid reaction product precipitates, which is filtered and washed with water until the aqueous filtrate is neutral. The solid acid amide is dried under vacuum to yield 27.7 g of raw product melting at 102°. After treating it with charcoal and recrystallisation from ethanol one obtains 125 g of crystalline title product, melting at 111°-112°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[OH:17].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1Cl.[CH3:24]S(O)(=O)=O.O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]2[O:17][C:24]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: Clc1cccs1
Reactant: Nc1cc(Cl)cc(CCc2ccccn2)c1O
Reactant: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1cc(CCc2ccccn2)c2oc(-c3cccs3)nc2c1
Yield: 31 %

Procedure:
This compound is prepared from 2-amino-4-chloro-6-[2-(pyridin-2-yl)ethyl]phenol and 2-thienyl chloride using method A, with ethyl acetate as solvent to give the crude amide in 99% yield. This is treated with methanesulphonic acid in toluene at reflux, with azeotropic removal of water to give the title compound, (31%) as a white crystalline solid after trituration and recrystallisation (EtOAc), m.p. 90-91° C. TLC (SiO2 ; EtOAc:hexanes 1:1, Rf=0.46). Mass Spectrum CI (methane), m/z=341 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH:34]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:40]4[CH2:41][CH2:42][N:37]([CH:34]5[CH2:36][CH2:35]5)[CH2:38][CH2:39]4)=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:32])([F:33])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: C1CN(C2CC2)CCN1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(N4CCN(C5CC5)CC4)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 186 step 7) and N-cyclopropylpiperazine bis hydrobromic salt (CAS # 159974-58-0). White solid (73%). MS (EI): 610.3 (M+H)+.
Reaction SMILES: Cl.[C:2](=N)(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29]([NH:31][NH2:32])=[O:30]>C(O)C.O1CCOCC1>[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29]1[O:30][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:32][N:31]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2)o1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of ethyl benzimidate hydrochloride (376 mg; 2.03 mmol) in ethanol (4 mL) was added at 0° C. sodium ethoxide (2.72 M in ethanol, 355 □L, 0.99 mmol) and stirred for 15 min. The suspension was filtered off and 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was added and stirred for 90 h at 70° C. The reaction mixture was suspended in dioxane (4 mL) and heated in the microwave for 30 min at 180° C. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (163 mg, 29%) as a white solid. MS: m/e=304.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:5]([NH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:6].[Cl-].[NH4+].O>C(O)C.C(O)(=O)C.[Fe]>[NH2:19][C:18]1[CH:17]=[CH:16][C:4]([C:5]([NH:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(NCCN1CCOCC1)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)NCCN2CCOCC2)cc1Cl
Reaction time: 1 h

Procedure:
3-chloro-N-(2-morpholin-4-ylethyl)-4-nitro-benzamide (Intermediate 53; 1.2 g, 3.82 mmol), iron powder (1.29 g, 22.95 mmol) and ammonium chloride (144 mg, 2.68 mmol) were heated in ethanol (27 mL) and water (9 mL at reflux for 1 h. A few drops of acetic acid were added and heating continued for a further 1 h. The reaction mixture was cooled, filtered and the filtrate concentrated. The residue was partitioned between DCM and sat NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated. Column chromatography of the residue gave the title compound as a white crystalline solid. (650 mg, 60%)
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17]O)=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCO)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCS(C)(=O)=O)nc21
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-4, 46.4 mg, 0.15 mmol, 1.0 equiv) was added to anhydrous DCM (1.5 mL) and cooled to −10° C. Triethylamine (90 μL, 0.64 mmol, 4.2 equiv) and methanesulfonyl chloride (26 μL, 0.33 mmol, 2.2 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 32-4. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give 32-5 as a clear, yellow oil. The crude product was carried forward without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.CCCCCC>[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]1[CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:36][CH:37]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a solution of dry diisopropylamine (7.7 ml, 5.5×10-2 mole) and dry THF (25 ml) under argon at 0° C. is added dropwise a hexane solution of n-butyllithium (21.1 ml, 5.5×10-2 mole). After stirring 1/2 hour at 0° C. a solution of t-boc-piperazinone (2) (5.0 g, 2.5×10-2 mole) and dry THF (125 ml) is added dropwise. The resultant mixture is stirred at 0° C. for 3 hours before a solution of p-benzyloxybenzyl chloride (6.40 g, 2.75×10-2 mole) and dry THF (20 ml) is added dropwise via syringe. This mixture is stirred an additional hour at 0° C. before the cooling bath is removed and the reaction allowed to warm to room temperature. After stirring overnight the mixture is quenched into saturated aqueous NH4Cl. The aqueous phase is extracted with Et2O (3 times) and CH2Cl2 (2 times). The ethereal extracts are combined and subsequently washed with saturated aqueous NaCl as are the CH2Cl2 extracts. The ethereal and CH2Cl2 extracts are then combined and dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives 3a as an almost colorless solid which crystallizes from ethyl acetate as colorless prisms 5.2 g (53%), m.p. 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[Cl:10][C:11]1[C:16]2[C:17](=[O:35])[N:18]3[CH2:34][CH2:33][CH2:32][C@H:19]3[C:20]3[N:21]([CH:22]=[N:23][C:24]=3[C:25](N3C=CN=C3)=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[Cl:10][C:11]1[C:16]2[C:17](=[O:35])[N:18]3[CH2:34][CH2:33][CH2:32][CH:19]3[C:20]3[N:21]([CH:22]=[N:23][C:24]=3[C:25]([O:7][C:2]3([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]3)=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CC1(O)CCCC1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(OC(=O)c2ncn3c2C2CCCN2C(=O)c2c(Cl)cccc2-3)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 g (12 mmol) of 1-methyl-cyclopentanol in 25 ml of dry dimethylformamide is treated with 0.5 g (10.3 mmol) of sodium hydride (55% oil dispersion) and to the resulting solution there are added portionwise at -20° 3.79 g (10.3 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole. The mixture is stirred at room temperature for 1 hour, poured into about 250 ml of water, the precipitated material is filtered off under suction, washed with water and dried. There is obtained 1-methyl-cyclopentyl 8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 190°-191°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]=1[C:15](Cl)=[O:16].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=1>ClCCl.CO>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:43]=[CH:44][C:45]([NH:48][C:15]([C:3]2[C:4](=[O:14])[N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]=2[I:1])=[O:16])=[N:46][CH:47]=1
Reactant: COc1cc2nccc(Oc3ccc(N)nc3)c2cc1OC
Reactant: O=C(Cl)c1c(I)ccn(-c2ccccc2)c1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(I)ccn(-c5ccccc5)c4=O)nc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of 4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonyl chloride (139 mg, 387 μmol) in dichloromethane (4 mL) at room temperature was added diisopropylethylamine (202 μl, 1160 μmol) followed by 5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-amine (115 mg, 387 μmol). The reaction mixture was stirred at room temperature for 2 h. An aliquot was taken and analyzed by LCMS: reaction was done. The reaction mixture was diluted with methanol and directly adsorbed on silica. Purification by MPLC(CH2Cl2/MeOH: 100/0 to 96/4) afforded N-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (162 mg, 261 μmol, 68% yield for two steps). MS (ESI pos. ion) m/z: 621 (MH+). Calc'd exact mass for C28H26IN4O5: 620.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[N:25]=[C:24](Cl)[C:23]([C:27]#[N:28])=[C:22]([CH3:29])[N:21]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:19][C:20]1[N:21]=[C:22]([CH3:29])[C:23]([C:27]#[N:28])=[C:24]([NH:18][CH:16]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])[N:25]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: CC(N)c1nc2cccnc2n1-c1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(N)nc(NC(C)c2nc3cccnc3n2-c2ccccc2)c1C#N
Temperature: 90 °C
Yield: 48.1 %

Procedure:
A mixture of 1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (66 mg, 0.28 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (38 mg, 0.23 mmol) and DIPEA (142 μL, 0.831 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 50-100% EtOAc in cyclohexane) followed by trituration from EtOAc to afford 366 as an off-white solid (41 mg, 40%). LCMS (Method K): RT 2.54 min [M+H]+ 371.10. 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, dd, J=4.77, 1.47 Hz), 8.14 (1H, dd, J=7.98, 1.47 Hz), 7.55-7.44 (6H, m), 7.33 (1H, m), 7.12-6.61 (2H, m), 5.52 (1H, m), 2.21 (3H, s), 1.47 (3H, d, J=6.81 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][I:13]>CC(C)=O>[IH:13].[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[NH:11])[S:10][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CC(N)=S)c1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)Cc1cccc(C)c1
Product: I

Procedure:
A solution of 3-methylphenyl(thioacetamide) (4.9 g.) and methyl iodide (12.6 g.) in acetone (15 ml.) was heated to reflux for 20 minutes. The mixture was cooled and filtered to give pure methyl 3-methylphenyl(thioacetimidate) hydriodide, m.p. 142°-144°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6]1.O1CCOCC1.[NH:40]1[C:48]2[C:43](=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=2)[CH:42]=[N:41]1.C([O-])([O-])=O.[K+].[K+]>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.O>[NH:40]1[C:48]2[C:43](=[C:44]([C:2]3[CH:3]=[C:4]4[C:31](=[CH:32][CH:33]=3)[O:30][CH2:29][C:25]3([CH2:28][O:27][CH2:26]3)[C:5]34[CH2:9][O:8][C:7]([NH2:10])=[N:6]3)[CH:45]=[CH:46][CH:47]=2)[CH:42]=[N:41]1
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CO1)c1cc(-c3cccc4[nH]ncc34)ccc1OCC21COC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
Under argon atmosphere, to a mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (300 mg, 0.571 mmol), dioxane (3.0 mL) and water (1.5 mL) were added 1H-indazol-4-ylboronic acid (185 mg, 1.14 mmol), K2CO3 (237 mg, 1.71 mmol) and bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.057 mmol), and the mixture was stirred for 3 hours at 100° C. The reaction mixture was cooled down to ambient temperature, partitioned between H2O and 10% MeOH in CHCl3. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated at reduced pressure. The residue was dissolved with dioxane (3.0 mL), and silica gel (neutral; 900 mg) was added to the mixture. After stirring for 2.5 hours at 110° C., the reaction mixture was cooled down to ambient temperature, and concentrated at reduced pressure. Purification of the residue with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%) afforded 6′-(1H-indazol-4-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (142 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7](C(=O)C(F)(F)F)[CH2:6][CH2:5]2.BrC1C=CC=C2C=1CN(C(=O)C(F)(F)F)CC2.CCN(C(C)C)C(C)C.[CH3:44][C@@:45]1([CH2:52][S:53](Cl)(=[O:55])=[O:54])[C:49](=[O:50])[NH:48][C:47](=[O:51])[NH:46]1>C(O)C.[OH-].[NH4+].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([S:53]([CH2:52][C@@:45]1([CH3:44])[NH:46][C:47](=[O:51])[NH:48][C:49]1=[O:50])(=[O:54])=[O:55])[CH2:6][CH2:5]2
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: O=C(N1CCc2cc(Br)ccc2C1)C(F)(F)F
Agent: O=C(N1CCc2cccc(Br)c2C1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(Br)ccc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 113.9 %

Procedure:
A 3:1 mixture (0.44 g, 1.4 mmol) of 6-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline and 8-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (prepared according to Tetrahedron Lett. 1996, 37(31), 5453-5456) was stirred in ethanol (10 mL) containing a few drops of 25% ammonium hydroxide at RT. After 2.5 h, the solution was concentrated, dissolved in dry THF (1.0 mL) under argon and cooled on an ice-bath. DIPEA (0.41 mL, 2.4 mmol) was added followed by a solution of [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl-chloride (0.27 g, 1.2 mmol) and dry THF (1.0 mL). The mixture was stirred at RT for 1 h and then concentrated. The crude product was taken up in water and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated to give 0.55 g of a mixture of (5S)-5-({[6-bromo-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione and (5S)-5-({[8-bromo-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione. The regioisomers were separated by preparative HPLC.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[CH:4][C:5]1[NH:6][C:7](=[O:29])[C:8]2[C:9]3[N:18]([CH3:19])[C:17]([NH:20][C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:28])=[N:16][C:10]=3[CH:11]=[CH:12][C:13]=2[C:14]=1[CH3:15].[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:17]1[N:18]([CH3:19])[C:9]2[C:8]3[C:7](=[O:29])[NH:6][C:5]([CH2:4][CH:3]=[CH:2][NH:1][C:37]([NH:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:38])=[C:14]([CH3:15])[C:13]=3[CH:12]=[CH:11][C:10]=2[N:16]=1
Reactant: Cc1c(C=CCN)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(CC=CNC(=O)Nc2ccccc2)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Yield: 86.8 %

Procedure:
A solution of the product of Example 28 (50 mg, 0.12 mmol) and phenyl isocyanate (17 mg, 0.13 mmol) in DMF (2 mL) was heated at 60° C. for 10 h. The resulting precipitate was filtered, triturated with MeOH/CH2Cl2 (90:10), and dried to provide the title compound (57 mg, 89%) mp>290° C.; MS (ES) 547 (MH+).