Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1>C(#N)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:19][C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: Cc1nc(CCl)no1
Reactant: O=c1[nH]c2ccc(F)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(Cn2c(=O)sc3cc(F)ccc32)no1
Yield: 91.3 %

Procedure:
A mixture of 6-fluoro-2(3H)-benzothiazolone (8.45 g), acetonitrile (100 ml) and potassium carbonate (7.6 g) was prepared. To this mixture was added dropwise 3-chloromethyl-5-methyl-1,2,4-oxadiazole (7.3 g) at a temperature of 40° to 50° C. under stirring. The reaction mixture was heated under refluxing for 5 hours. The reaction mixture was then cooled and filtered. The filtrate was distilled under a reduced pressure, and the residue was admixed with ethyl acetate (200 ml) and water (100 ml). The resultant organic layer was separated and washed with a 5% aqueous potassium hydroxide solution, with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was dissolved in a minimum amount of ethanol under heating. The solution thus formed was cooled to a temperature of 0° to 5° C. to precipitate a crystalline product, which was then separated by filtration, and dried, so that the aimed compound, i.e. 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (12.1 g) was obtained. m.p. 142°-144° C.
Reaction SMILES: [I:1]Cl.C[O:4]/[N:5]=[C:6](/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])\[C:7]#[C:8][CH3:9].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:6]1[C:7]([I:1])=[C:8]([CH3:9])[O:4][N:5]=1
Reactant: CC#C/C(=N\OC)c1ccc(F)cc1F
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1onc(-c2ccc(F)cc2F)c1I
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Iodine monochloride (2.13 g, 13.1 mmol) was dissolved in DCM (15 mL) then the solution was added over about 10 min to the (E)-1-(2,4-difluorophenyl)but-2-yn-1-one O-methyl oxime (2.29 g, 10.9 mmol) in DCM (100 mL). The mixture was stirred for about 1 h then saturated aqueous sodium thiosulfate (50 mL) was added. The mixture was stirred for about 10 min then the layers were separated. The aqueous layer was extracted with DCM (25 mL) then the combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel with heptane/EtOAc (95:5) as an eluent to give the title compound (1.64 g, 47%): LC/MS (Table 1, Method g) Rt=2.65 min; MS m/z: 322.0 (M+H)+.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:23]=[C:21]1[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](=[O:28])[N:22]1[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of 1,1-dimethylethyl (2-hydroxy-2-phenylethyl)carbamate (2 g, 8.44 mmol), phthalimide (1 g, 7.03 mmol) and triphenylphosphine (2.76 g, 10.5 mmol) in THF (35 mL) at 25° C. was added DEAD (1.7 mL, 10.5 mmol) dropwise. After 0.5 h, the solution was concentrated and purified via column chromatography (silica, 15% EtOAc in hexanes) affording the title compound (2 g, 80%) as a white foam: LC-MS (ES) m/z=367 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C@H:24]([CH2:36][OH:37])[CH2:25][CH2:26][N:27]2[CH2:34][CH2:33][C:30]3([CH2:32][CH2:31]3)[C@H:29]([OH:35])[CH2:28]2)[C:20](=[O:38])[C@@H:19]1[CH3:39])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.C(NCC)C>>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C@H:24]([CH2:36][O:37][C:1](=[O:3])[CH3:2])[CH2:25][CH2:26][N:27]2[CH2:34][CH2:33][C:30]3([CH2:32][CH2:31]3)[C@H:29]([OH:35])[CH2:28]2)[C:20](=[O:38])[C@@H:19]1[CH3:39])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCNCC
Product: CC(=O)OC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Yield: 71.5 %

Procedure:
Acetic anhydride (42 mg, 0.41 mmol) was added at 0° C. to a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (intermediate 39; 182 mg, 0.41 mmol) and pyridine (32 mg, 0.41 mmol). The ice bath was removed, then after 16 h excess reagent was destroyed by addition of diethylamine (15 mg, 0.21 mmol). After evaporation of volatile material, chromatography (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (143 mg, 72%). Colorless gum, MS (ISP)=488.4 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:29]=[CH:28][C:24]([C:25]([Cl:33])=[O:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid (prepared according to the method of Example 1) (379 mg; 0.98 mmol ) was suspended in dry dichloromethane (20 ml) and treated with oxalyl chloride (2 ml) and N,N-dimethylformamide (1 drop). This mixture was stirred at ambient temperature for 5 h then evaporated to dryness under reduced pressure to give the title compound as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>C1COCC1.C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=2[F:21])[O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[CH:7]=2)=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Nc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1F
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1F
Yield: 76.4 %

Procedure:
Dissolve N-[6-(3-amino-4-fluoro-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (400 mg, 1.4 mmol) in THF (4 mL) and DCM (10 mL), add 4-chloro-3-(trifluoromethyl)phenyl isocynate (1.4 g, 6.3 mmol). Stir the reaction at room temperature overnight. Filter and collect the solid to get the title compound (545 mg, 77%). MS: (M+1): 510.2.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:22][OH:23])[C@@H:15]([C:18]([F:19])([F:20])[F:21])[O:16][CH2:17]1
Reactant: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl isothiocyanate (19.0 mL) was added to a solution containing ((2S,3R,4S)-4-amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (28.72 g) in DCM (150 mL), and the mixture was stirred at RT for 18 h. Sodium bicarbonate (sat., aq., 200 mL) was then added, the mixture extracted with EtOAc (3×300 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% to 30% EtOAc in hexanes) to obtain the title compound (37.07 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.22 (dd, J=8.1, 4.5 Hz, 1H), 3.31 (td, J=8.0, 3.0 Hz, 1H), 3.94-4.07 (m, 1H), 4.31-4.46 (m, 1H), 4.53 (d, J=9.9 Hz, 1H), 4.83 (d, J=9.9 Hz, 1H), 6.97-7.14 (m, 1H), 7.22 (td, J=7.7, 1.3 Hz, 1H), 7.31-7.45 (m, 1H), 7.49-7.61 (m, 2H), 7.61-7.70 (m, 1H), 7.75 (td, J=8.1, 1.5 Hz, 1H), 7.79-7.93 (m, 2H), 8.90 (s, 1H), 11.85 (s, 1H)
Reaction SMILES: [CH:1]1([NH:7][C:8]2([CH2:13]O)[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17]>Cl>[ClH:17].[Cl:17][CH2:13][C:8]1([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OCC1(NC2CCCCC2)CCCC1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: ClCC1(NC2CCCCC2)CCCC1
Temperature: 70 °C
Yield: 195.8 %

Procedure:
A 4M HCl solution (p-dioxane, 40 mL) containing 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane (Method B4a; 1.9 g, 9.6 mmol) and SOCl2 (0.84 mL, 11.5 mmol) was heated to 70° C. for 18 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure to yield crude 1-(chloromethyl)-1-(cyclohexylamino)cyclopentane HCl salt (2.84 g), which was used in the next step without firer purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:5]1[N:6]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)cc(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Yield: 25.3 %

Procedure:
The title compound (1.1 g, 25%) was prepared from 2-butyl-4-methyl-1,6-dihydro-6-pyrimidone (2.3 g, 13.85 mmol), 4-[2-bromoethoxy]benzaldehyde (3.17 g, 13.85 mmol) in the presence of K2CO3 (3.82 g, 27.7 mmol) as base by a similar procedure to that described in preparation 1.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl[CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>CC(=O)CC>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: ClCCCCOC1CCCCO1
Agent: [Na]
Solvent: CCC(C)=O
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCCCCOC1CCCCO1

Procedure:
A mixture of 5-(N,N-dibenzylglycyl)salicylamide, sodium salt (3.96 g), 2-(4-chlorobutoxy)tetrahydropyran (1.92 g) sodium iodide (1.40 g) and butanone (100 ml) was heated under reflux for 30 hours and filtered. The filtrate was evaporated to give an oil which crystallised from isopropanol to afford the ether as colourless crystals (2.95 g), m.p. 118°-123°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])[NH2:30]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:36]3[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:29]([NH2:30])=[O:31])[C:18]2=[O:27])=[CH:12][CH:11]=1)=[O:28]
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: NC(=O)c1cccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Yield: 73 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-carbamoylphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (73%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].[Cl:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][S:18]([CH2:17][CH2:16][CH2:15][Cl:14])(=[O:20])=[O:19]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)CCCCl)c(OC)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a solution of 2,4-dimethoxy-benzylamine hydrochloride (1 eq.) and TEA (2 eq.) in DCM was added dropwise at 0° C. a solution of 3-chloro-propane-1-sulfonyl chloride (1 eq.) in DCM. The reaction was stirred at 20° C. for 20 h. The crude was diluted with DCM, washed twice with water, twice with aqueous HCl (0.1N) and twice with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 100/0 to 20/80) to afford 3-chloro-propane-1-sulfonic acid 2,4-dimethoxy-benzylamide.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[SH:23])C=CC=CC=1.C(N(CC)CC)C>CO>[OH:1][C:3]1([CH2:2][SH:23])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: S[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 808.6 %

Procedure:
To a mixture of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (35.3 g, 16.55 mmol) and triphenylsilanethiol (48.4 g, 16.55 mmol) in anhydrous methanol (1.0 L) was added triethylamine (23.1 ml, 16.55 mmol) drop-wise over the course of 30 minutes. The reaction was stirred for 1 hour at room temperature and the methanol was evaporated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in hexanes to 40% EtOAc in hexanes) to afford 81% (33.1 g) pure final product. M.p.=54-55° C.; 400 MHz 1H NMR (CDCl3) δ: 3.97-3.78 (m, 2H), 3.19-3.08 (m, 2H), 2.61 (d, J=4.4 Hz, 2H), 1.70-1.55 (m, 2H), 1.50-1.38 (m, 11H); LCMS: 248 [M+H].
Reaction SMILES: C([N:4]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][C:6]([NH:12][C:13]2[C:18]([C:19]#[CH:20])=[CH:17][N:16]=[C:15]([C:21]3[S:25][C:24]([S:26]([NH:29][C:30](=[O:32])[CH3:31])(=[O:28])=[O:27])=[CH:23][CH:22]=3)[N:14]=2)=[N:5]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CCO>[CH:9]1([C:8]2[NH:4][N:5]=[C:6]([NH:12][C:13]3[C:18]([C:19]#[CH:20])=[CH:17][N:16]=[C:15]([C:21]4[S:25][C:24]([S:26]([NH:29][C:30](=[O:32])[CH3:31])(=[O:27])=[O:28])=[CH:23][CH:22]=4)[N:14]=3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: C#Cc1cnc(-c2ccc(S(=O)(=O)NC(C)=O)s2)nc1Nc1cc(C2CC2)n(C(C)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cnc(-c2ccc(S(=O)(=O)NC(C)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
The mixture of crude N-(5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-ylsulfonyl)acetamide and K2CO3 (43 mg, 0.31 mmol, 2.4 eq) in EtOH (10 mL) was stirred at room temperature for 1 h. The reaction mixture was filtered, the filtrate was concentrated. The residue was diluted with EtOAc and washed with water, brine, dried (Na2SO4), and filtered. The filtrate was concentrated and crystallized with ether to yield N-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-ylsulfonyl)acetamide (Compound 192) (65 mg, 84%). LC-MS (m/z)=429 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.74-0.77 (m, 2H), 0.97-0.99 (m, 2H), 1.71 (s, 3H), 1.92-1.99 (m, 1H), 4.87 (s, 1H), 6.49 (s, 1H), 7.41 (d, J=4.0 Hz, 1H), 7.66 (d, J=3.6 Hz, 1H), 8.47 (s, 1H), 8.57 (bs, 1H), 12.31 (bs, 1H)
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:29])=[C:6]([CH:24]=[C:25]([CH2:27][CH3:28])[CH:26]=1)[NH:7][C:8]([C:10]1[N:14](CC2C=CC(OC)=CC=2)[N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2].COC1C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]([C:4]1[C:5]([OH:29])=[C:6]([CH:24]=[C:25]([CH2:27][CH3:28])[CH:26]=1)[NH:7][C:8]([C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CCc1cc(NC(=O)c2nnnn2Cc2ccc(OC)cc2)c(O)c(C(C)=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(NC(=O)c2nnn[nH]2)c(O)c(C(C)=O)c1
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
A solution of 3'-acetyl-5'-ethyl-2'-hydroxy-1-(4-methoxybenzyl)-1H-tetrazole 5-carboxanilide (10.0 g) and methoxybenzene (10.0 g) in trifluoroacetic acid (150 ml) was heated at reflux for 45 minutes, and then the solvent was removed in vacuo. The residue was stirred with diethyl ether (100 ml) for 20 minutes, and the precipitated solid was filtered off and recrystallised from a mixture of dimethylformamide and water to give 3'-acetyl-5'-ethyl-2'-hydroxytetrazole-5-carboxanilide (6.5 g), m.p. 239°-242° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:20]1([C:26]([C:28]2[S:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:33][C:31]4[S:32][C:28]([C:26]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[O:27])=[CH:29][CH:30]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: O=Cc1ccc(C(=O)N2CCOCC2)s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(C(=O)N2CCOCC2)s1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
The mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (90 mg, 0.32 mmol), 5-(morpholine-4-carbonyl)-thiophene-2-carbaldehyde (82 mg, 0.36 mmol), and triethylamine (2 drops) in ethanol (3 mL) was heated at 90° C. oil bath for 2 hours, and cooled to room temperature. The solvent was evaporated and the residue was purified on a silica gel column eluting with methylene chloride-methanol (98:2 and 95:5) to provide pure 4-(3-chloro-4-fluoro-phenylamino)-5-{1-[5-(morpholine-4-carbonyl)-thiophen-2-yl]-methylidene}-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (41 mg, 28%). MS 486 [M++1].
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([O:15]CC)=[O:14])[C:6]=2[CH:18]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]=2[CH:18]=1
Reactant: CCOC(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 123.3 %

Procedure:
Ethyl (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate (22.0 g, 0.072 mol) was suspended in 400 mL of THF and treated with LiOH (3.46 g, 0.144 mol) dissolved in 80 mL of water at room temperature. The reaction was magnetically stirred and maintained at room temperature for 20 hours. The reaction was then quenched with 30 mL of concentrated HCl and stirred for 20 minutes. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=7.5 min) was gone and that a single product (Rt=6.0 min) had formed. The solvent was removed by rotary evaporation to give an off-white solid that was further dried under high vacuum to give 24.5 g of a mixture of the title compound (77 % by mass) and LiCl (23% by mass) which was used in subsequent reactions without further purification. Actual product yield is 18.9 g (0.068 mol, 95%). MS (ES) m/e 276 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:18]([O-])=[O:19].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:18]=[O:19])[C:5]([N:7]([CH3:17])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2 g of 1-(2-chloroethyl)-3-methyl-3-D-ribofuranosylurea are dissolved in 10 ml of formic acid, and 1.1 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 1-(2). 1.4 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-D-ribofuranosylurea are thereby obtained as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:25][CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH:13]2[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:25][CH:14]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][CH:13]3[CH2:12]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-pyrimidine (2.00 g, 12.3 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4.64 g, 20.5 mmol) in EtOH (25 mL) was added Et3N (2.62 g, 25.9 mmol). The reaction mixture was stirred at 50° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as yellow oil (2.42 g, 55.9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.[Br:25]N1C(=O)CCC1=O>CC#N.C1COCC1>[Br:25][C:19]1[C:20]([O:22][CH3:23])=[CH:21][C:16]2[O:15][CH2:14][CH2:13][N:12]([C:10]3[S:9][C:5]4[C:6](=[O:8])[NH:7][C:2]([CH3:24])([CH3:1])[CH2:3][C:4]=4[N:11]=3)[C:17]=2[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)OCCN2c1nc2c(s1)C(=O)NC(C)(C)C2
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1cc2c(cc1Br)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a stirred solution of Example 489 (0.05 g, 0.145 mmol) in MeCN (1 mL) and THF (1 mL) was added N-bromosuccinimide (0.026 g, 0.145 mmol). The mixture was stirred at r.t. overnight and then concentrated in vacuo. EtOAc (10 mL) and 1% aqueous sodium sulfite (5 mL) were added and the mixture was rapidly stirred for 10 minutes. The aqueous layer was extracted with EtOAc (10 mL) and then DCM (2×10 mL). The EtOAc extracts were concentrated in vacuo and the residue was dissolved in DCM (5 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4), filtered and the solvent was evaporated in vacuo to give the title compound (0.062 g, 100%) as a light brown solid. δH (CDCl3) 8.17 (1H, s), 6.52 (1H, s), 5.22 (1H, s), 4.35-4.30 (2H, m), 4.10-4.05 (2H, m), 3.86 (3H, s), 2.88 (2H, s), 1.39 (6H, s). LCMS (ES+) 424.1, 426.0 (M+H)+, RT 3.47 minutes (Method 1).