Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:12]=[C:8]2[C:7](=[O:20])[NH:6][CH2:5]1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22].O>C(Cl)Cl>[CH3:24][S:21]([O:1][CH2:2][CH2:3][CH:4]1[N:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:12]=[C:8]2[C:7](=[O:20])[NH:6][CH2:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCC(CCO)n2cc(-c3cccc(Cl)c3)cc21
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 4-(2-hydroxyethyl)-7-(3-chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (128 mg, 0.44 mmol) in DCM (10 ml), mesyl chloride (58 ul, 0.748 mmol) and TEA (200 ul, 1.48 mmol), were added. The resulting solution was stirred at room temperature, after 1 h the reaction mixture was portioned between DCM and water. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give 2-[1-oxo-7-(3-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]ethyl methanesulfonate as a solid 157 mg (97%).
Reaction SMILES: [N+]([O-])(OCCCCC)=O.N[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[N:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]2[OH:26].[S:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>>[OH:26][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)[CH:12]=2)[N:17]=[N:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: c1ccsc1
Agent: CCCCCO[N+](=O)[O-]
Product: CCOC(=O)c1nnc2ccc(-c3cccs3)cc2c1O

Procedure:
Amyl nitrate (1 ml.) was added to a stirred suspension of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (1 g.) in thiophen (100 ml.). The suspension was stirred and heated under reflux for 2 hours. The suspension was filtered whilst hot and the filtrate was evaporated, giving a brown crystalline residue. The solid was applied to a silica column (100 g. of Kieselgel 60) and eluted with a 10% v/v mixture of dry ethanol and chloroform. The appropriate fractions were evaporated, and the residue was crystallised from 1:1 v/v aqueous ethanol to give ethyl 4-hydroxy-6-thienylcinnolin-3-yl carboxylate, m.p. 258°-260° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:17][CH3:18])[CH:5]=1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[CH3:18][O:17][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][O:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)COc1ccc(CCO)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)-2-methoxyphenoxy]acetate (1.53 g) in dichloromethane (30 ml) were added triethylamine (1.26 ml) and p-toluenesulfonyl chloride (1.26 g), and the mixture was stirred for 24 hours at room temperature. The reaction mixture was washed with 1N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) gave ethyl 2-[2-methoxy-4-[2-(p-toluenesulfonyloxy)ethyl]phenoxy]acetate (2.04 g).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:3]=1[C:21]#[N:22].Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([O:8][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])[N:7]=1
Reactant: N#Cc1c(N)[nH]c(=O)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(F)cc2)nc1COc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
250 mg (0.81 mmol) of the compound from Example 102A, 228 mg (1.013 mmol) of 4-(chloromethyl)-2-(4-fluorophenyl)-5-methyl-1,3-oxazole and 224 mg (1.62 mmol) of potassium carbonate are initially charged in 8.6 ml of dry DMF and stirred at 70° C. for 2 h. The solvent is then removed on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). The product is then purified once more by HPLC (column: Waters Sunfire C 18 5 nm, 250 mm×20 mm; mobile phase gradient: water/ethanol 55:45→5:95; flow rate: 25 ml/min; temperature: 30° C.; detection: 210 nm).
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=O>C(O)C>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 91.8 %

Procedure:
To a solution of the compound (2.99 g, 14.0 mmol) obtained in Example 1b in ethanol (30 mL) was added 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (3.74 g, 14.0 mmol), and the mixture was heated under reflux for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with diluted aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (4.90 g, 91%) as a colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[CH:7]=1.[CH3:16]O>>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[C:8]([Cl:15])[CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1Cl
Temperature: 60 °C

Procedure:
Thionyl chloride (1.64 ml) was added dropwise to a suspension of 4-bromo-2-chlorobenzoic acid (6.92 g) in methanol, and heated to 60 ° C. for 2 hours. The solvent was removed in vacuo, the residue redissolved in ethyl acetate, and washed sequentially with 0.5 N sodium hydroxide (2×), water, and brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent removed in vacuo to afford upon evaporation of the solvent in vacuo 7.8 g of the title compound as an oil. 1H NMR (300 Mhz), d: 3.87 (s,3H), 7.68-7.9 (m, 3H).
Reaction SMILES: CN(C=O)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[F:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:20]([O:32][CH3:33])[CH:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C>[F:17][C:18]1[C:23]([F:24])=[CH:22][C:21]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)=[CH:29][CH:30]=2)=[C:20]([O:32][CH3:33])[CH:19]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of DMF (5 ml), 1-bromomethyl-3-nitro-benzene (0.92 g, 4.2 mmol), and 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (1 g, 4.2 mmol) was added lithium bis(trimethylsilyl)amide (1M in THF, 4.4 ml). The reaction was stirred at room temperature overnight and was then diluted with ethyl acetate (200 mL), washed with water (200 mL), aqueous ammonium chloride (10%, 200 mL) and brine, dried over magnesium sulfate and concentrated to yield 4,5-difluoro-2-methoxy-4′-(3-nitro-benzyloxy)-biphenyl as yellow solid (1.5 g, 95%). LC-MS (ES) calculated for C20H15F2NO4, 371.1; found m/z 370 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1.C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:26][CH:25]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1F
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3F)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Chloro-2-fluoro-benzenesulfonyl chloride (10.5 g) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (10.0 g) were added to a reaction vessel containing a magnetic stirring bar, followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for 20 h before being cooled on an ice-bath and quenched with 1M aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate and evaporated to afford the crude product. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded the title compound as a colorless solid after evaporation of the solvents under reduced pressure. Yield: 14.14 g (75%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[OH:39][CH2:38][C:37]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)CO)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C1COCC1.[O:33](C(OC(C)(C)C)=O)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][N:15]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])[C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(CNc3ccc(N4CCOCC4)cc3)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(CN(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 123 (689 mg, 1.89 mmol) in THF (100 ml) Et3N (289 μl, 2.08 mmol) was added dropwise. (BOC)2O was added slowly and the mixture was stirred at room temperature overnight under nitrogen, THF was evaporated off and the residue was partitioned between water and CH2Cl2. Organic layer was separated, dried over MgSO4, evaporated to form another residue which was purified by flash column chromatography (EtOAc/hexane, 7:3) to afford the title compound 124 (692 mg, 79%). 1H-NMR (CDCl3) δ: 8.24 (m, 1H), 8.09 (m, 1H); 7.76 (dd, J=8.2, 1.4 Hz, 1H); 7.55 (d, J=8.8 Hz, 1H); 7.13 (d, J=2.5 Hz, 1H); 6.93 (m, 3H); 4.97 (s, 2H); 3.94 (s, 3H); 3.89 (m, 4H); 3.16 (m, 4H); 1.47 (s, 9H).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[CH2:14]([N:16]([CH2:19]C)[CH2:17][CH3:18])[CH3:15].N1CCCC1>O1CCCC1>[N:16]1([CH2:19][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[CH2:17][CH2:18][CH2:15][CH2:14]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CCN(CC)CC
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(ncn2CN2CCCC2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Equivalent amounts of theophylline and triethylamine were allowed to equilibrate with 2 equivalents of 37% aqueous H2C=O for a few minutes until a solution was obtained. Then, 2 equivalents of pyrrolidine was added and the mixture was diluted with tetrahydrofuran and allowed to stir at room temperature overnight. The solution was then concentrated in vacuo at <40°. The residue was triturated with ether and the suspension filtered. The residue from the suspension was dried to give the desired 7-(1-pyrrolidinyl)methyltheophylline in 72% yield; mp 105°-108°, lit mp 108° (J. Org. Chem. 24, 562 (1959); NMR, UV and TLC consistent with the desired product.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[Br-].[CH2:19]([Zn+])[CH:20]([CH3:22])[CH3:21]>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>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:3][C:4]=2[O:16][CH3:17])[N:8]=1
Reactant: CC(C)C[Zn+]
Reactant: COc1cc(Br)ccc1Oc1cccc(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: COc1cc(CC(C)C)ccc1Oc1cccc(F)n1
Temperature: 105 °C
Yield: 19.6 %

Procedure:
To a suspension of Pd(PPh3)4 (0.025 mmol; 17 mg) under argon, in anhydrous, degased dioxane (2 mL), sheltered from light, were added 2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine (0.51 mmol; 151 mg), then isobutyl zinc bromide (1.0 mmol; 2.0 mL). The reaction was heated to 105° C. for 24 hr. The mixture was then hydrolysed with water (3 mL), extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over MgSO4, concentrated under reduced pressure. The crude was then purified by preparative chromatography (cyclohexane/dichloromethane) to yield the desired product as a clear oil (28 mg; 0.10 mmol; 20%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:12][CH:13]([F:16])[CH2:14][NH2:15]>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH2:14][CH:13]([F:16])[F:12])[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NCC(F)F
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)CNc1nc(Cl)nc2ccoc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (2 g, 10.58 mmol, Arkpharm), DCM (20 mL) and TEA (2.95 mL, 21.16 mmol). A solution of 2,2-difluoroethanamine (0.858 g, 10.6 mmol, Matrix) in DCM (5 mL) was added drop-wise and the mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure. To the residue was added 1,4-dioxane (20 mL), TEA (2.95 mL, 21.2 mmol) and a solution of 2,2-difluoroethanamine (0.858 g, 10.58 mmol, Matrix) in 1,4-dioxane (5 mL). The mixture was stirred at rt for about 4 h, and then at about 55° C. overnight. The mixture was concentrated under reduced pressure, and the residue was taken up in EtOAc (120 mL) and water (25 mL). The organic layer was isolated and washed with water (2×25 mL). The combined aqueous layers were washed with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL), dried with MgSO4, filtered, concentrated under reduced pressure, and dried in a vacuum oven at about 70° C. over 2 days to give 2-chloro-N-(2,2-difluoroethyl)furo[3,2-d]pyrimidin-4-amine (2.20 g, 89%): LC/MS (Table 2, Method c) Rt=1.69 min.; MS m/z: 234 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1.CC(C)=O>O>[N:1]([CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: OCC1(CBr)COC1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC1(CO)COC1
Yield: 94 %

Procedure:
A mixture of sodium azide (9.5 g, 0.14 mol), 3-bromomethyl-3-hydroxymethyloxetane (24.0 g, 0.14 mol), 20 mL of acetone and 20 mL of water was refluxed for 12 h. The acetone was evaporated and the resulting residue was extracted with two portion of 40 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate (MgSO4). The solvent was removed by evaporation. 18.0 g, representing a 94% yield, of 3-azidomethyl-3-hydroxymethyloxetane were obtained as an oil. This oil was found to be essentially pure by gas-liquid chromatography (GLC) analysis. NMR: 1H NMR 3.70 (s, 2 H), 3.84 (d, J=4.9 Hz, 2 H), 4.44 (s, 4 H); 13C NMR 44.283, 53,852, 64,073, 76.227.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:9]([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=1)=[O:5])[CH3:2].C1C(=O)N([Br:36])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:36][CH2:21][C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][CH:16]=2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(CBr)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To a stirred solution of Ethyl 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (Compound 1b, 4.0 g, 9.17 mmol) in chlorobenzene (50 ml) were added NBS (1.77 g, 10.09 mmol) and AIBN (1.65 g, 10.09 mmol) at 25° C. The reaction mixture was then stirred at 85° C. for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature and was quenched in aqueous sodium chloride solution (50 ml). The mixture so obtained was then extracted with Ethyl acetate (2×50 ml). The organic layer was washed with brine (1×50 ml) and dried over sodium sulfate and concentrated under reduced pressure to obtain crude product (4.0 g). The crude product was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (2.8 g, 59.32%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[CH:9][C:10]([O:32][CH3:33])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[C:17]([C:30]#[N:31])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:32][CH3:33])=[CH:9][C:8]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:31]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Reaction time: 1.5 h

Procedure:
A solution of acryloyl chloride (39 mg, 0.43 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile (Intermediate 90, 200 mg, 0.43 mmol) and DIPEA (0.081 mL, 0.47 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH2Cl2 (25 mL). This mixture was then washed with sat. NaHCO3 (50 mL). The aqueous washes were further extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 5% 7N methanolic ammonia in CH2Cl2 gave the title compound together with some residual starting material. Further purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave a residue after concentration of the appropriate fractions in vacuo. This residue was dissolved in a small amount of CH2Cl2 and trituration with diethyl ether gave a solid that was collected by filtration and dried in vacuo to give the title compound (106 mg, 48%) as a cream solid; 1H NMR: 2.27 (3H, s), 2.57 (4H, br s), 2.92 (4H, br s), 3.74 (3H, s), 3.91 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.63 (1H, dd), 6.90 (1H, s), 7.01 (1H, br s), 7.25 (1H, s), 7.52 (1H, d), 7.88 (1H, br s), 8.02 (1H, s), 8.48 (1H, s), 8.67 (1H, s), 9.03 (1H, s), 9.40 (1H, s); m/z: ES+ MH+ 523.27.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5](=[O:9])[C:6]=1[CH2:7][CH3:8].[H-].[Na+].[CH3:12][CH:13](Cl)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1>CN(C)C=O>[CH3:1][C:2]1[NH:3][N:4]([CH:13]([CH3:12])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:5](=[O:9])[C:6]=1[CH2:7][CH3:8]
Reactant: CC(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCC1=C(C)N=NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(C)[nH]n(C(C)c2ccc(Cl)c(Cl)c2)c1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
25.2 g of 3-methyl-4-ethylpyrazol-5-one were added in portions to a suspension of 10.0 g (0.22 mol) of sodium hydride in 200 ml of absolute dimethylformamide. After the evolution of H2 had ceased, 41.8 g (0.2 mol) of α-methyl-3,4-dichlorobenzyl chloride were added dropwise to the reaction solution. The mixture was then stirred for 2 hours at 60° C, the solvent was distilled off in vacuo and the residue was taken up in water and acidified with dilute acetic acid. The crude product thereby obtained was recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>CCCCCCC.CCOC(C)=O>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc2c(c1)N(CCCCl)C(=O)CO2
Yield: 42.1 %

Procedure:
6-Methoxy-4H-benzo[1,4]oxazin-3-one (81MF2249a) (0.212 g, 1.18 mmol), Cs2CO3 (0.578 g, 1.77 mmol) and 3-chloro-1-iodopropane (0.265 g, 1.3 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 10:1-2) gave the title compound (81MF2249b) (0.127 g, 42%). 1H NMR (CDCl3) δ 6.88 (d, J=8.8 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.50 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.50 (s, 2H), 4.05-4.01 (m, 2H), 3.76 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 2.16-2.09 (m, 2H); 13C NMR (CDCl3) δ 164.8, 155.5, 139.3, 129.2, 117.4, 107.8, 101.9, 67.8, 55.8, 42.4, 38.9, 30.0.