Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:19][C:20]([NH2:22])=[S:21]>>[NH2:22][C:20]1[S:21][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\OC1CCOCC1)C(=O)CBr
Product: CCOC(=O)/C(=N\OC1CCOCC1)c1csc(N)n1
Yield: 70 %

Procedure:
Ethyl 4-bromo-(Z)-2-(tetrahydro-4H-pyran-4-yloxyimino)-3-oxobutyrate (0.52 g) was treated with thiourea as described in Example 4d. Crystallisation from diisopropyl ether gave the title compound as a pale yellow solid (0.34 g, 70%), m.p. 110.0°-110.5° C. [Found: C: 48.37, H: 5.99, N: 13.59. C12H17N3O4S requires C: 48.15, H: 5.72, N: 14.04%]. νmax (KBr) 3138, 1733, 1616, 1538 cm-1. δH (CDCl3) 1.39 (3H, t), 1.76 (2H, m), 2.01 (2H, m), 3.56 (2H, m), 3.88 (2H, m), 4.42 (2H, q), 4.53 (1H, m), 5.29 (2H, br s, exch. D2O), 6.73 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[C:6]=2[N:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[NH2:19].C(N(CC)C(C)C)(C)C.C1CN(C(ON2N=NC3C2=CC=CC=3)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.O.CN(C)C=O>[CH3:26][O:25][C:21]1[CH:20]=[C:18]([NH:19][C:11]([C:8]2[C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[S:10][CH:9]=2)=[O:13])[CH:17]=[C:16]([O:15][CH3:14])[C:22]=1[O:23][CH3:24]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)c1csc2cnc(Cl)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2OC(N1CCCC1)=[N+]1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2csc3cnc(Cl)nc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.050 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0854 g (0.466 mmole) of 3,4,5-trimethoxyaniline, 0.122 mL (0.699 mmole) of N,N-diisopropylethylamine and 1.55 mL of dimethylformamide was added 0.111 g (0.256 mmole) of O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate. The mixture was stirred at room temperature for 2 hours. Water and dichloromethane were added. The aqueous layer was washed three times with dichloromethane. The combined organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in high vacuum to give 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4,5-trimethoxy-phenyl)-amide as a yellow solid
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([NH:38][NH2:39])=O>ClCCl.C(OCC)(=O)C>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:36]([C:32]3[S:31][CH:35]=[CH:34][N:33]=3)=[N:38][N:39]=[C:26]2[CH2:25]1)=[O:23]
Reactant: NNC(=O)c1nccs1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2nccs2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (144 mg, 0.756 mmol) was added to a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (200 mg, 0.687 mmol) in dry dichloromethane (DCM) (1.7 ml). The reaction was stirred at room temperature 1 h—everything dissolved. 1,3-thiazole-2-carbohydrazide (I50)(118 mg, 0.824 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and 1-butanol (1.700 ml) was added to the residue. The resulting reaction mixture was stirred at reflux for 9 h. The reaction mixture was diluted with ethyl acetate (I25 mL) and washed with water (2×25 mL), sat. NaHCO3 (25 mL) and brine (2×25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP (acidic method). The resulting residue was triturated with Et2O and dried 3 days at 50° C. under vacuum to afford desired product in 30.5 mg as a white solid.
Reaction SMILES: BrCC([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]1([NH2:18])C=CC=C[C:12]=1[NH2:17].CCN(C(C)C)C(C)C>C(O)C>[N:17]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:18]=[CH:11][CH:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccccc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2nccnc2c1

Procedure:
To a magnetically stirred solution of the appropriate α-bromoacetophenone (1 eq) in 5 ml of ethanol was added the appropriate 1,2-phenylenediamine (2.7 eq), followed by DIPEA (3.4 eq). The resultant solution was stirred at room temperature overnight with an air atmosphere. The reaction was concentrated, then purified by reverse phase chromatography on a C-18 column using a 0 to 90% gradient of CH3CN in water, with both containing 0.05% TFA. Product containing fractions were lyophilized to give a powder.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].CCN(CC)CC>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (3.6 ml) was treated with ethanesulfonyl chloride (26.6 μL, 275 μmol) and Et3N (41.8 μL, 300 μmol). After ½ h the mixture was stirred at room temperature for 3 h, cooled down (0° C.) and treated again with ethanesulfonyl chloride (7.3 μL, 75 μmol) and Et3N (11.5 μL, 82.5 μmol). After 2 h at room temperature, the mixture was concentrated in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, CH2Cl2/MeOH (0.5 to 1.5%)) to give after precipitation from CH2Cl2 with n-pentane the pure title compound (43 mg, 50%) as a off-white powder. MS: 342.1 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH2:16]([O:15][CH2:14][C@@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(COC[C@@H]2CNCCN2Cc2ccccc2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: c1ccc(COC[C@@H]2CNCCN2)cc1
Temperature: 80 °C
Yield: 81.6 %

Procedure:
A solution of 0.30 gm (1.01 mMol) 1-benzyl-2(S)-(benzyloxymethyl)piperazine in 20 mL 1,2-dichloroethane was cooled to 0° C. To this solution were added 1.09 mL (10.1 mMol) 1-chloroethyl chloroformate and the resulting mixture was heated at 80° C. for 4 hours. The reaction mixture was then cooled again to 0° C. and an additional 2.18 mL (20.2 mMol) 1-chloroethyl chloroformate were added. The reaction mixture was heated at reflux overnight and was then concentrated under reduced pressure. The residue was dissolved in 40 mL methanol and heated at reflux for 2 hours. The mixture was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with dichloromethane containing 0–10% methanol and 0.1% ammonium hydroxide. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.17 gm (81%) of the title compound.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.Cl[C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:15](=[CH:16][C:17]([CH3:24])=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:9][C:5]1[CH:4]=[C:3]([C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:15](=[CH:16][C:17]([CH3:24])=[CH:18][CH:19]=3)[N:14]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(OB([O-])[O-])c1
Reactant: Cc1ccc2cc(C)c(Cl)nc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc3cc(C)ccc3cc2C)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
3-Methylphenyl borate (1.3 mmol), 2-chloro-3,7-dimethylquinoline (1 mmol), tetrakis(triphenylphosphine)palladium(O) (0.05 mmol) and potassium carbonate (3 mmol) were dissolved in THF (30 mL) and H2O (10 mL). The resulting solution was stirred in a bath at 100° C. for 24 hours. After completion of the reaction, the THF and the toluene were removed. The reaction mixture was extracted with dichloromethane and water. The extract was distilled under reduced pressure and purified by silica gel column chromatography. The eluate was distilled under reduced pressure and recrystallized from dichloromethane and petroleum ether to obtain a precipitate. The precipitate was filtered to yield 2-(3-methylphenyl)-3,7-dimethylquinoline as a solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:18])[C@@H:15]([OH:17])[CH3:16])[C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=3[C:7]3[CH:23]=[CH:24][CH:25]=[CH:26][C:6]2=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35].C(OC(=O)C)C.C1CCCCC1>ClCCl>[N+:43]([C:40]1[CH:39]=[CH:38][C:37]([O:36][C:34](=[O:35])[O:17][C@H:15]([C:14](=[O:18])[NH:13][C@@H:10]2[C:11](=[O:12])[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]3[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=3[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]2=3)[CH3:16])=[CH:42][CH:41]=1)([O-:45])=[O:44]
Reactant: C[C@H](O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Yield: 0.1 %

Procedure:
0.46 g (1.32 mmol) (S)—N—((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-hydroxy-propionamide in 15 ml dichloromethane were stirred with 213 μl (2.64 mmol) pyridine and 0.33 g (1.58 mmol) 4-nitrophenyl chloroformate at room temperature overnight. Chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0) gave 0.63 mg (92%) carbonic acid (S)-1-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester 4-nitro-phenyl ester as a white foam; MS: m/e: 516.5 (M+H+), [α] 589=−164° (0.94% in MeOH).
Reaction SMILES: C(OP([C:9]([F:26])([F:25])[C:10](=[O:24])[CH2:11][C:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH3:13])(=O)OCC)C.[OH-].[Na+]>CO.O>[F:26][CH:9]([F:25])[C:10](=[O:24])[CH2:11][C:12]([CH3:13])([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH3:14]
Reactant: CCOP(=O)(OCC)C(F)(F)C(=O)CC(C)(C)c1cc(F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of [1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]phosphonic acid diethyl ester (1.0 g) in methanol (12.0 mL) was added a solution of sodium hydroxide (0.04 g) in water (1 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with hexanes (50 mL) and water (50 mL) and the organic phase was separated, dried, filtered, and evaporated in vacuo to give 1,1,-difluoro-4-methyl-4-(2-methoxy-5-fluorophenyl)pentan-2-one (0.63 g) as an oil which was used without additional purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[C:5]([CH3:18])([CH3:17])[CH2:4][CH2:3]1)[NH:13][C:12](=O)[CH2:11][CH2:10]3.[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>C1COCC1>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:24]([CH2:23][N:13]2[C:14]3[C:9](=[CH:8][C:7]4[C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:18])([CH3:17])[C:6]=4[CH:15]=3)[CH2:10][CH2:11][CH2:12]2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCC(=O)N3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCc3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Temperature: 60 °C
Yield: 61.3 %

Procedure:
To a solution of 6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-1H-benzo[g]quinolin-2-one (130 mg, 0.50 mmol) in THF (4 mL) was added NaH (18 mg, 0.76 mmol) in one portion at ambient temperature. To this solution was added methyl 4-(bromomethyl)-benzoate (229 mg, 1.01 mmol) in THF (8 mL). The mixture was then heated at 60° C. for 8 h, cooled to ambient temperature, quenched with aqueous saturated NH4Cl (20 mL), extracted with EtOAc (100 mL), dried with (MgSO4), concentrated, and purified by column chromatography (10% ether in hexane) to afford 4-(6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-1H-benzo[g]quinolin-1-ylmethyl)benzoic acid methyl ester (120 mg, 58%): 1H NMR (400 MHz, CDCl3) δ 8.10 (½ ABq, 2H, J=8.0 Hz, ArH), 7.48 (½ ABq, 2H, J=8.0 Hz, ArH), 7.08 (s, 1H, ArH), 6.70 (s, 1H, ArH), 5.20 (s, 2H, CH2), 4.51 (s, 3H, CH3), 2.91 (t, 2H, J=7.0 Hz, ring CH2), 2.81 (broad m, 2H, ring CH2), 1.60 (s, 4H, 2CH2), 1.23 (s, 12H, 4CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14][NH:13][CH2:12]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:59]([C:61]1[CH:62]=[CH:63][C:64]([N:67]2[CH2:72][CH2:71][CH:70]([C:73](O)=[O:74])[CH2:69][CH2:68]2)=[N:65][CH:66]=1)#[N:60]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14][N:13]([C:73]([CH:70]3[CH2:69][CH2:68][N:67]([C:64]4[CH:63]=[CH:62][C:61]([C:59]#[N:60])=[CH:66][N:65]=4)[CH2:72][CH2:71]3)=[O:74])[CH2:12]2)[CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A mixture of 125 mg (0.36 mmol) ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid 4-fluoro-phenyl ester, 137 mg (0.36 mmol) HATU, 63 uL (0.36 mmol) DIPEA and 69.4 mg (0.3 mmol) 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid in 4 mL DMF was shaken for 2 h at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 106 mg (63%) of the title compound as off-white solid. MS m/e: 560.2 [M+H]+.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:43][C:44]1[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:45]=1[C:46]([NH:48][O:49][CH3:50])=[O:47].[CH3:57][N:58]1[CH:62]=[C:61]([NH:63][C:64]2[CH:69]=[C:68](I)[C:67]([C:71]([F:74])([F:73])[F:72])=[CH:66][N:65]=2)[C:60]([CH3:75])=[N:59]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:57][N:58]1[CH:62]=[C:61]([NH:63][C:64]2[CH:69]=[C:68]([NH:43][C:44]3[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:45]=3[C:46]([NH:48][O:49][CH3:50])=[O:47])[C:67]([C:71]([F:73])([F:72])[F:74])=[CH:66][N:65]=2)[C:60]([CH3:75])=[N:59]1
Reactant: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Reactant: CONC(=O)c1c(N)cccc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CONC(=O)c1c(Nc2cc(Nc3cn(C)nc3C)ncc2C(F)(F)F)cccc1OC
Temperature: 90 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (34.1 mg, 0.06 mmol), palladium(II) acetate (7.93 mg, 0.04 mmol), 2-amino-N,6-dimethoxybenzamide (131 mg, 0.67 mmol), N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) and cesium carbonate (256 mg, 0.79 mmol) were weighed out in a microwave vial, sealed and dioxane (5 mL) was added. Argon was bubbled through the mixture for 5 minutes. The reaction was stirred at 90° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with DCM and MeOH. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (25 g) eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness. The residue was triturated in Et2O and the resulting precipitate was collected by filtration, washed with Et2O and dried to a constant weight to afford the title compound (131 mg, 74.1%) as a off-white solid. NMR Spectrum: (DMSOd6) 2.04 (s, 3H), 3.62 (s, 3H), 3.69 (s, 3H), 3.81 (s, 3H), 6.31 (bs, 1H), 6.89 (d, 1H), 7.06 (d, 1H), 7.43 (dd, 1H), 7.79 (s, 1H), 7.86 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 11.38 (s, 1H); Mass spectrum: MH+ 451.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH:34][CH:35]2[CH2:37][CH2:36]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[CH:35]1([NH:34][S:31]([C:27]2[CH:26]=[C:25]([NH:24][C:21]([C:20]3[CH:19]=[N:18][N:12]4[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:22])[CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:37][CH2:36]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.7) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Light yellow solid. MS (ISP) 550.0 [(M−H)−]; mp 254° C.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)C=CC=CC=1>C(#N)C>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:32]([N:14]2[CH2:15][CH2:16][CH:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:1])([F:17])[O:3][C:4]=4[CH:10]=3)[CH2:13]2)=[O:31])[CH:35]=1
Reactant: FC1(F)Oc2ccc(CC3CCNC3)cc2O1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 35 °C
Yield: 38.8 %

Procedure:
To a solution consisting of 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-pyrrolidine (111 mg, 0.399 mmol), triethylamine (0.1 mL, 0.72 mmol) and acetonitrile (2 mL) was added pyridin-3-yl-carbamic acid phenyl ester (90.1 mg, 0.421 mmol). The mixture was heated at 35° C. for 18 h, cooled to rt and then concentrated. The crude residue was purified (FCC) to give the title compound (56 mg, 39%). MS (ESI): mass calcd. For C18H17F2N3O3, 361.12. m/z found, 362.2 [M+H]+. 1H NMR (CD3OD): 8.63-8.59 (m, 1H), 8.16-8.13 (m, 1H), 7.97-7.92 (m, 1H), 7.35-7.30 (m, 1H), 7.16-7.09 (m, 2H), 7.06-7.02 (m, 1H), 3.66-3.53 (m, 2H), 3.48-3.38 (m, 1H), 3.19-3.11 (m, 1H), 2.85-2.72 (m, 2H), 2.62-2.50 (m, 1H), 2.11-2.02 (m, 1H), 1.78-1.66 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([C:24](=[O:26])[CH3:25])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1.Cl[Si](C)(C)C.[Br-:32].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:32][CH2:25][C:24]([C:6]1([CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[C:7]2[C:3](=[C:2]([F:1])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[O:26]
Reactant: COc1ccc2c(c1F)CCC2(Cc1ccc(C(F)(F)F)nc1)C(C)=O
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1F)CCC2(Cc1ccc(C(F)(F)F)nc1)C(=O)CBr
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1-(4-fluoro-5-methoxy-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydro-1H-inden-1-yl)ethanone (600 mg, 1.6 mmol) was diluted in THF (3 ml). This solution was cooled to −78° C. and Sodium bis(hexamethylsilyl) amide (1.8 ml, 1.8 mmol) was added. After stirring for 10 min, chloro trimethylsilane (230 μl, 1.8 mmol) was added drop wise at −78° C., after which the reaction was warmed to 0° C., and left stirring for 30 min. To this solution was added Phenyltrimethylammonium tribromide (680 mg, 1.8 mmol) portion wise, and THF (1 mL) was added for solubility purposes. The reaction mixture was allowed to warm to room temp. Aqueous work up, extracted with dichloromethane, dried over magnesium sulfate, filtered, concentrated under reduced pressure furnished 2-bromo-1-(4-fluoro-5-methoxy-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydro-1H-inden-1-yl)ethanone. Used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([CH3:15])=[CH:10][N:9]=1.[CH3:16][C:17]1[N:22]=[C:21](B2OCCN(C3C=CC=CC=3)CCO2)[CH:20]=[CH:19][CH:18]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu]Cl>[CH3:15][C:11]1[C:12]([NH2:14])=[CH:13][C:8]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[N:22]=2)=[N:9][CH:10]=1
Reactant: Cc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Reactant: Cc1cnc(Br)cc1N
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2cc(N)c(C)cn2)n1
Temperature: 105 °C
Yield: 21.7 %

Procedure:
Cesium carbonate (331 mg, 1.017 mmol), palladium acetate (5.71 mg, 0.025 mmol), 1,1′-bis(diphenylphosphino)ferrocene (28.5 mg, 0.051 mmol), copper(I)chloride (50.4 mg, 0.509 mmol), 2-bromo-5-methylpyridin-4-amine (200 mg, 1.069 mmol) and 2-(6-methylpyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (287 mg, 1.017 mmol) were combined in DMF (5 mL) and heated at 105° C. for 2 days. The reaction mixture was then cooled and evaporated on a rotovap to give a residue which was purified by preparative HPLC eluting with a gradient of 5-30% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 30×75 mm column to afford the title compound as a yellow crystalline solid (44 mg). ESI-MS: m/z 200.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[S:8])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[C:20](OC(OCC)OCC)(=O)C>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[N:3]=[C:2]3[N:1]=[CH:20][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[S:8])[N:6]3[N:5]=2)=[CH:18][CH:17]=1
Reactant: CCCNC(=S)n1nc(-c2ccc(Cl)cc2)nc1N
Reactant: CCOC(OCC)OC(C)=O
Product: CCCn1cnc2nc(-c3ccc(Cl)cc3)nn2c1=S
Yield: 71.5 %

Procedure:
The synthesis method of Example 55 was applied. The compound (280 mg) obtained in Example 44 and diethoxymethyl acetate (6.0 g) were used as reagents. The mixture was reacted at 100° C. for 2.5 hours to give 207 mg of white crystals (yield 71%).