Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:12]>O1CCCC1>[CH:1]1([CH2:6][CH2:7][S:8]([NH2:12])(=[O:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)CCC1CCCC1
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)CCC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(cyclopentyl)ethanesulfonyl chloride (14.1 g, 71.4 mmol) in dry tetrahydrofuran (40 ml) was saturated with gaseous ammonia at 0° C. The resulting solution was stirred at room temperature under nitrogen for 2 hours and then concentrated under vacuum. The residue was dissolved in ethyl acetate (50 ml) and water (50 ml) and the aqueous phase was then acidified to pH 2 with 2.0 M aqueous hydrochloric acid. The organic phase was separated and then washed with water (2×30 ml), dried (sodium sulfate) and concentrated under vacuum. Purification of the residue by chromatography on silica (500 g) using 65/35 pentane/ethyl acetate as eluant gave the title compound as an off-white solid (6.48 g), Rf 0.7 (pentane/ethyl acetate 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]([O:14]C)=[O:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:12]([OH:14])=[O:13])([CH3:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Cc1ccc(Br)cc1)C(=O)O
Yield: 82.6 %

Procedure:
1-bromo-4-(2-methoxycarbonyl-2-methylpropyl)benzene (7.79 g) was dissolved in methanol (60 ml) and 2M aqueous sodium hydroxide solution (30 ml) was added. The solution was heated to reflux for 2 hours then cooled. The volume was reduced to ~25 ml by evaporation and the residue extracted with ethyl acetate (15 ml) then acidified with 2M hydrochloric acid and re-extracted with ethyl acetate (3×25 ml). The combined organic extract of the acidified aqueous phase was dried (MgSO4) and evaporated to give l-bromo-4-(2-carboxy-2-methylpropyl)benzene (6.1 g); 1H NMR (d6 -DMSO): 1.08 (s, 6H), 2.78 (s, 2H), 7.11 (m, 2H), 7.46 (m, 2H); mass spectrum (CI+) 256 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:23][CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:23][CH:24]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.3 %

Procedure:
1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) (0.50 g), 1,1-dimethylethyl 5-bromo-2-pyridinecarboxylate (may be prepared as described in Description 12) (0.66 g), BINAP (0.15 g) and Cs2CO3 (1.6 g) were added to toluene (20 ml) under argon and the reaction mixture degassed by sequential freezing in dry ice followed by warming to room temp under vacuum (3×). After stirring for 5 min Pd(OAc)2 (0.05 g) was added and the reaction mixture heated at 80° C. for 20 h. The reaction mixture was filtered and evaporated, after which chromatography (silica gel, eluting with methanol/dichloromethane, 0-20%) afforded the title compound (E3) as a solid (0.23 g). MS electrospray (+ion) 414 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]([OH:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1C(=O)c2ccccc2OC1c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1C(O)c2ccccc2OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A solution of racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate (100 mg, 285 μmol) in THF (2.0 mL) was diluted with methanol (4.0 mL) and stirred on an ice/acetone bath. Sodium borohydride (11 mg, 285 μmol) was added and the resulting mixture was stirred for 40 min. After this time, the mixture was diluted with water and stirred while warming to rt. The resulting white solid was collected by filtration, washed with water and dried under vacuum to provide methyl 2-(3,4-dichlorophenyl)-4-hydroxychroman-3-carboxylate (90 mg). 1H NMR (400 MHz, CDCl3) δ ppm 3.49 (s, 3 H) 3.51 (m, 1 H) 5.26 (d, J=6.1 Hz, 1 H) 5.35 (d, J=2.5 Hz, 1 H) 6.94 (dd, J=8.1, 1.0 Hz, 1 H) 7.06 (td, J=7.6, 1.0 Hz, 1 H) 7.22-7.29 (m, 2 H) 7.47 (d, J=8.6 Hz, 1 H) 7.56 (d, J=1.5 Hz, 1 H) 7.58 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]2.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([Cl:25])[CH:24]=1>N1C=CC=CC=1.ClCCl>[Cl:25][C:23]1[CH:22]=[C:21]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]3)(=[O:27])=[O:28])[CH:20]=[C:19]([Cl:18])[CH:24]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6 g tert-butyl 5-amino-2,3-dihydro-indole-1-carboxylate are dissolved in 50 ml of pyridine and 50 ml dichloromethane. To this is added dropwise a solution of 6.5 g 3,5-dichlorophenylsulphonyl chloride in 50 ml dichloromethane and the mixture is stirred for 1 hour at ambient temperature. Then it is diluted with dichloromethane and washed with 1 N hydrochloric acid and with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 30:70).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[NH:6][C:5]2=[O:17])[CH2:3][CH2:2]1.O1CCCC1.[H-].[Na+].[N+:25](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:25][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:17]
Reactant: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Nn1c(=O)c2cc(F)c(F)cc2n(C2CC2)c1=O
Temperature: 50 °C
Reaction time: 0.42 h

Procedure:
To a solution of a 1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 23) in 1:1 dry tetrahydrofuran or dioxane and dry N,N-dimethylformamide is added portionwise sodium hydride (1.1 eq., 60% mineral oil dispersion) at room temperature. After stirring at 50° C. for 20 to 30 minutes, the resulting solution is cooled to room temperature and 2,4-dinitrophenylhydroxylamine (4 eq.) is added. The mixture is heated at 60° C. to 80° C. for 30 minutes, cooled, and the dioxane removed reduced pressure. The residue is poured into ice water and extracted with ethyl acetate. The organic layers are combined, washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue is purified by flash column chromatography (ethyl acetate/hexanes) to afford a 3-amino-1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[F:15][C:16]([F:32])([O:23][C:24]1[CH:30]=[CH:29][C:27]([CH3:31])([NH2:28])[CH2:26][CH:25]=1)[CH:17]([F:22])[C:18]([F:21])([F:20])[F:19]>C(O)(=O)C>[F:15][C:16]([F:32])([O:23][C:24]1[CH:25]=[CH:26][C:27]([N:28]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])([CH3:31])[CH2:29][CH:30]=1)[CH:17]([F:22])[C:18]([F:19])([F:20])[F:21]
Reactant: CC1(N)C=CC(OC(F)(F)C(F)C(F)(F)F)=CC1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: CC1(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C=CC(OC(F)(F)C(F)C(F)(F)F)=CC1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
In 30 ml of acetic acid were dissolved 1.93 g of 3-nitrophthalic anhydride and 2.73 g of 4-(1,1,2,3,3,3-hexafluoropropoxy)-1-methylaniline. A reaction was carried out for 3 hours with heating under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was washed with a mixture of ether and hexane, whereby 4.4 g of the objective compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[CH3:54][O:55][C:56](C1C=C(C=CC=1)C(O)=O)=[O:57].C(N(CC)CC)C>CN(C)C=O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([CH:31]=[CH:30][CH:29]=3)[C:56]([O:55][CH3:54])=[O:57])=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)NC(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn2)c1

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.17 g, 0.56 mmol), 3-(methoxycarbonyl)benzoic acid (0.18 g, 0.62 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (0.24 g, 0.62 mmol) and triethylamine (0.17 mL, 1.2 mmol) in N,N-dimethylformamide (5 mL) gave methyl 3-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}benzoate (0.26 g) as a white solid. MS m/z 468 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13]([Cl:21])[C:14]2[CH:19]=[C:18]([CH3:20])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([CH3:20])[S:17][C:15]=2[N:16]=1.[Cl:10][C:11]1[N:12]=[C:13]([Cl:21])[C:14]2[C:19]([CH3:2])=[CH:18][S:17][C:15]=2[N:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: Cc1csc2nc(Cl)nc(Cl)c12

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[CH:5]1[C@@H:10]([O:11][C:12](=O)[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37]C(=O)C)=[CH:33][CH:32]=3)[CH:24]=2)[O:6]1)(=O)C.[BrH:41].[OH2:42]>CC(O)=O.C(Cl)Cl>[C:12]([O:11][C@H:10]1[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[CH:24]=2)[O:6][CH:5]1[Br:41])(=[O:42])[CH3:13]
Reactant: CC(=O)Oc1ccc(Cc2cc([C@@H]3OC(OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: O
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)OC(Br)[C@H]1OC(C)=O
Reaction time: 0.1 h
Yield: 90 %

Procedure:
To (3S,4R,5S,6S)-6-(3-(4-acetoxybenzyl)-4-chlorophenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (2.03 g, 4.03 mmol) a 33% solution of HBr in AcOH (6 mL) was added at r.t. and stirred for 0.1 h. The reaction mixture was diluted with DCM (20 mL) and stirred for 30 min. Water was added to the resulting mixture and stirred for another 1 h. It was diluted with DCM (50 mL), washed with water (50 mL), saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo to afford the title compound (2.02 g, 90%)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[C:5]([CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[CH2:16]([NH:15][C:13]([C:4]1[S:3][C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:41]=[CH:40][C:39]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:47][CH:46]=2)=[N:6][C:5]=1[CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: CCN(CC)Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)Cc1nc(NC(=O)c2ccc(Cc3ccccc3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.7 %

Procedure:
To a solution of 2-amino-N-benzyl-4-((diethylamino)methyl)thiazole-5-carboxamide (0.052 g, 0.16 mmol) and diisopropylethylamine (0.30 mL, 1.70 mmol) in dichloromethane (5 mL) was added 4-benzylbenzoic acid (0.046 g, 0.21 mmol) followed by the addition of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.076 g, 0.20 mmol). The reaction mixture was stirred at ambient temperature for 18 h, diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (acetone/water gradient) to afford the title compound (0.003 g); MS (ES+) m/z 513.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[N:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:14])([F:1])[F:15])[S:4][CH:5]=3)[CH2:9]2)[CH3:26])=[CH:20][CH:19]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: FC(F)(F)c1nc(C2CNCCO2)cs1
Product: COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-(2-trifluoromethyl-thiazol-4-yl)morpholine with 4-methoxyphenyl-propan-2-one followed by purification of the base on a silica gel column using chloroform/ethyl acetate=9:1 as eluant.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:16]([CH3:24])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2.[Br:25]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:25][CH2:24][C:16]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:18][C:17]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:7][CH:6]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1CBr
Yield: 90.5 %

Procedure:
A mixture of 4-chloro-2-ethoxycarbonyl-1-methyl-7-trifluoromethylimidazo[1,2-a]quinoxaline (830 g, 232 mmol), N-bromosuccinimide (68,0 g, 382 mmol) and 2,2'-azobis(2-methylpropionitrile)(200 mg, 1.2 mmol) in tetrachloromethane (1.5 l) was heated at reflux for 18 h, allowed to cool and the product collected by filtration. The product was dissolved in dichloromethane (2 l) and washed with water, dried (MgSO4), followed by purification with silica gel 60 (1 g). The organic phase was filtered and evaporated in vacuo. The residue was suspended in petroleum ether to yield 91.7 g (91%) of 1-bromomethyl-4-chloro-2-ethoxycarbonyl-7-trifluoromethyl-imidazo[1,2-a]quinoxaline which was collected by filtration. M.p. 196°-198° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11].Cl.[O-:21][C:22]#[N:23].[K+]>O.CO>[C:22]([NH:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11])(=[O:21])[NH2:23]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CNC(N)=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Of the compound from Example 40A, 192 mg (0.63 mmol) were introduced in 11 ml of water/methanol 1:2 and admixed in succession at RT with 0.63 ml (0.63 mmol) of 1M hydrochloric acid and 166 mg (2.05 mmol) of potassium cyanate. The reaction mixture was stirred at RT overnight and then freed from the methanol on a rotary evaporator. The residue was taken up in DMSO and purified by preparative HPLC [Method 20]. The product fraction was concentrated on a rotary evaporator. Drying of the residue in an HV gave 177 mg (73% of theory) of the title compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:35]#[N:36])[N:19]=3)=[CH:13][C:12]=2[F:37])[CH:7]=[CH:6][N:5]=1.Cl>CO.C1COCC1.CCOCC.[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[ClH:1].[NH2:36][CH2:35][C:20]1[N:19]=[C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=3)=[C:12]([F:37])[CH:13]=2)[C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])=[O:25])=[CH:22][N:21]=1
Reactant: N#Cc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)n1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)n1
Reaction time: 2 h
Yield: 110.4 %

Procedure:
To a solution of 4-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-2-cyano-N-(2,4-difluorophenyl)pyrimidine-5-carboxamide, dihydrochloride salt (48 mg, 0.092 mmol) in methanol (1 mL) was added 1 N HCl in ether (30 μL, 0.03 mmol), and 20% palladium hydroxide on carbon (48 mg). The suspension was purged with hydrogen and was stirred 2 h. Additional palladium hydroxide (38 mg) and methanol (1 mL) was added and the mixture was stirred an additional 4 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and treated with Amberlyst A-21 ion exchange resin, filtered and concentrated in vacuo to give the freebase. The residue was dissolved in anhydrous THF (2 mL), and acidified with 1N HCl in ether. The reaction mixture was stirred for 10 min, the solvent was removed in vacuo and the solid was triturated in ether to afford the amine (20 mg, 39%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.99 (s, 1H), 10.78 (s, 1H), 9.16 (s, 1H), 8.48 (br s, 2H), 8.17 (dd, 1H, J=12.9, 2.4 Hz), 7.99 (d, 1H, J=7.2 Hz), 7.87 (br s, 2H), 7.62 (m, 2H), 7.43 (m, 2H), 7.20 (m, 1H), 6.70 (dd, 1H, J=7.2, 2.4 Hz), 6.21 (d, 1H, J=2.3 Hz), 4.21 (m, 2H); MS(ESI+) m/z 482 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccc(Cl)c(Cl)c5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3,4-dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[NH:13][C:12]3=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:13]([CH3:21])[C:12]3=[O:18])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C23CC2C(=O)NC3=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C23CC2C(=O)N(C)C3=O)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1.2 g of 1-(4-acetylaminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione, 120 mg of sodium hydride and 25 ml of N,N'-dimethylformamide are stirred, under nitrogen, for 15 minutes at 50° C. The mixture is cooled to 20° C. and then a solution of 0.32 ml of methyl iodide in 2.5 ml of dimethylformamide is slowly added dropwise. The reaction mixture is stirred for 16 hours at room temperature. Excess sodium hydride is destroyed with methanol and the reaction mixture is freed from solvent in a high vacuum. The residue is partitioned repeatedly between ethyl acetate and a dilute solution of sodium chloride. The organic phases are dried over magnesium sulfate, filtered, concentrated, and the residue is crystallised from ethyl acetate/petroleum ether. The title compound is obtained in the form of white crystals with a melting point of 183°-184° C. and with Rf=0.37 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1).
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][N:25]=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]([CH3:37])[S:33]([NH2:36])(=[O:35])=[O:34].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([NH:36][S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])=[O:23])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][N:25]=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=NCN12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=NCN12
Temperature: 45 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of 10-cyclohexyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylic acid (50 mg, 0.13 mmol) and N,N-dimethylsulfamide (78 mg, 0.63 mmol) in DMA (2 mL), was added DMAP (77 mg, 0.63 mmol) and then EDCI-HCl (96 mg, 0.50 mmol). The mixture was stirred at 45° C. overnight, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl-N-((dimethylamino)sulfonyl)-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxamide (20 mg, 0.040 mmol, 31%) as light pink solid. 1H NMR (500 MHz, CD3OD) δ 1.16-1.26 (m, 1H), 1.39-1.55 (m, 3H), 1.73-1.83 (m, 2H), 1.93-2.22 (m, 4H), 2.86-2.96 (m, 1H), 3.04 (s, 6H), 5.14 (d, J=15.9 Hz, 1H), 6.05 (d, J=15.9 Hz, 1H), 7.66 (dd, J=8.55, 1.5 Hz, 1H), 7.72-7.80 (m, 3H), 7.82-7.87 (m, 1H), 7.99 (d, J=8.5, 1H), 8.34 (s, 1H), 9.08 (s, 1H). LCMS: m/e 505 (M+H)+, ret time 1.94 min.