Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]2[CH:17]=[CH:18][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:20][C:5]=2[N:4]=1)[CH3:2].Br[C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1.C([O-])(O)=O.[Na+]>COCCOC.O.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>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=2)[C:6]2[CH:17]=[CH:18][C:19]([C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:20][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(CCO)cc1
Reactant: Brc1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1nc2cc(-c3cncnc3)ccc2n1-c1ccc(CCO)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 50.3 %

Procedure:
To a solution of 2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1, 100 mg, 0.26 mmol) and 5-bromopyrimidine (45 mg, 0.28 mmol) in 1,2-dimethoxyethane (3.5 ml) was added sat. NaHCO3 aq. (1.2 ml) and Pd(PPh3)4 (60 mg, 0.05 mmol). This mixture was stirred at 70° C. for 17 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×10 ml). The organic layer was dried (MgSO4) and concentrated to give light brown oil. This mixture was purified by SiO2 preparative TLC (CH2Cl2/methanol=10/1) to afford 45 mg (50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(F)c(F)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.37 g, 1.6 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.43 g, 0.8 mmol), and N,N-diisopropylethylamine (0.41 g, 3.2 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give the title compound: Rf=0.36 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(O)CCN
Reactant: Fc1ccc2ncc(Br)n2n1
Product: CC(C)(O)CCNc1ccc2ncc(Br)n2n1
Yield: 82 %

Procedure:
The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was reacted with 4-amino-2-methylbutan-2-ol using the same reaction conditions as described in example 5.6.42, Part A to obtain 82% product.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](Cl)=[O:4].[CH3:13][CH:14]([CH3:28])[CH:15]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1>C(Cl)Cl.N1C=CC=CC=1>[CH3:1]/[C:2](=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[C:3]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH:15]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:14]([CH3:28])[CH3:13])=[CH:22][CH:23]=1)=[O:4]
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Reactant: CC(C)C(c1ccc(N)cc1)n1cncn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C/C(=C\c1ccccc1)C(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
A solution of 2-methyl-3-phenyl-2-propenoyl chloride (0.0554 mol) in CH2Cl2 (50 ml) was added dropwise to a solution of (±)-4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-benzenamine (0.037 mol) in pyridine (8ml) and CH2Cl2 (100 ml) and the mixture was stirred at RT for 4 hours. The solvent was evaporated and the residue was taken up in water/EtOAc. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/1/0.1). The pure fractions were collected and evaporated. The residue was crystallized from (C2H5)2O/methylethylketone, yielding 2.7 g (21%) of (±)-(E)-2-methyl-N-[4-[2-methyl-1-(1H-1,2,4-triazol- 1-yl)propyl]phenyl]-3-phenyl-2-propenamide (compound 154).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][Cl:26]>CS(C)=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)n(C)c(=O)c2c1
Reactant: ClCCCBr
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(OCCCCl)cc3)n(C)c(=O)c2c1
Temperature: 25 °C

Procedure:
2.8 gm (10 mmols) of 2-(4-hydroxy-phenyl)-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 20 ml of dimethylsulfoxide, and the solution was mixed, while stirring, with 1.35 gm (10 mmols+20%) of potassium tert. butylate. Subsequently, 2.8 ml of 1-bromo-3-chloropropane were added, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was then poured into ice water, the aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were evaporated in vacuo after drying over sodium sulfate. The resulting oil, which solidified into crystals, was recrystallized from acetone/ether.
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1SCC(OCC)=O.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[N:39][S:40]([C:43]2[S:44][CH:45]=[CH:46][CH:47]=2)(=[O:42])=[O:41])[CH:31]=[C:30]1[S:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52]>>[OH:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([NH:39][S:40]([C:43]2[S:44][CH:45]=[CH:46][CH:47]=2)(=[O:42])=[O:41])=[CH:31][C:30]=1[S:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52]
Reactant: COC(=O)CCSC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: CCOC(=O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: COC(=O)CCSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O

Procedure:
5.2.22 Methyl 3-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)propanoate (9b) was prepared according to the procedure for 9a except using 8b affording 28 mg (93%) title compound as a pale yellow solid without column purification, m.p.: 117-119° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=2)[CH:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15]([CH2:16][CH:17]([CH3:19])[CH3:18])=[O:28])=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CSc1ccc2cc([N+](=O)[O-])c(N)cc2c1
Solvent: ClC(Cl)Cl
Product: CC(C)CS(=O)c1ccc2cc([N+](=O)[O-])c(N)cc2c1

Procedure:
To 0.1 mol of 2-amino-7-isobutylthio-3-nitronaphthalene, prepared in Example 5, stirring in 200 ml of chloroform at 4°-6° (ice bath), is added 0.1 mol of m-chloroperbenzoic acid in 160 ml of chloroform over 3 hours. Consumption of starting material is confirmed by TLC (silica gel, ether). The reaction mixture is washed 3 times with saturated NaHCO3 solution, dried (Na2SO4), and filtered. The filtrate is evaporated to dryness under vacuum and the residue recrystallized from ethanol (absolute) to yield the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:10]=[C:11]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:12]3[N:18]=[C:17]([CH:19]=[C:20]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=2[N:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[N:8]([C:9]2[N:10]=[C:11]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:12]3[N:18]=[C:17]([CH2:19][CH:20]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)ccc2n1
Solvent: CO
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)ccc2n1
Temperature: 60 °C

Procedure:
tert-butyl 3-((2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylene)azetidine-1-carboxylate (0.2 g) was brought up in MeOH (20 mL) and the flask was purged with nitrogen before addition of 10% Palladium on Carbon (20 mol %). The reaction was heated at 60° C. for 6 hours, cooled and filtered thru celite to obtain the crude tert-butyl 3-((2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidine-1-carboxylate following solvent evaporation.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(Cl)c1
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 3-amino-5-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+] 351.9 & 353.9.
Reaction SMILES: CCN(CC)CC.[C:8]([C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:9].[SH2:21]>N1C=CC=CC=1>[C:8]([C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[S:21])[NH2:9]
Reactant: CCOC(=O)c1cccnc1C#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cccnc1C(N)=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Et3N (10 ml) was added to a solution of ethyl 2-cyanonicotinate (1.9 g, 10.78 mmol) in 20 ml of pyridine. Hydrogen sulfide was passed through the reaction mixture at 5° C. for 20 minutes, then the mixture was stirred for 1 hour at room temperature. For work up the solution was purged with nitrogen for 30 minutes, evaporated to dryness, and the remaining solid dissolved in 200 ml of dichloromethane. The organic layer was washed successively with water and brine, dried, evaporated and treated with ethylacetate to give 2.15 g of a red oil which was reacted without further purification.
Reaction SMILES: Br[C:2]1[C:10]([Cl:11])=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.B([O-])[O-].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C.O.ClCCl>[Cl:11][C:10]1[C:2]([C:2]2[CH:10]=[CH:9][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:3][C:4]2[C:5]([CH:9]=1)=[N:6][O:7][N:8]=2
Reactant: Clc1cc2nonc2cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [O-]B[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(-c2cc3nonc3cc2Cl)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Palladium tetrakis-triphenylphosphine (37 mg, 32 μmol) was added to a degassed solution of bromide 94 (150 mg, 643 μmol) and boronate 84 (211 mg, 964 μmol) in dioxane:acetonitrile:water (9:9:2, 3.2 mL) and potassium carbonate (205 mg, 964 μmol). The resulting mixture was heated under argon at 95° C. with stirring for 1 h. The mixture was then cooled, diluted with dichloromethane (25 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 95 (35 mg, 22%) as a solid: LRESIMS m/z 246.0 [M+H]+, calcd. for C12H9Cl1N3O1 246.0.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][N:12]1[CH:16]=[CH:15][C:14]([NH2:17])=[N:13]1.C1(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:17][C:14]2[CH:15]=[CH:16][N:12]([CH3:11])[N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1ccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2cccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 130 °C
Yield: 54.4 %

Procedure:
3,5-Dibromo-1-methyl-1H-pyridin-2-one (469 mg, 1.76 mmol), 1-Methyl-1H-pyrazol-3-ylamine (205 mg, 2.1 mmol), tris(dibenzylidineacetone)dipalladium(0) (80 mg, 0.087 mmol), 2,2′-bis(diphenylphosphino-1,1′-binaphthalene (82 mg, 0.13 mmol), and cesium carbonate (801 mg, 2.46 mmol) were deposited in a sealed vial with 10 mL toluene. This was heated at 130° C. for 18 hours. The resulting mixture was poured into 50 mL water. This was extracted with ethylacetate. The ethylacetate layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (eluted with ethylacete/hexanes) to yield 5-Bromo-1-methyl-3-(1-methyl-1H-pyrazol-3-ylamino)-1H-pyridin-2-one (271 mg, 0.957 mmol). MS (ESI) 284.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:16])[C:10]2[C:5](=[CH:6][C:7]([NH:12][CH3:13])=[C:8]([NH2:11])[CH:9]=2)[C:4]([F:15])([F:14])[O:3]1.O[CH:18]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)S([O-])(=O)=O.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:16][C:2]1([F:1])[C:10]2=[CH:9][C:8]3[N:11]=[C:18]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[N:12]([CH3:13])[C:7]=3[CH:6]=[C:5]2[C:4]([F:14])([F:15])[O:3]1
Reactant: CNc1cc2c(cc1N)C(F)(F)OC2(F)F
Reactant: O=S(=O)([O-])C(O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccncc2)nc2cc3c(cc21)C(F)(F)OC3(F)F
Temperature: 120 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of 0.59 g of 1,1,3,3-tetrafluoro-N-methyl-1,3-dihydroisobenzofuran-5,6-diamine, 0.63 g of sodium hydroxy-pyridin-4-yl-methanesulfonate and 5 ml of DMF was stirred for 1 hour while heating at 120° C. After cooling down to room temperature, a saturated sodium hydrogen carbonate aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.71 g of 5,5,7,7-tetrafluoro-1-methyl-2-(pyridin-4-yl)-5,7-dihydro-1H-furo[3′,4′:4,5]benzo[1,2-d]imidazole (hereinafter, referred to as present active compound 1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[CH2:8][N:9](C(OCC)=O)[CH2:10][C:4]=2[CH2:3]1>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[CH2:8][NH:9][CH2:10][C:4]=2[CH2:3]1
Reactant: CCOC(=O)N1CC2=C(CN(C)CC2)C1
Solvent: O
Product: CN1CCC2=C(CNC2)C1

Procedure:
6.3 g (30 mmol) of ethyl 5-methyl-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3, 4-c]pyridine-2-carboxylate and 18.9 g (60 mmol) of Ba(OH)2. 8H2O are refluxed for 15 hours in 75 ml of water. After cooling, the BaCO3 is filtered off with suction, the filtrate is concentrated, and the residue is extracted by boiling five times with 50 ml portions of dioxane. The dioxane solutions are concentrated, and the residue is distilled.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([OH:17])=O)[CH3:2].[Cl-].[NH4+].C([N:22](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>O.CN(C=O)C>[CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:22])=[O:17])[CH3:2]
Reactant: CCNc1cc(-c2ccncc2)sc1C(=O)O
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1cc(-c2ccncc2)sc1C(N)=O
Reaction time: 0.08 h
Yield: 62.5 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxylic acid (0.415 g, 1.67 mmol), ammonium chloride (0.893 g, 16.7 mmol), triethylamine (2.35 mL, 16.7 mmol) and DMF (10 mL) was stirred for 5 min. Then, 1-hydroxybenzotriazole (0.676 g, 5.00 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.956 g, 5.00 mmol) were added and stirring was continued for 3 days. The mixture was then poured into sat. aqueous sodium hydrogen carbonate (100 mL) and water (60 mL). Extraction with ethyl acetate-tetrahydrofuran (3:1, 2×100 mL), washing with sat. aqueous sodium hydrogen carbonate and brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a yellow solid. This solid was triturated with dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.258 g, 62%) as a yellow solid:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C1C=CC=CC=1.C(OC)(C)(C)C>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:42]([C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=1)(=[O:43])=[O:44])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: c1ccccc1
Product: CC(C)CC(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-(2-amino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (308 mg, 0.70 mmol), 4-nitrobenzenesulfonyl chloride (190 mg, 0.77 mmol), N,N-diisopropylethyl-amine (181 mg, 1.4 mmol) and DMAP (20 mg), in benzene (5 mL) was heated under reflux for 3 hours, then concentrated in vacuo and the residue dissolved in ethyl acetate, and washed with saturated NaHCO3 solution, water, and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The tan solid thus obtained was triurated in warm tert-butylmethyl ether, and filtered to give 419 mg (95%) of the title compound as a white solid, mp=121-123° C.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:23])[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:24].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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:24][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])[N:8]([CH3:23])[C:7]=2[C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(-c3ccccc3)c2n1C
Temperature: 140 °C
Yield: 74.5 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine, (0.10 g, 0.26 mmol), phenylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 45 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume and partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 431 as a white solid (0.075 g, 76%). LCMS (Method K): RT 3.21 min [M+H]+ 388.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.98 (1H, s), 8.26-8.11 (2H, m), 7.93-7.86 (1H, m), 7.64 (1H, dd, J=8.82, 4.74 Hz), 7.54-7.39 (5H, m), 7.15-7.08 (1H, m), 5.82-5.71 (1H, m), 3.21 (3H, s), 1.65 (3H, d, J=6.74 Hz). Signals split due to presence of tautomers