Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]([O:11][CH3:10])=[O:13])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Cc1ccc(N)cc1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: COCCOC
Product: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Temperature: 90 °C
Yield: 51.8 %

Procedure:
3-Bromo-4-methylaniline (744 mg, 4.0 mmol), (4-methoxycarbonylphenyl)boronic acid (864 mg, 4.8 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.087 mmol) and caesium carbonate (2.4 g, 7.37 mmol) were mixed in DME (30 ml) and heated at 90° C. for 20 h. The reaction was absorbed onto silica applied to a silica SPE (10 g) and eluted with ethyl acetate/cyclohexane (0–100% ethyl acetate). The solvent was evaporated from the product fractions under vacuum to give methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (500 mg, 43%).
Reaction SMILES: [OH-:1].[Na+:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]4[CH2:27][O:26][C:25](=[O:28])[C:14]=4[CH:15]=[C:16]4[C:24]=3[C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=[CH:17]4)=[CH:11][C:6]=2[O:5][CH2:4]1>CO>[Na+:2].[O:23]1[C:19]2[CH:18]=[CH:17][C:16]([C:15]3[C:14]([CH2:25][OH:28])=[C:13]([C:27]([O-:1])=[O:26])[CH:12]=[C:10]4[C:11]=3[C:6]3[O:5][CH2:4][O:3][C:7]=3[CH:8]=[CH:9]4)=[CH:24][C:20]=2[O:21][CH2:22]1
Reactant: [OH-]
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Agent: [Na+]
Solvent: CO
Product: O=C([O-])c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1CO)OCO3
Temperature: 70 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
1 N aqueous NaOH solution (2.9 mL) was added to the solution of 2 (100 mg, 0.29 mmol) in MeOH (10 mL). The mixture was stirred at 70° C. for 1 h. The solvent was evaporated to give a crude product, which was purified by silica gel column chromatography using CH2Cl2/MeOH (3:1, v/v) to afford 3 (110 mg, 98%) as a white powder. mp 128-130° C.;
Reaction SMILES: C([O:4][C@@H:5]([CH3:41])[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][O:14][C@@H:13]([C@H:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[C:25]([C:27](=[O:39])[NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH3:38])[CH:31]=4)[N:24]=[C:23]([CH3:40])[N:22]=3)[CH2:17]2)[CH2:12][O:11]1)=[O:7])(=O)C.[OH-].[Li+]>C(#N)C.CCOC(C)=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:27]([C:25]2[CH:26]=[C:21]([C:18]3[CH2:17][C@@H:16]([C@H:13]4[CH2:12][O:11][C@H:10]([CH2:9][NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[CH3:41])[CH2:15][O:14]4)[O:20][N:19]=3)[N:22]=[C:23]([CH3:40])[N:24]=2)=[O:39])=[CH:31][C:32]=1[O:37][CH3:38]
Reactant: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CNC(=O)[C@H](C)OC(C)=O)CO4)C3)nc(C)n2)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CNC(=O)[C@H](C)O)CO4)C3)nc(C)n2)ccc1F
Reaction time: 3 h
Yield: 53.9 %

Procedure:
To a stirred solution of (S)-1-(((2R,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methylamino)-1-oxopropan-2-yl acetate (0.11 g, 0.192 mmol) in ACN (3 mL) was added 2.5M lithium hydroxide (1.151 mL, 2.88 mmol) at RT. The reaction mixture was stirred for 3 h, diluted with EtOAc (25 mL) and washed with brine solution (2×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by preparative TLC eluting with 100% EtOAc to afford N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-(((S)-2-hydroxypropanamido) methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide 0.055 g (52%); 1H NMR (400 MHz, DMSO): δ 9.48 (t, J=6.4 Hz, 1H), 8.13 (s, 3H), 7.68 (t, 1H), 7.17-7.13 (m, 2H), 6.88 (m, 1H), 5.5 (d, J=4.8 Hz, 1H), 4.81-4.75 (m, 1H), 4.48 (d, J=6.0 Hz, 2H), 3.96-3.86 (m, 2H), 3.81 (s, 3H), 3.76-3.73 (m, 1H), 3.66-3.63 (m, 1H), 3.52-3.3.36 (m, 4H), 3.29-3.11 (m, 1H), 3.09 (m, 2H), 2.75 (s, 3H), 1.19 (d, J=6.8 Hz, 3H); LC/MS (Table 1, method c) Rt=2.89 min; MS: m/z 532 (m+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:13]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:12]=2)=[CH:7][N:6]=1)(=O)=O.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[N:32]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[C:13]([C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[C:27](=[O:31])[CH2:26][CH2:25]5)[CH:12]=3)=[CH:7][N:6]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1ncc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cn1
Product: O=C1CCc2cc(-c3cc(-c4cnc(N5CCNCC5)nc4)oc3-c3ccncc3)ccc21
Yield: 65 %

Procedure:
The title compound (0.10 g, 65%) was prepared from the product of Example 7 Step 6 and piperazine using the method of Example 7 Step 7; MS(ES+) m/e 438 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:13][S:14]([O:17][C@@H:18]([CH3:22])[C:19](Cl)=[O:20])(=[O:16])=[O:15]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:19](=[O:20])[CH:18]([O:17][S:14]([CH3:13])(=[O:16])=[O:15])[CH3:22])[CH:7]=[CH:6]2
Reactant: COc1ccc2ccccc2c1
Reactant: C[C@H](OS(C)(=O)=O)C(=O)Cl
Solvent: Clc1ccccc1Cl
Product: COc1ccc2cc(C(=O)C(C)OS(C)(=O)=O)ccc2c1
Temperature: 25 °C

Procedure:
791 Mg (5.00 mmols) of β-methoxynaphthalene and 933 mg (5.00 mmols) of (S)-2-(methylsulfonyloxy)propionyl chloride were dissolved in 5 ml of anhydrous o-dichlorobenzene, followed by stirring at room temperature. To the solution was added 296 mg of dry ferric sulfate obtained by drying ferric sulfate heptahydrate at 150° C. for 3 hours in vacuo, and the mixture was stirred at 70° C. for 18 hours under an argon gas stream. 30 Ml of water was added to the mixture, which was then extracted with methylene chloride (30 ml×2). The extract was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel, methylene chloride) to obtain (S)-1-(6-methoxy-2-naphthyl-2-methylsulfonyloxy-1-propanone as a colorless glass-like material having [α]D26 -35.6°(c=0.982, CHCl3). The resulting product was crystallized in methanol and recrystallized from the same solvent to obtain colorless needles having a melting point of 156°-157° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1ccc2sc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5cc([N+](=O)[O-])ccc5s4)cc3CC[C@@H]12
Yield: 58.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-5-nitrobenzothiazole (99 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 97 mg (58%) of the title compound as an amorphous solid mp 96°-100°. FDMS: m/e=439. α[D]589 =+61.35 (c=0.64, chloroform).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[NH2:41][C:38]1[N:39]=[CH:40][C:35]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:36][N:37]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnc(N)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 17.3 %

Procedure:
To a 5-mL microwave vial was added DMSO (2 mL) and it was degassed with nitrogen for 5 min. Next added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine (49.7 mg, 0.225 mmol), sodium carbonate (59.5 mg, 0.562 mmol) and bis(triphenylphosphine)palladium(II) chloride (9.20 mg, 0.013 mmol). The mixture was degassed for additional 5 min, sealed, and irradiated (microwave) at 135° C. for 15 h. The mixture was filtered and the residue was washed with DMSO. The DMSO solution of the crude product was purified using reverse-phase HPLC. The TFA salt of the product was neutralized with saturated NaHCO3 solution, filtered, washed with water, and dried under high vacuum to give 14 mg (17%) of product. LCMS E-S (M+H)=433.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.4 Hz, 6 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 4.40 (d, J=4.6 Hz, 2 H) 5.22-5.41 (m, 1 H), 5.90 (s, 1 H), 7.18 (m, 2 H), 8.08 (s, 1 H), 8.34 (s, 1 H), 8.86 (m, 1 H), 9.11 (s, 2 H), 11.58 (br. s., 1 H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[S:19](=[O:21])(=[O:20])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:28])[CH2:16]2)=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1.C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].Cl>C(Cl)Cl>[CH2:30]([O:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][C:17](=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[S:19]1(=[O:21])=[O:20])[CH2:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3NS(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-[4-((1S*,2R*)-2-aminocyclohexylmethyl)-2-benzyloxy-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (153 mg, 0.238 mmol) and diisopropylethylamine (92 mg, 0.712 mmol) in methylene chloride (5 mL) is added methanesulfonyl chloride (30 mg, 0.258 mmol) and the mixture is stirred at RT for 14 h. The mixture is poured into 1N HCl and extracted with EtOAc and the organic phase is washed with saturated NaHCO3. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]([NH:41][CH3:42])([CH3:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]([CH:38]([CH3:40])[CH3:39])[CH3:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CNC(C)C
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC(C)N(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-isopropylmethylamine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.94 (bs, 6 H), 1.58 (s, 6 H), 2.70 (bs, 1 H), 3.26-3.31 (m, 7 H), 6.19 (d, J=6.0 Hz, 1 H), 6.96 (d, J=12.4 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.51-7.62 (m, 3 H), 7.82 (d, J=7.6 Hz, 1 H), 7.97 (d, J=8.0 Hz, 1H), 8.22-8.24 (m, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:18]=[C:17]3I)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:18]=[C:17]3[C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)c(I)nn3C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)c(C#C[Si](C)(C)C)nn3C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 105.7 %

Procedure:
A suspension of tert-butyl 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-iodo-1H-indazole-1-carboxylate (200 mg; 0.38 mmol; 1.0 eq.), (Trimethylsilyl)acetylene (53 μl; 0.38 mmol; 1.0 eq.), TEA (158 μl) and bis(triphenylphosphine)palladium(II) chloride (10.7 mg; 0.02 mmol; 0.04 eq.) was heated at 70° C. overnight in a sealed tube. The reaction mixture was diluted with EtOAc and washed with a saturated solution of NH4Cl and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the tittle compound as a brown gum (200 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J=8.7 Hz, 1H), 7.63-7.54 (m, 2H), 4.15-4.04 (m, 2H), 2.99-2.74 (m, 3H), 1.86-1.74 (m, 2H), 1.64 (s, 9H), 1.61-1.52 (m, 2H), 1.42 (s, 9H), 0.32 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[N:14]#[C:15][NH2:16].Cl>C(O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:15]([NH2:16])=[NH:14])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(N)cc1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: Cc1nccn1-c1ccc(NC(=N)N)cc1
Yield: 64.4 %

Procedure:
To a solution of 4-(2-methyl-1H-imidazol-1-yl)aniline (2 g, 11.55 mmol) in ethanol (25 mL) was added cyanamide (0.728 g, 17.32 mmol) and hydrochloric acid (1.422 mL, 17.32 mmol). The reaction mixture was refluxed for 4 h. An additional 1 eq of hydrochloric acid (1.422 ml, 17.32 mmol) was added and precipitation occurred. The precipitated product was filtered off and washed with DCM to give 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (1.600 g, 64.4%). MS (ESI+)/(ESI−) m/z 216/214
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:18]([F:20])[F:19])[N:6]2[CH:13]([CH3:17])[C:14]([OH:16])=O.[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:23].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:18]([F:20])[F:19])[N:6]2[CH:13]([CH3:17])[C:14]([N:22]([CH3:23])[CH3:21])=[O:16]
Reactant: CC(C(=O)O)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C(=O)N(C)C)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a solution of 2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]propanoic acid (0.010 g, 0.034 mmol) in anhydrous DMF (1.5 mL) was added HATU (0.014 g, 0.037 mmol) and DIEA (0.0048 g, 0.0037 mmol) and stirred at rt. After 10 min, dimethylamine (2M in THF, 0.17 mL, 0.34 mmol) was added and stirred at rt for 45 min. The mixture was partitioned between Et2O and 0.2N HCl. The organic phase was washed with 0.2N HCl, 0.2N NaOH and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-1% MeOH—CH2Cl2 gradient) and the product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.007 g, 64% yield): MS (ES) m/z 326 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[C:13]([Cl:19])=[N:14][CH:15]=[N:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[C:13]([Cl:19])=[N:14][CH:15]=[N:16][C:17]=2[Cl:18])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1c(Cl)ncnc1Cl
Product: O=C(Nc1c(Cl)ncnc1Cl)c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 5-amino-4,6-dichloropyrimidine as a white solid as described in Example 1. 1H NMR (CDCl3): 8.95 (d, J=2.4, 1H), 8.78 (s, 1H), 8.25-8.22 (m, 1H), 7.57 (s, 1H), 7.54 (d, J=8.4, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(=O)=O>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Agent: O=C=O
Product: CSc1ncc(Cl)cn1
Yield: 89.2 %

Procedure:
5-Chloro-2-methylthio-4-pyrimidine carboxylic acid (30 g) was heated at 180°-200° C. until all the solid had melted and the evolution of carbon dioxide had ceased (5 min). The residue was allowed to cool and then washed with several portions of chloroform. The chloroform washings were filtered to remove dark insoluble material and the filtrate was concentrated to give 5-chloro-2-methylthiopyrimidine as a pale brown crystalline solid (21 g, 89%), m.p. 55° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[CH3:6])[CH3:2].Br[C:26]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=1[CH:28]=[O:29]>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:7]1[CH:8]=[C:9]([C:26]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=2[CH:28]=[O:29])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)C(C)c1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-[4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)(=O)C.[Pt](=O)=O>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c([nH]1)CCCC2
Yield: 33.3 %

Procedure:
Ethyl indole-2-carboxylate (0.5 g) and platinum (IV) oxide (0.1 g) in acetic acid (20 ml) were stirred under an atmosphere of hydrogen for 16 hours at ambient temperature. The reaction was then filtered through a pad of celite and basified by addition of aqueous sodium hydroxide (2N). The resulting precipitate was filtered and dried in vacuo to give the product as a white solid (0.17 g, 33%), NMR d(CDCl3) 1.35 (3H, t), 1.80 (4H, m), 2.50 (2H, t), 2.60 (2H, t), 4.30 (2H, q), 6.65 (1H, d), 8.70 (1H, bs); M/z (+) 194 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:27])[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]1>>[NH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:20]([NH:27][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:21]1
Reactant: NC1CCCC(N)C1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Product: NC1CCCC(Nc2cccc3nc(NC(=O)c4ccccc4)nn23)C1
Reaction time: 0.08 h

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 52 mg; 0.19 mmol; 1.0 eq) and 1,3-cyclohexanediamine (1.0 mL). The crude was directly purified by preparative HPLC (Starting with 45% ACN in water for 5 min, then up to 60% in 10 min.). The title compound was isolated after lyophilisation as a white powder (63 mg, 94%). HPLC, Rt: 1.84 min. (purity 98.2%). LC/MS, M+(ESI): 351.4, M−(ESI): 349.4.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])O[C:11](=[O:15])[C:10]2[N:6]1[CH:7]=[CH:8][CH:9]=2.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+]>CN(C)C(=O)C.CO>[CH2:22]([O:21][C:19]([C:18]1[C:13](=[O:14])[N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:16])[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]2[C:11]=1[OH:15])=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccn21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Temperature: 120 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
To a solution of 4-(3-methyl-butyl)-6-oxa-3a,4-diaza-indene-5,7-dione (Example 1e, 0.080 g, 0.36 mmol) and diethyl malonate (0.58 mL, 3.6 mmol) in N,N-dimethylacetamide (1 mL) was added sodium hydride (0.017 g, 0.43 mmol) and 1 drop of methanol. The reaction mixture was heated to 120° C. and stirred for 16 h. The reaction was allowed to cool to 25° C. and quenched with saturated aqueous ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×3 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/dichloromethane, 2-5%) to afford the desired product, 4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (0.058 g, 0.20 mmol, 55% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (6H, d, J=6.4 Hz), 1.30 (3H, t, J=6.8 Hz), 1.49 (2H, q, J1=15.2 Hz, J2=7.6 Hz), 1.63 (1H, m), 4.23-4.30 (4H, m), 6.56 (1H, m), 6.87 (1H, m), 7.68 (1H, m); LC-MS (ESI) calcd for C15H20N2O4 292.33, found 293.30 [M+H+].