Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:25][S:26]([N:29]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30]1)(=[O:28])=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][S:26]([N:29]1[CH2:33][CH2:32][CH:31]([NH:34][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[CH:11]=2)=[O:15])[CH2:30]1)(=[O:28])=[O:27]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: CS(=O)(=O)N1CCC(N)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
In a round-bottomed flask were combined 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (130 mg, 0.39 mmol), 1-methanesulfonyl-pyrrolidin-3-ylamine hydrochloride (134 mg, 0.66 mmol), EDC (82 mg, 0.43 mmol), and HOBt (58 mg, 0.43 mmol). Then added DMF (1.7 mL) followed by i-Pr2NEt (0.17 mL, 1.0 mmol). The reaction mixture was stirred at room temperature overnight then quenched with H2O and extracted with Et2O (2×). The combined organics were washed with H2O (2×) and brine then dried over Na2SO4 and concentrated. The residue was purified by chromatography over 12 g of SiO2 using EtOAc/hexanes (gradient: 0-90% EtOAc) to afford 179 mg (96%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-yl)-amide as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH3:16])[C:10]=2[N+:17]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C.[Pd]>[NH2:17][C:10]1[C:11]([NH:15][CH3:16])=[N:12][CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[C:2]([F:1])[CH:7]=1
Reactant: CNc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c(F)c2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c(F)c2)c1N

Procedure:
Tert-butyl 2-fluoro-4-(2-(methylamino)-3-nitropyridin-4-yloxy)phenylcarbamate (5.3 mg, 14 mmol) was dissolved in absolute ethanol (600 mL) and hydrogenated on a 10% Pd/C cartridge through an H-Cube apparatus, to give the title compound as a yellow solid.
Reaction SMILES: [SH:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].Cl[CH2:19][C:20]1[C:21]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:22]1[C:21]2[C:26](=[CH:27][C:28]3[C:33]([C:20]=2[CH2:19][S:1][CH2:2][C@H:3]2[O:7][C@@H:6]([N:8]4[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]4=[O:10])[CH2:5][C@@H:4]2[OH:17])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CS)O2)c(=O)[nH]c1=O
Reactant: ClCc1c2ccccc2cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CSCc3c4ccccc4cc4ccccc34)O2)c(=O)[nH]c1=O
Yield: 34.8 %

Procedure:
258 mg (1 mmol) of 5'-deoxy-5'-mercaptothymidine was added to 20 ml of acetone. 272 mg (1.2 mmol) of 9-chloromethylanthracene and 1 g of anhydrous potassium carbonate were then added to the solution under an atmosphere of nitrogen. The resulting mixture was then stirred whilst being heated under reflux for 2 hours. At the end of this time, precipitates were filtered off from the reaction mixture, and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was crystallized from 10 ml of ethanol, to give 156 mg (yield 35%) of the title compound as pale yellow crystals.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C@@H:30]([C:39]([NH:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C@@H:30]([C:39]([NH:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[NH2:11])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
0.58 g (0.80 mmol) of the compound from Example 228A are dissolved in 27 ml of ethanol, and 0.06 g (0.06 mmol) of Pd/C are added. The mixture is hydrogenated under atmospheric pressure for 12 h and, after filtration through celite, the filtrate is concentrated in vacuo. The solid obtained in this way is reacted further without purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([S:26][C:23]2[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(Br)cc2)CC1
Yield: 95.9 %

Procedure:
N-BOC 4-mesyloxypiperidine (40 g, 0.14 mol), 4-bromothiophenol (32 g, 0.17 mol) and potassium carbonate (30 g, 0.22 mol) were mixed at room temperature in CH3CN (300 ml) and heated at reflux for 18 h. Work-up by partitioning between water and EtOAc afforded 50 g of material as a yellow oil. δH (360 MHz, CDCl3) 1.44 (9H, s), 1.45-1.55 (2H, m), 1.85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.10-3.20 (1H, m), 3.95-4.05 (2H, m), 7.25-7.30 (2H, m), 7.40-7.45 (2H, m).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O-])(=[O:13])[CH3:12].[Na+].C(OC(=O)C)(=O)C.O>CCCCCC>[CH3:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[O:1][C:11](=[O:13])[CH:12]=[CH:4]2
Reactant: Cc1cccc(C=O)c1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCCCCC
Product: Cc1cccc2ccc(=O)oc12
Temperature: 177.5 °C
Yield: 53.9 %

Procedure:
The suspension of 2-Hydroxy-3-methyl benzaldehyde (30 gm, 0.220 mole) and anhydrous Sodium acetate (45 gm, 0.55 mole) in Acetic anhydride (45 gm, 0.44 mole) was heated at 175-180° C. for 6 hours. The reaction mixture was cooled; water (150 ml) and Hexane (60 ml) were added. It was stirred for an hour and filtered. The obtained solid was stirred with Diethyl ether (30 ml). Finally the suspension was filtered and dried to give 19 gm desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:3]=1[NH:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11]Cl)(=[O:7])=[O:6].[K].CC(C)([O-])C.O>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:3]=1[N:4]1[CH2:11][CH2:10][CH2:9][CH2:8][S:5]1(=[O:7])=[O:6]
Reactant: Cc1ccc(NS(=O)(=O)CCCCCl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCCCS2(=O)=O)c(Cl)c1

Procedure:
1.27 g (4.29 mmol) 2-chloro-N-(4-chlorbutyl-sulphonyl)-4-methyl-aniline are stirred together with 722 mg (6.43 mmol) potassium-tert.-butoxide in 50 ml DMF for 16 hours at 60° C. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=3:2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][C:13]=2[O:18]C)=[O:11])=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:13](=[O:18])[NH:14][N:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1nnccc1C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1[C@@H](CC(=O)c1ccn[nH]c1=O)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
To a solution of (S)-3-(4-bromophenyl)-1-(3-methoxypyridazin-4-yl)-3-o-tolylpropan-1-one (example 4, step 1; 312 mg, 759 μmol) in 1,4-dioxane (9 ml) was added 37% aq. hydrochloric acid solution (1.27 ml, 15.2 mmol) and the resulting solution was first stirred at 60° C. for 3 h and then for 2½ h at 80° C. After cooling the reaction mixture was poured onto ice water and ethyl acetate, neutralized with sat. aq. sodium hydrogen carbonate solution and the pH was adjusted to 6.85 with 1 M aq. potassium phosphate buffer solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (327 mg, quantitative), which was directly used in the next step. Light red foam, MS: 397.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:8][C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:13]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[C:12]3[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[CH:6][CH:5]=1)=[O:3].Cl>C(OCC)(=O)C>[NH2:24][CH2:23][C:13]1[C:14]([CH2:19][CH:20]([CH3:22])[CH3:21])=[N:15][C:16]2[C:11]([C:12]=1[C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)=[CH:10][C:9]([C:7]1[O:8][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=1)=[CH:18][CH:17]=2
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4ccc(C(N)=O)o4)cc23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(CN)c(CC(C)C)nc3ccc(-c4ccc(C(N)=O)o4)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of tert-butyl {[6-[5-(aminocarbonyl)-2-furyl]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.5 g, 1.0 mmol) in ethyl acetate (5 ml) was added 4N solution of hydrogen chloride in ethyl acetate (2 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from diisopropyl ether. The obtained crystals were dissolved in ethyl acetate (5 ml) and triethylamine (1 ml) was added. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give 5-[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]-2-furamide (0.29 g, yield 71%) as white crystals.
Reaction SMILES: [ClH:1].Cl.CN[C@H]1CCN([CH2:10][CH:11]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)C1.OC1(C(C2C=CC=C(C(F)(F)F)C=2)C([N:39]2[CH2:43][CH2:42][C@H:41]([NH:44][C:45](=O)OC(C)(C)C)[CH2:40]2)=O)CCCCC1>>[ClH:1].[ClH:1].[CH3:45][NH:44][C@H:41]1[CH2:42][CH2:43][N:39]([CH:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH3:10])[OH:28])[CH2:40]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: CN[C@H]1CCN(CC(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CN[C@H]1CCN(C2CCCCC2(O)C(C)c2cccc(C(F)(F)F)c2)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-{2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl ((3S)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethyl)phenyl]acetyl}pyrrolidin-3-yl)carbamate MS (ESI) m/z 371; HRMS: calcd for C20H29F3N2O+H, 371.23102; found (ESI, [M+H]+), 371.2293.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](Cl)=[O:14])[N:12]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([N:25]([O:26][CH3:27])[CH3:24])=[O:14])[N:12]=1
Reactant: CNOC
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride (4.71 g, 13.4 mmol, prepared by the method described in Example 13, step 1) in 10 mL dichloromethane was added to a solution of N,O-dimethylhydroxyamine hydrochloride (1.44 g, 14.7 mmol) and triethylamine (5.6 mL, 40.2 mmol) in 60 mL dichloromethane in an ice water bath under argon with stirring. The bath was removed upon completion of addition. Stirring was continued for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated down under reduced pressure. The crude product was purified on silica gel, eluting with ethyl acetate to yield 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N-methyl-1H-imidazole-4-carboxamide as an off-white solid (4.20 g, 83%): Rf=0.22 (ethyl acetate).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH:11]1([NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: O=C(NC1CCCCC1)c1cccc(Br)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)c1cccc(N2CCCCC2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
6-bromo-N-cyclohexylpicolinamide (55 mg, 0.194 mmol), piperidine (18 mg, 0.213 mmol), Pd2(dba)3 (3.5 mg, 0.00388 mmol), xantphos (6.7 mg, 0.0116 mmol), and sodium-tert-butoxide (27.4 mg, 0.285 mmol) were suspended in toluene (3 ml), and then stirred at 100° C. under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 51 mg of pale yellow oil (83%). MS (ESI): 288 [M+H]+
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:23])[C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[C:18]3[C:14]([C:15](I)=[N:16][NH:17]3)=[CH:13][CH:12]=2)[C:8]([CH3:21])=[C:7]([F:22])[CH:6]=1)[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH:37]=2)O1.C(=O)([O-])O.[Na+]>C(O)(C)C.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]([NH:3][C:4]([C:5]1[CH:6]=[C:7]([F:22])[C:8]([CH3:21])=[C:9]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=4)=[N:16][NH:17]3)=[CH:13][CH:12]=2)[CH:10]=1)=[O:23])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(I)n[nH]c3c2)c1
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: CC(C)O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 66.5 %

Procedure:
A mixture of N-ethyl-3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide (Intermediate 19, 2.34 g), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.71 g), aqueous sodium hydrogen carbonate (1M, 11.1 ml) and tetrakis(triphenylphosphine)palladium(0) (129 mg) in isopropanol (10 ml) was divided into three portions then stirred in sealed vials at 150° C. for 25 min in a microwave oven. The reaction mixtures were combined, the solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated using a hydrophobic filter tube, the solvent was evaporated and the residue was purified by chromatography on a silica column eluting with an ethyl acetate:cyclohexane gradient, to give the title compound as a yellow foam (1.76 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].[Cl:12][CH2:13][C:14](Cl)=[O:15]>ClC=CCl>[Cl:12][CH2:13][C:14]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])=[O:15]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC=CCl
Product: Cc1cccc(C)c1NC(=O)CCl
Yield: 95 %

Procedure:
In 4 l of 1,2-dichloroethylene was dissolved 182 g of 2,6-xylidine, and 1.6 l of a 1N sodium hydroxide aqueous solution was added thereto, followed by stirring. To the mixture was added dropwise 203 g of chloroacetyl chloride over 1.5 hours at an inner temperature between 20 and 35° C. The mixture was stirred at that temperature for 1.5 hours. The reaction mixture was separated into two layers, and the organic layer was concentrated under reduced pressure. The precipitate was collected by filtration and dried under reduced pressure to obtain 282 g (95%) of the titled compound.
Reaction SMILES: [CH2:1]([C:8]1([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([O-])([O-:18])=[O:17].[K+].[OH-].[Na+]>OS(O)(=O)=O>[N+:16]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:8]2([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:9][CH2:10]2)=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: CCC(=O)NC1(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CCC(=O)NC1(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
To H2SO4(20 ml) at 0-10° C. N-(1-benzyl-cyclopropyl)-propionamide (2 g, 9.84 mmol) was slowly added. The mixture was stirred until a clear solution was obtained. Then KNO3 (1 g, 9.89 mmol) was added in portions at 0-5° C. The mixture was stirred at room temperature for 16 h after which it was poured into ice water, and 50% NaOH was added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. The residue was triturated with isopropylether and the precipitate filtered and dried in vacuo to give the product as a brown powder (900 mg, 37%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11](=O)/[CH:12]=[CH:13]/[N:14](C)[CH3:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([N:21](CC)CC)C.Cl.C(N)=N>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][N:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)/C=C/C(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: N=CN
Product: CC(C)(C)OC(=O)NC1(c2ccncn2)CC1
Temperature: 77.5 °C
Reaction time: 14 h
Yield: 20.4 %

Procedure:
To a solution of [1-((E)-3-Dimethylamino-acryloyl)-cyclopropyl]-carbamic acid tert-butyl ester (600 mg, 2.4 mmol) was added triethylamine (1.3 mL, 9.4 mmol) and formamidine hydrochloride (570 mg, 7.1 mmol) at room temperature. The reaction was stirred at 75-80° C. for 14 h. The volatiles were removed in vacuo to give a crude solid mass that was purified by preparative reversed phase HPLC to give 115 mg of the title compound as a light yellow solid, m/z 236.36 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.[CH3:19][CH:20]([NH2:22])[CH3:21].I[Si](C)(C)C>C1COCC1.CCOC(C)=O.C1S(=O)(=O)CCC1>[CH:20]([NH:22][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12)([CH3:21])[CH3:19]
Reactant: COc1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: CC(C)N
Agent: C[Si](C)(C)I
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Nc1ncnc2c1cnn2-c1ccc(O)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To a mixture of compound 44C (388 mg, 1.48 mmol) and propan-2-amine (0.14 mL, 1.63 mmol) in THF (10 mL) was added TEA (0.456 mL, 3.27 mmol). The resulting mixture was stirred at 30° C. overnight and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and dried. To the crude material was added iodotrimethylsilane (1.0 mL, 7.06 mmol) in tetramethylene sulfone (5 mL). The reaction mixture was heated at 80° C. overnight. The reaction was slowly poured into ice-water (5 mL). The precipitate was collected, washed with water, and purified by reverse phase HPLC (mobile phase: 0%-50% acetonitrile in 0.1% TFA aqueous solution during 40 minutes) to provide the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 9.68 (1H, s, br), 8.55 (1H, s, br), 8.39 (1H, s), 8.35 (1H, s), 7.82 (2H, d), 6.88-6.94 (2H, m), 4.34-4.46 (1H, m), 1.28 (6H, d)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23](B(O)O)=[CH2:24].C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.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>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:23]=[CH2:24])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C=CB(O)O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 100 °C
Yield: 37 %

Procedure:
A suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (6.8 g, 20 mmol), vinyl boronic acid [CAS-No. 4363-34-2] {Bull. Soc. Chim. Fr. 1966, (8), 2557-64} (4.312 g, 60 mmol) and K2CO3 (8.29 g, 60 mmol) in water (10 mL) and dioxane (50 mL) was purged by Ar-stream at 23° C. for 10 min, then tetrakis(triphenylphosphine)palladium(0) (693 mg, 0.6 mmol) was added and the mixture was heated to 100° C. for 20 h, filtered, evaporated and purified by column chromatography on silica gel (hexane/ethyl acetate 9:1) to yield a light yellow solid (2.476 g, 37%).