Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CN.C1COCC1.C[CH2:38][N:39]=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22]([NH:39][CH3:38])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared from 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from step 1 above) (1.5 g, 3.57 mmol) in dichloromethane (35 ml). To this mixture, 2.0 M methyl amine in THF (3.6 ml, 7.14 mmol) was added, followed, in order, by EDCI (0.67 g, 4.28 mmol), 1-hydroxybenzotriazole (0.58 g, 4.28 mmol) and triethylamine (0.99 ml, 7.14 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with NH4Cl and extracted 3 times with ethyl acetate. The combined organic layer was then washed with saturated NaHCO3 (aq.) and extracted 3 times with ethyl acetate. The organic layers were combined and washed with H2O and extracted 3 times with ethyl acetate. The organic layers were combined and dried over Na2SO4 and evaporated. The resulting residue was triturated with diethyl ether/hexane to obtain a solid, which was dried in vacuo to give a white solid (1.5 g, 72%). 1H NMR (300 MHz, CD3OD) δ 7.90 (dd, J=8.06, 1.81 Hz, 1H), 7.67 (app q, J=6.44 Hz, 1H), 7.55 (d, J=8.06 Hz, 1H), 7.13-7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s, 2H), 2.93 (s, 3H), 2.13 (s, 3H), 2.04 (s, 3H); ES-MS m/z 433 (M+H). ES-HRMS m/z 433.1153 (M+H calcd for C22H20ClF2N2O3 requires 433.1125).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([CH3:19])[C:16](O)=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.C(Cl)Cl.[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>>[CH3:25][S:26]([NH:29][C:16](=[O:17])[C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([C:2]([F:21])([F:20])[F:1])[N:4]=2)=[CH:10][CH:11]=1)[CH3:19])(=[O:28])=[O:27]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Solvent: ClCCl
Product: C[C@H](C(=O)NS(C)(=O)=O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71875 %

Procedure:
To a solution of (2S)-2-4-{[4-trifluoromethyl)-1,3-thiazol-2yl]amino}phenyl)propanoic acid (3) (0.1 g, 0.32 mmol) in dry CH2Cl2 (2 mL) CDI (0.055 g, 0.34 mmol) was added and the resulting solution was stirred for 1 h at T=0° C. After ice-water bath removal methanesulfonamide (0.032 g, 0.34 mmol) and TEA (40 μl, 0.29 mmol) were added and the resulting mixture was stirred at room temperature for 12 h. At the complete disappearance of the starting material, a buffer H3PO4/H2PO4− solution (pH=2.0, 5 ml) was added and the reaction mixture was trasferred into a reparatory funnel. The two phases were separated and the organic one washed with the same buffer (3×5 mL), dried over Na2SO4 and evaporated under vacuum to give a crude which was purified by flash chromatography. Pure compound 11 (0.089 g, 0.23 mol) was isolated as a yellow oil (71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[Cl:17][C:18]1[C:19]([CH:26]=O)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:17][C:18]1[C:19]([CH2:26][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]3([CH3:15])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]3)[CH:7]=2)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)CCOC(N)=N1
Reactant: O=Cc1nn(C(F)F)cc1Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: C[C@@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)CCOC(N)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
In a 5 ml-reaction tube a solution of (S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.4) (22 mg, 0.1 mmol) in methanol (0.3 ml) was treated at room temperature at under an inert atmosphere with 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (19.9 mg, 110 μmol). The tube was closed and the reaction mixture was stirred at 25° C. for 60 minutes. Then decaborane (24.4 mg, 200 μmol) was added in one portion, the tube was closed, and the mixture was warmed to 45° C. for 15 hours. For the workup, the reaction solution was quenched with a solution of sodium carbonate (10%). Methanol was removed at reduced pressure, then the residue was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduce pressure. The crude product was purified by basic preparative HPLC and after evaporation triturated with a mixture of ether and heptane. The (S)-4-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (8 mg, 20% yield) was obtained as a colorless oil. MS (ISP): m/z=388.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:57])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)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.[Cu]I>[CH3:24][O:25][C:26](=[O:57])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53]([C:22]#[C:21][C:18]4[NH:17][C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=4)=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(Br)cc3)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 15 h
Yield: 12.3 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (44 mg, 0.138 mmol), (1-{2-[5-(4′-Bromo-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (67 mg, 0.128 mmol), Pd(PPh3)4 (15 mg, 0.0128 mmol), CuI (2 mg, 0.0128 mmol) and triethylamine (0.180 mL, 1.28 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 15 hours then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (12 mg, 12%). 1H NMR (MeOH-d4, 400 MHz) 7.73 (d, J=8.4 Hz, 2H), 7.66-7.64 (m, 4H), 7.52 (d, J=8.2 Hz, 2H), 7.35 (s, 1H), 7.24 (s, 1H), 6.98 (m, 2H), 5.18 (m, 1H), 5.11 (m, 1H), 4.26-4.19 (m, 2H), 4.01-3.80 (m, 4H), 3.65 (s, 6H), 2.37-2.01 (m, 10H), 1.00-0.88 (m, 12H); MS (ESI) m/z 763 [M+H]+.
Reaction SMILES: [Na].[P:2]([O-:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[F:10][CH:11]([F:32])[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14](F)[C:13]=1[C:28]([O:30][CH3:31])=[O:29].O>C1COCC1>[F:32][CH:11]([F:10])[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]([P:2]([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:9])[C:13]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1F
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.4 %

Procedure:
To a mixture of 0.26 g (0.011 mol) of sodium metal in 35 ml of dry THF was added 3.14 g (0.023 mol) of diethyl phosphite. This solution was stirred at room temperature under a N2 atmosphere for 18 hours. To this salt solution was added 2.0 g (0.006 mol) of product of Example 107. This mixture was stirred at reflux for 18 hours. The mixture was cooled to room temperature and poured into H2O. The H2O mixture was extracted twice with diethyl ether. The combined ether phases were then washed with H2O, dried (MgSO4), and concentrated in vacuo affording 2.18 g of an orange oil. This oil was kugelrohr distilled at 80 and collected at 150°-151° C. pot temperature yielding 1.68 g (63%) of a clear oil, n25D 1.4536.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]#[N:7])(=[O:4])=[O:3].[C:8](=O)([O-])[O-].[K+].[K+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:24]=[C:25]=[S:26])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.CI>CC(C)=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][C:25]([S:26][CH3:8])=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]#[N:7])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(N=C=S)cc(OC)c1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)CC#N
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 48.2 %

Procedure:
To a solution of methanesulfonylacetonitrile (0.55 g, 4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g, 9.3 mmol) and then 3,5-dimethoxyphenyl isothiocyanate (0.96 g, 4.9 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 23 h, then filtered and washed with ethanol. To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (sodium sulfate) and concentrated. The residue was recrystallised from ethyl acetate to give the title compound (0.728 g, 48%). 1H NMR (200 MHz, CDCl3): δ=2.27 (s, 3H), 3.19 (s, 3H), (s, 3H), 3.80 (s, 6H), 6.48 (t, 1H), 6.44 (d, 2H) EI SP/MS: 328 (M+).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.Cl.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30]>>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:30][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To an ethanolic solution (100 ml) of diphenylacetonitrile (28 g) were added DBU (6 ml) and ethyl acrylate (30 ml) and the mixture was heated and stirred at 80° C. for 16 hours. After cooling, 200 ml of 2N-hydrochloric acid was added to the reaction mixture, which was then extracted with isopropyl ether. The organic layer was washed with water, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The resulting crude crystals were recrystallized from hexane/isopropyl ether to provide ethyl 4-cyano-4,4-diphenylbutyrate (34 g).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO[C:13]1[C:18]([CH:19]=O)=[CH:17][CH:16]=[CH:15]N=1.O([CH3:23])[Na]>C1COCC1>[C:18]1([CH:19]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:13]=[CH:23][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CO)c1ccccc1
Reactant: CO[Na]
Reactant: COc1ncccc1C=O
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 60 %

Procedure:
2.39 g (17.6 mmol) of 2-hydroxyacetophenone, 2.10 g of 2-methoxy-3-pyridinecarboxaldehyde (15.3 mmol), and 10 ml of 25% NaOCH3 were reacted in 50 ml of dry THF to give 2.35 g (60%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.85 (s, 1H), 8.24 (d, d, J=1.8, 4.8 Hz, 1H), 8.02 (d, J=15.6 Hz, 1H), 7.94-7.86 (m, 2H), 7.90 (d, J=15.9 Hz, 1H), 7.52 (d, d, J=8.4, 8.7 Hz, 1H), 7.06-6.98 (m, 3H), 4.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:30][CH3:31])[CH:23]=1>>[ClH:1].[CH2:30]([N:29]([CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1)[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:31]
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)cc3)nc2c1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2cc(C)ccn12
Product: Cl
Yield: 69.5 %

Procedure:
According to the method of Example 14, 2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(3-pyridinylmethyl)ethylamine were used as raw materials for synthesis, to obtain light yellow solid powder, yield 69.5%. m.p. 236-238° C., ESI-MS m/z: 420[M+H]+, 1H NMR(D2O, 400 MHz)δ: 0.95(t, 0.7H, J=7.00 Hz), 1.11(t, 2.3H, J=7.00 Hz), 2.39(s, 2.3H), 2.40(s, 0.7H), 3.27(q, 0.5H, J=7.00 Hz), 3.48(q, 1.5H, J=7.00 Hz), 4.13(s, 0.5H), 4.32(s, 1.5H), 4.60(s, 1.5H), 4.71(s, 0.5H), 7.15-7.22(m, 1H), 7.32-7.44(m, 4H), 7.51(s, 1H), 7.84(m, 1H), 8.12-8.14(m, 1H), 8.26(m, 1H), 8.52-8.53(m, 2H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([N+:28]([O-:30])=[O:29])=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]I.[OH-].[Na+].O>CN(C=O)C>[CH3:31][N:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]1[CH:20]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14][CH2:13]2)[CH:16]=[CH:17][C:18]=1[N+:28]([O-:30])=[O:29]
Reactant: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1)c1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Yield: 86.4 %

Procedure:
A solution of 5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (2.0 g, 5.00 mmol), methyl iodide (0.31 ml, 5.00 mmol) and sodium hydroxide (0.26 g, 6.5 mmol) in 25 ml DMF was stirred at 0° C. for 2 hours. 100 ml water was added to the mixture to quench the run, and the mixture was extracted with ethyl acetate (2×20 ml). The extraction was washed with water (3×30 ml) and dried over anhydrous sodium sulfate. N-methyl-5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (1.8 g, 90%) was obtained after remove of solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 3.38 (s, 3H), 3.37-3.87 (m, 8H), 6.72 (m, 4H), 6.84 (m, 1H), 7.21 (m, 2H), 7.45 (m, 5H), 8.07 (d, J=9.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 40.5, 47.7, 47.9, 111.1, 114.6, 115.3, 119.8, 127.6, 129.1, 129.2, 129.6, 130.7, 135.6, 137.3, 145.4, 148.4, 155.1, 171.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)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>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=2)=[C:16]([F:23])[CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cnc(C)cc1Cl
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 29.9 %

Procedure:
A mixture of methyl 4-chloro-6-methylnicotinate (0.1 g, 0.539 mmol), (4-chloro-2-fluorophenyl) boronic acid (0.094 g, 0.539 mmol), Pd(PPh3)4 (0.031 g, 0.027 mmol) and Cs2CO3 (0.527 g, 1.616 mmol) in 1,4-dioxane (10 mL) was heated at 80° C. for 16 h. After cooling, the mixture was diluted with water (30 mL) and ethyl acetate (50 mL). The organic phase was collected, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc in pet. ether) to afford methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate (0.045 g, 0.161 mmol, 30% yield) as a yellow liquid. LCMS (ESI) m/e 280.0 [(M+H)+, calcd for C14H12ClFNO2 280.04]; LC/MS retention time (Method H): tR=2.51 min. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.13-7.29 (m, 3H), 6.44 (s, 1H), 3.94 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[OH:15])(=[O:3])[CH3:2]>C(O)C.[H][H].[Pt]>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cc([N+](=O)[O-])ccc1O
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CC(=O)NCc1cc(N)ccc1O

Procedure:
2.3 g (0.012 mole) of the nitro compound of step 3 is dissolved in ethanol and hydrated with hydrogen using a platinum catalyst. After absorbing the theoretical quantity of hydrogen the catalyst is suction filtered off, acidified with hydrochloric acid, and the solvent is evaporated in a vacuum. The compound forms a non-crystallizing oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17]O)[CH2:6]2.C(N(CC)CC)C.S(Cl)([Cl:29])=O.[OH-].[Na+]>ClCCl.O>[Cl:29][CH2:17][CH2:16][CH2:15][N:14]([CH2:13][C@H:7]1[CH2:6][C:5]2[C:8]1=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:19]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(cc1OC)[C@@H](CN(C)CCCO)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CCCCl)C2
Reaction time: 3 h
Yield: 89 %

Procedure:
To a mixture of 3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)-amino]-1-propanol (20.8 g, 78.4 mmoles) and triethylamine (11 mL, 78.9 mmoles) in 200 mL of dichloromethane add, at ambient temperature, 8.65 mL of thionyl chloride (157 mmoles). After being in contact for 3 hours at 40° C., hydrolyse the mixture using 150 mL of water and 30 mL of aqueous 1N NaOH solution. Adjust the pH of the aqueous phase to 10 using aqueous 10N NaOH solution and extract with 50 mL of dichloromethane. Combine the organic phases and wash them with saturated aqueous Na2CO3 solution (100 mL), dry them over MgSO4 and carry out drying in vacuo to obtain 19.8 g of a brown oil corresponding to the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[C:9]([NH2:24])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:13]=1.[NH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>O1CCOCC1.CN(C=O)C>[NH2:24][C:9]1[C:8]([C:31]2[CH:32]=[CH:33][C:28]([C:26]([NH2:25])=[O:27])=[CH:29][CH:30]=2)=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][N:10]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc(C(N)=O)cc3)c2)cc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 56 %

Procedure:
Aqueous K2CO3 solution (1 M, 0.4 mL) was added to a suspension of 3-bromo-5-[4-(methylsulfonyl)phenyl]pyridin-2-amine obtained as described above (0.15 g, 0.46 mmol), 4-aminocarbonylphenylboronic acid (0.120 g, 0.51 mmol) and Pd[(PPh)3]4 (0.016 g, 0.02 mmol) in dioxane (5 mL) and DMF (2 mL) under N2. The reaction mixture was stirred at 120 ° C. for 14 h, poured onto H2O (10 mL) and extracted with MeOH/CHCl3 (1:4) (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (5% MeOH/EtOAc) to yield the desired product (0.26 g, 56%). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, 1H, J=2.4 Hz), 8.07 (s, 1H), 8.02-7.92 (m, 6H), 7.78 (d, 1H, J=2.4 Hz), 7.64 (d, 2H, J=8.4 Hz), 7.44 (bs, 1H), 6.11 (bs, 2H) and 3.24 (s, 3H). LC-MS APCI: Calculated for C19H17N3O3S, 367; Observed m/z 368 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.C(Cl)[Cl:11]>S(Cl)(Cl)=O>[Cl:11][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: Cc1ccc(CO)cn1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (6-methylpyridin-3-yl)methanol (13 g) in DCM (260 mL), thionyl chloride (13 mL) was added slowly under nitrogen at RT. The mixture was stirred at RT for 1 h, the reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was concentrated under reduced pressure, the residue was suspended in saturated aq. NaHCO3 (pH 8) and extracted with DCM (2×100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum to obtain 12.5 g of product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C.C(OCC)(=O)C>[CH3:11][O:9][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1cccnc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ncccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
400 mg (2.9 mmol) of 3-amino-pyridine-2-carboxylic acid was dissolved in 3 mL of methanol. To this solution 1.6 mL of 2 M (trimethylsilyl)diazomethane solution in diethyl ether was added dropwise at 0° C., followed by stirring of the mixture for 2 hours at room temperature The solution was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. Flash chromatography afforded the ester product. LC-MSD, m/z for C7H8N2O2 [M+H]+=153.0; HPLC retention time: 0.2 minutes.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][N:13]([CH2:18][C:19](O)=[O:20])[CH2:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:23]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:24]1[NH2:25].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.[F:48][P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:48][C:29]1[C:23]([CH3:30])=[C:24]([NH:25][C:19](=[O:20])[CH2:18][N:13]2[CH2:12][CH:11]3[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)CN1CC2CCC(C1)N2S(=O)(=O)c1ccccc1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CC1(F)C=CC=CC1N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(F)cccc1NC(=O)CN1CC2CCC(C1)N2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product of step (iii) (0.45 mmol), 2-fluoro-2-methylaniline (60 μl), PyBroP (0.25 g), N,N-dimethylaminopyridine (54 mg) and N,N-diisopropylethylamine (0.23 ml) in N,N-dimethylformamide (5 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography eluting with 1% ethanol in dichloromethane followed by further chromatography with 20% ethyl acetate/iso-hexane to give the title compound as a white solid. Yield: 30 mg.