Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:18][CH2:17]3)=[CH:22][CH:23]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1cc(-n2cnnn2)ccc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step A, Example 1; 100 mg, 0.319 mmol) and triethylamine (97 mg, 0.96 mmol) were dissolved in dichloromethane (5 mL). Isobutyl chloroformate (52 mg, 0.38 mmol) was added. The mixture was stirred at RT for 30 min and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (12 g RediSep, eluted with dichloromethane/methanol, 199:1, 500 mL). The product containing fractions were combined and concentrated under reduced pressure. The compound was further purified by prep-HPLC (SunFire C18 OBD, 10 μm, 50×150 mm, 118 mL/min, acetonitrile/water 10:90 to 90:10 at 25 min, total run 30 min) provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.20-4.10 (m, 4H), 3.86 (d, J=6.6 Hz, 2H), 2.85-2.60 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.70 (m, 2H), 1.60-1.45 (m, 1H), 1.40-1.25 (m, 2H), 1.10-0.90 (m, 2H), 0.94 (d, J=6.7 Hz, 6H), 0.80-0.65 (m, 2H), −0.09 (q, J=5.2 Hz, 1H). MS (ESI) m/z 414 [M+H]+. GPR119 Human EC50:1.6 nM
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([NH:24]C(=O)OC(C)(C)C)[CH3:23])=[CH:18][CH:17]=2)=[C:4]([O:32]C)[CH:3]=1.B(Br)(Br)Br>>[ClH:1].[NH2:24][C@@H:22]([C:19]1[CH:20]=[CH:21][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:32])=[CH:17][CH:18]=1)[CH3:23]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: C[C@@H](N)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 161.3 %

Procedure:
Following General Procedure F, tert-butyl 1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (0.35 mg, 0.07 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 2 mL, 2 mmol) to afford the desired product (23 mg, 84%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.67-7.61 (m, 2H), 7.59 (d, J=5.4 Hz, 1H), 7.44-7.39 (m, 2H), 7.30 (s, 1H), 6.07 (d, J=5.4 Hz, 1H), 4.62 (q, J=6.8 Hz, 1H), 1.76 (d, J=6.9 Hz, 3H); ESI MS m/z 371 [C19H15ClN2O2S+H]+; HPLC 97.2% (AUC), tR=9.58 min.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:13]1([CH2:19][CH2:20][C:21]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8]2)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.4 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 3-phenyl-1-(2-phenylmorpholin-4-yl)propan-1-one are collected and the solvent is removed in vacuo to give 528 mg of colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O.[NH:22]1[CH:26]=[CH:25][N:24]=[N:23]1>C(OCC)(=O)C.O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:23]2[N:24]=[CH:25][CH:26]=[N:22]2)[CH:7]=1.[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:22]2[CH:26]=[CH:25][N:24]=[N:23]2)[CH:7]=1
Reactant: c1c[nH]nn1
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Brc1cncc(-n2ccnn2)c1
Product: Brc1cncc(-n2nccn2)c1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
3,5-dibromopyridine (400 mg) and cesium carbonate (550 mg) were added to an N-methylpyrrolidone (4 ml) solution containing 1H-1,2,3-triazole (117 mg), followed by stirring at 100° C. for 21 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was collected, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=10:0 to 2:3), and a white solid of 3-bromo-5-(2H-1,2,3-triazol-2-yl)pyridine (55 mg) and a white solid of 3-bromo-5-(1H-1,2,3-triazol-1-yl)pyridine (48 mg) were thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[NH:10][N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:29][CH:31]3[CH2:32][O:33]3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: ClCC1CO1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(Cl)c([N+](=O)[O-])c3)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (6.4 g, 20.0 mmol) in DMF (60 mL) was treated with cesium carbonate (13.0 g, 40 mmol) and epichlorohydrin (15.6 mL, 200.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for an additional 24 h before it was diluted with ethyl acetate (350 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10% acetone/CH2Cl2) to provide 7.5 g (83%) of a light yellow powder. MS (electrospray): m/z 377.0 (377.0, calculated for C17H17ClN4O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.15-8.05 (m, 1H), 7.75-7.65 (m, 1H), 7.55-7.45 (m, 1H), 4.80-4.65 (m, 1.2H), 4.60 (s, 0.8H), 4.45-4.35 (m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30-3.20 (m, 1H), 2.90-2.67 (m, 3H), 2.55-2.48 (m, 1H), 2.15 (s, 1.7H), 2.10 (s, 1.3H).
Reaction SMILES: [C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2].[C:17]([O-])(=O)[CH2:18][CH2:19]NC(=O)[C@@H](C(CO)(C)C)O.F[C:33](F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.COC(OC)(C)C>[CH3:17][C:18]1([CH3:19])[O:7][CH:6]([C:5]([NH:4][CH2:3][CH2:2][C:1]([O:15][CH3:33])=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH2:11][O:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: COC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Reaction time: 8 h

Procedure:
A 5.0 g portion of calcium pantothenate was slurred in 100 ml of acetone:2,2-dimethoxypropane (1:1). Trifluoroacetic acid (3.0 ml) was added until solution was complete and stirring was continued overnight. A 10 g portion of potassium carbonate was added, this mixture stirred vigorously for 10 minutes and then concentrated to a gummy solid. A 100 ml portion of acetonitrile and 10 ml of methyl iodide were added to the solid. This mixture was stirred for 1 day, then poured into water and extracted twice with ethyl acetate. The extracts were combined, dried and concentrated, giving 4.8 g of the desired compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14]([C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17])#[N:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([C:16]([C:14]#[N:15])([CH3:17])[CH3:18])=[CH:27][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: CC(C)(C#N)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C#N)c1ccc(C(=O)NNc2cnc3ccc(Br)cc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
To a solution of 7-bromo-2-hydrazinylquinoxaline (1.5 g, 0.063 mol) and 4-(2-cyanopropan-2-yl) benzoic acid (1.1 g, 0.063 mol) in DMF (5 mL) was added HATU (2.4 g, 0.063 mol) and DIEA (1.2 g, 0.095 mol). The reaction mixture was then stirred at r.t. overnight. The solution was diluted with water (5 mL), and the solid was collected on a filter to give N′-(7-bromoquinoxalin-2-yl)-4-(2-cyanopropan-2-yl)benzohydrazide as a yellow solid (2.2 g, yield 85.0%). MS (m/z): 412 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(Br)ccc2[nH]ncc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)ccc2nn(C)cc12
Reaction time: 2.5 h
Yield: 72.2 %

Procedure:
To a solution of methyl 5-bromo-1H-indazole-4-carboxylate (4.50 g, 17.6 mmol) in ethyl acetate (176 mL) was added trimethyloxonium tetrafluoroborate (3.38 g, 22.9 mmol) at room temperature, and the mixture was stirred for 2.5 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70) to give the title compound (3.42 g, yield 73%).
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([CH:16]([CH3:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]#[N:27])C(=O)[O-])(C)C>C(Cl)Cl>[NH2:12][CH:16]([CH3:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:26]#[N:27]
Reactant: CC(COc1ccc(F)cc1C#N)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)COc1ccc(F)cc1C#N
Yield: 82 %

Procedure:
A solution of 1.0 mL trifluoroacetic acid and 1.2 g (4.08 mmol) of 1,1-dimethylethyl[2-(2-cyano-4-fluorophenoxy)-1-methylethyl]carbamate in 10 mL methylene chloride was stirred at ambient temperature for 3 days. Solvent was removed and the residue was taken up in aqueous Na2CO3 and ethyl acetate. The organic layer was separated and washed with water and brine. Drying (MgSO4) and removal of solvent gave 650 mg of 2-(2-aminopropoxy)-5-fluorobenzonitrile as an oil.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17].[I:18]N1C(=O)CCC1=O>>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([I:18])=[CH:12][C:11]=1[F:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: Fc1cc(I)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
Trifluoromethanesulfonic acid (9.9 mL, 110 mmol) was added to 2-chloro-1,4-difluorobenzene (2.2 g, 15 mmol) at room temperature and then cooled to 0° C. N-Iodosuccinimide (3.16 g, 14.1 mmol) was then added in multiple portions. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured over ice-water and extracted with hexane. The organic layer was washed with saturated Na2SO4, dried and concentrated. The crude product was purified by silica gel chromatography (100% hexanes) to give 1-chloro-2,5-difluoro-4-iodobenzene (3.0 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J=5.4, 7.8, 1H), 7.17-7.08 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]([S:8][CH2:9][C@@H:10]2[O:14][CH2:13][C@@H:12]([S:15]C(=O)C)[CH2:11]2)[NH:6][C:5](=[O:19])[C:4](=[O:20])[NH:3]1.C[O-].[Na+].CO>O1CCCC1>[CH3:1][N:2]1[CH:7]([S:8][CH2:9][C@H:10]2[CH2:11][C@H:12]([SH:15])[CH2:13][O:14]2)[NH:6][C:5](=[O:19])[C:4](=[O:20])[NH:3]1
Reactant: CC(=O)S[C@@H]1CO[C@@H](CSC2NC(=O)C(=O)NN2C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1NC(=O)C(=O)NC1SC[C@H]1C[C@H](S)CO1
Yield: 47.7 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.357 g of product from Example 84, 281 microliter of 25% sodium methoxide/methyl alcohol and 500 microliter of tetrahydrofuran to give 0.148 g of the desired product.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]=[C:14]([CH:5]2[CH:6]([C:11]([OH:13])=[O:12])[CH:7]3[CH2:10][C:4]2([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]3)[OH:15])=[CH:18][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=Nc1ccc(O)cc1
Reaction time: 1 h

Procedure:
408 g of an isomeric mixture of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are heated with 238.26 g of 4-aminophenol to 200° C.; the pressure is lowered to 2.7 Pa and the mixture is held for 1 hour under these conditions. There are thus obtained 535 g of a red solid resin (87.7% of theory) having a glass transition temperature of 58° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Reactant: Nc1cncc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1Nc1cncc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-bromo-2-fluoro-3-nitrobenzene (5.69 g, 25.9 mmol) and 3-amino-5-fluoropyridine (2.6373 g, 23.53 mmol) in DMF (39.2 mL) was added potassium tert-butoxide (5.28 g, 47.1 mmol) and the solution was stirred under nitrogen at rt overnight. After 5 additional h, the mixture was poured into water (150 mL) and extracted with EtOAc (2×100 mL). The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to provide the crude material as a orange solid. The orange solid was purified by chromatography through a Redi-Sep™ pre-packed silica gel column (120 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(2-bromo-6-nitrophenyl)-5-fluoropyridin-3-amine as orange syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (1H, s), 8.09 (1H, dd, J=8.1, 1.5 Hz), 8.03 (1H, dd, J=8.2, 1.4 Hz), 7.97 (1H, d, J=2.5 Hz), 7.88 (1H, t, J=1.9 Hz), 7.44 (1H, t, J=8.1 Hz), 6.77 (1H, dt, J=11.2, 2.3 Hz); LC-MS (ESI) m/z 312.0 [M+H (79Br)]+ and 313.9 [M+H (81Br)]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[Cl:66])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[Cl:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[NH:59][CH:56]1[CH2:55][CH2:54][N:53]([C:51](=[O:52])[CH2:50][NH:49][C:13]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[NH:12][N:11]=2)=[O:15])[CH2:58][CH2:57]1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)[nH]n1
Reactant: NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccc(O)cc2)[nH]n1
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a stirred solution of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (0.1 g, 0.00049 mol) in DMF (5 mL) was added DIPEA (0.253 g, 0.00196 mol), HOBt (0.0827 g, 0.00061 mol) and EDCI.HCl (0.117 g, 0.00061 mol) at ambient temperature. After 5 minutes 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone dihydrochloride (0.164 g, 0.00054 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and recrystallized from ethyl acetate to afford 0.092 g (41%) of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 426.16 (M+1)+, 91.47%, 1H NMR (DMSO-d6): δ 13.5 (s, 1H), 9.7 (s, 1H), 8.0 (s, 1H), 7.58 (d, 2H), 7.1 (m, 2H), 6.8 (m, 4H), 6.56 (m, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.8 (m, 11H), 3.6 (m, 11H), 3.1 (m, 1H), 2.7 (m, 1H), 1.9 (m, 2H), 1.3 (m, 2H)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1.C(Cl)Cl.C(N)CN>[CH3:19][C:13]1[C:12]([C:9]2[C:8]3[N:7]=[CH:6][CH:5]=[N:4][C:3]=3[C:2]([C:20]#[N:21])=[CH:11][CH:10]=2)=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=1
Reactant: N#C[Cu]
Reactant: Cc1cnc(C)c(-c2ccc(Br)c3nccnc23)c1
Solvent: NCCN
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1cnc(C)c(-c2ccc(C#N)c3nccnc23)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
A mixture of 5-bromo-8-(2,5-dimethyl-pyridin-3-yl)-quinoxaline (Step 99.4) (189 mg, 0.60 mmol) and CuCN (70 mg, 0.78 mmol, 1.3 equiv) in NMP (2 mL) was stirred for 6 h at 160° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with DCM/10% aqueous solution of ethylenediamine (25 mL), extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 150 mg of the title compound as a yellow solid. Title compound: ESI-MS: 261.2 [M+H]+; tR=1.92 min (System 1); TLC: Rf=0.68 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][NH:20][C:21]([CH3:26])([C:23]([NH2:25])=[O:24])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]=O>>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]([CH3:26])([C:23]([NH2:25])=[O:24])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)(C)C(N)=O
Reactant: C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C(C)(C)C(N)=O
Yield: 76 %

Procedure:
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-2-methylalaninamide (Example 97) was coupled with aqueous formaldehyde using an analogous method to that described for the equivalent step in Example 96 to give the title product as a white solid, (0.078 g, 76%); 1H NMR Spectrum: (DMSO-d6) 1.24 (s, 3H), 2.14 (s, 3H), 3.55 (s, 2H), 3.95 (s, 3H), 7.11 (m, 1H), 7.21 (s, 1H), 7.30 (t, 1H), 7.37 (m, 1H), 7.52-7.58 (m, 2H), 8.44 (m, 2H), 9.76 (s, 1H); Mass Spectrum: (M+H)+ 432.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH:17][CH3:18])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1.[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[O:27][CH2:28][C:29](O)=[O:30])=[O:23].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])[CH2:28][O:27][C:26]3[CH:25]=[C:24]([CH:34]=[CH:33][CH:32]=3)[C:22]([O:21][CH3:20])=[O:23])=[C:12]([NH:17][CH3:18])[CH:11]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Reactant: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1N
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1cc(Oc2cc(C)nc(OC)c2)ccc1NC(=O)COc1cccc(C(=O)OC)c1
Yield: 61.9 %

Procedure:
The reaction and post-treatment were carried out according to Example (16e) using 4-[(2-methoxy-6-methylpyridin-4-yl)oxy]-N2-methylbenzene-1,2-diamine produced in Example (17c) (4.13 g, 15.9 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid produced in Example (1c) (3.68 g, 17.5 mmol), triethylamine (4.44 mL, 31.8 mmol), pivaloyl chloride (1.96 mL, 15.9 mmol) and dichloromethane (80 mL) to obtain the title compound (4.44 g, 64%) as a white powder.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1)[CH2:2][CH2:3]C.N=C(CC)C(OCC)=O>CO>[CH2:1]([C:5]1[NH:9][N:8]=[C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCCc1nc(CNC(=O)OC(C)(C)C)n[nH]1
Agent: CCOC(=O)C(=N)CC
Solvent: CO
Product: CCCc1nc(CNC(=O)OC(C)(C)C)n[nH]1

Procedure:
Under nitrogen, a solution of 18.9 g (100 mmol) of N-Boc glycine hydrazide (from step 2 of Example 3) in 100 mL of methanol is treated with 11.5 g (100 mmol) of ethyl iminobutyrate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)]. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-propyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
To a solution of 1-diphenylmethylazetidin-3-ol (see Preparation 10) (65.9 g, 275.7 mmol) in dry dichioromethane (700 ml) at 0° C. under nitrogen was added triethylamine (57 ml, 1.2 mol. equiv.). After five minutes, methanesulphonyl chloride (25.6 ml, 1.5 mol. equiv.) was added and the mixture stirred for one hour. Water (300 ml) was then added and the mixture extracted with dichloromethane (3×300 ml). The combined organic layers were dried over magnesium sulphate. The solution was then filtered and the solvent removed from the filtrate under reduced pressure. The residue was chromatographed using silica gel eluting with methanol:dichloromethane (1:49, by volume) to give the title compound (73.4 g) as a solid.