Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH2:13][CH:14]=O)[CH2:9]1)=[O:7].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:30].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CC=O)(c3ccccn3)C2)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccn4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 6 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-oxoethyl)pyrrolidine and (0.24 mmol), (1-(2-ethyloxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.28 mmol), and 3 Å molecular sieves (about 12 g) in methanol (5 mL). After 6 hours, add sodium cyanoborohydride (0.15 g, 2.4 mmol) and stir under an inert atmosphere. After 18 hours, add a solution of 2 M sodium hydroxide and dichloromethane. After 1 hour, filter, separate the layers in the filtrate, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cccc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncccc1-c1ccccc1
Yield: 17 %

Procedure:
Using the procedure given above in Example 1, 3-methyl-2(1H)-pyridone (VIII) was refluxed in phosphorus oxychloride followed by work-up to give a 17% yield of 2-chloro-3-methylpyridine (VI).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6](O)=O)[CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][NH:43][C:44]1[C:45]([NH2:50])=[CH:46][CH:47]=[CH:48][CH:49]=1>C1COCC1>[CH3:42][N:43]1[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[N:50]=[C:6]1[CH:4]1[CH2:5][C:2](=[O:1])[CH2:3]1
Reactant: CNc1ccccc1N
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1c(C2CC(=O)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-oxocyclobutanecarboxylic acid (0.5 g, 4.4 mmol) and DIPEA (2.2 mL, 13.2 mmol) in dry THF (10 mL) under N2 was added HATU (2.0 g, 5.3 mmol) and N′-methylbenzene-1,2-diamine (0.8 g, 6.6 mmol) in one portion. The reaction mixture was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. AcOH (5 mL) was added and the mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was partitioned between EtOAc and a 5% NaHCO3 aqueous solution. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (eluent: 1/1, Pet ether/EtOAc) to give Intermediate 1 as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.75-7.58 (m, 1H), 7.35-7.09 (m, 3H), 3.86-3.61 (m, 4H), 3.60-3.35 (m, 1H), 2.74 (s, 3H). MS: m/z=200.1 (M+).
Reaction SMILES: [N+]([C:4]1[C:5](=O)[N:6](C)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.N.[CH3:16][N:17]1[CH2:22]C[C:20](=O)[C:19](C)([CH3:24])[CH2:18]1>CO>[N+:10]([C:8]1[CH:7]=[N:6][C:5]2[C:19]([CH3:24])([CH3:20])[CH2:18][N:17]([CH3:22])[CH2:16][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CN1CCC(=O)C(C)(C)C1
Agent: N
Solvent: CO
Product: CN1Cc2cc([N+](=O)[O-])cnc2C(C)(C)C1
Temperature: 70 °C

Procedure:
3,5-Dinitro-1-methylpyridin-2-one [prepared by the method of E. Matsumura, M. Ariga and Y. Tohda. Bull. Chem. Soc. Japan, 1979, 52, 2413-2419] (2 g; 10 mmol) was suspended in MeOH (50 ml) and treated with 0.88 aq, ammonia (10 ml; 157 mmol). 1,3,3-Trimethylpiperidin-4-one (1.7 g; 12 mmol) was added and the mixture heated at 70° C. for 5 h. The mixture was cooled to room temperature then evaporated to dryness in vacuo. The residue was digested with dichloromethane (2×50 ml) and the hot solution decanted from the red gum. The extracts were combined, evaporated to dryness in vacuo and the residue purified by chromatography on SiO2, with 50% ethyl acetate: 60-80° C. petroleum to give the title compound as a yellow oil, which solidified on standing (1.05 g; 48%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:9]=[N:8][N:7]([CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[C:6]=2[CH2:4][OH:3])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nnn1C[Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)Cn1nnc(-c2ccc(F)cc2)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 5-(4-fluoro-phenyl)-3-trimethylsilanylmethyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (880 mg, 2.74 mmol) in dry THF (8.2 mL) was added portionwise lithiumaluminiumhydride (119 mg, 3.15 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 1 h. Then water (119 μL) and NaOH (15%, 119 μL) was added followed by water (357 μL). The precipitate was then filtered off and the filtrate evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (649 mg, 85%) as a white solid. MS: m/e=280.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[NH:12][C:11]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:10]1[C:35]([O:37][CH3:38])=[O:36].C(N(CC)C(C)C)(C)C.[F:48][C:49]([F:60])([F:59])[CH2:50]OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][CH2:50][C:49]([F:60])([F:59])[F:48])[NH:12][C:11]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:10]1[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2[N+](=O)[O-])N1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2NCC(F)(F)F)N1
Temperature: 130 °C

Procedure:
To a stirred solution of dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-nitrophenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate (example 10, 1.56 g/2.92 mmol) and N,N-diisopropylethylamine (3.78 g/29.2 mmol) in toluene (50 ml) was added trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (6.78 g/29.2 mmol) at room temperature. The reaction mixture was refluxed at 130° C. for 1 day. The reaction was quenched with water and the separated organic layer was washed with sat.NaHCO3 and brine, dried over MgSO4, filtered and concentrated to afford a crude mixture. This crude was purified by column chromatography on silica gel (Hexane:EtC,Ac=2:1) to afford a pale yellow oil (1.34 g/75%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9](=[O:12])[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C(O)(C)C>[CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@H:9]([OH:12])[CH2:10][Cl:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
25.57 g of methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate were added portionwise at 22° C. to a suspension of 21.44 g of aluminum isopropoxide in 260 ml of isopropanol. The suspension was stirred at 50° C./400 mbar for 2 hours, hydrolyzed at 0° C. with 100 ml of 3N hydrochloric acid, subsequently concentrated to a volume of 125 ml, diluted with 125 ml of water, cooled to 0° C. and filtered. The residue was washed with water/isopropanol (4:1) and dried, there being obtained 13.01 g (89%) of isomerically-pure methyl (1S,2S)-(1-benzyl-3-chloro 2-hydroxy-propyl)-carbamate, m.p. 162°-163.5° C. IR (KBr): 3323s, br. (NH, OH), 1689 (C=O), 1546s (amide II).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]C)[C:5]([C:10](=[O:23])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:24]>Cl>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:10](=[O:23])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:24]
Reactant: CCCCN1CCC(CCC(=O)c2cc(Cl)c(N)nc2OC)CC1
Agent: Cl
Product: CCCCN1CCC(CCC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1
Temperature: 25 °C
Yield: 12.5 %

Procedure:
A mixture of 1-[6-amino-5-chloro-2-(methyloxy)-3-pyridinyl]-3-(1-butyl-4-piperidinyl)-1-propanone (step 1 in example 10, 50 mg, 0.129 mmol) in 10% methanolic hydrochloric acid (2 ml) was refluxed for 1 h. The mixture was added concentrated hydrochloric acid (0.6 ml) and the resulting mixture was refluxed for 6 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate (150 ml) and tetrahydrofuran (150 ml), washed with 2 N aqueous sodium hydroxide (10 ml), water (20 ml) and brine (20 ml), and dried over potassium carbonate. Removal of solvent gave a pale red solid, which was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (0.2:1:10 ) to afford a pale yellow solid. The solid was washed with ethyl acetate to yield 5.5 mg (13%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(C)C=CC=C[CH:14]=1.C([Sn](CCCC)(CCCC)C=C)CCC>C(OCC)C.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]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Product: C=Cc1cc(C(=O)OC)cc(Cl)n1
Yield: 70 %

Procedure:
Add methyl 2,6-dichloroisonicotinate (3.8 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium (0) (1.15 g, 0.99 mmol), triphenyhlphosphine (524 mg, 2 mmol) and toluene (40 mL) in a previously nitrogen-filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(vinyl)tin (6.98 mL, 24.0 mmol) under nitrogen and heat the sealed mixture at 95° C. overnight with vigorous stirring. Cool the reaction to room temperature, dilute with diethyl ether and filter through a filtering agent. Wash the organic filtrate with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (70%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=2)=[CH:9][CH:8]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>O>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[N:14]=2)=[CH:9][CH:8]=1
Reactant: O=C(CCl)OCc1ccccc1
Reactant: CN(C)CCCOc1ccc(-c2n[nH]c3ncccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCOc1ccc(-c2nn(CC(=O)OCc3ccccc3)c3ncccc23)cc1
Reaction time: 4 h

Procedure:
To a suspension of 9 g of 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine, 30 ml of dimethylformamide and 6.2 g of potassium carbonate was added dropwise 6.6 g of benzyl chloroacetate at 50° C. over the period of 2 hours. The mixture was kept at the same temperature for 4 hours. After the completion of the reaction, the reaction mixture was cooled. Water was added thereto, and the mixture was extracted with toluene. The extract was washed with water. After toluene was distilled off, diisopropyl ether was added to the residue for crystallization. The resulting crystals were recrystallized from diisopropyl ether - ethyl acetate to give benzyl 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetate, m.p. 90°-92° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCCCC/C=C\CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC/C=C\CCCOc1ccccc1C(=O)OC
Yield: 90 %

Procedure:
88 mg of 28 (578 μmol) and 77 mg of K2CO3 (557 μmol) are added to 140 mg of 13 (500 μmol) in anhydrous DMF (2 mL). After reaction for 8 hours at 90° C., the reaction medium is concentrated, taken up in DCM and then washed with water. 137 mg of a yellow oil are obtained, and are chromatographed on silica gel in pentane/ethyl acetate (40/1). 100 mg of a yellow oil are isolated, i.e. a yield of 66%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.[NH2:12][C@@H:13]([CH3:37])[C:14]([NH:16][C@@H:17]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>ClCCl.O>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:12][C@@H:13]([CH3:37])[C:14]([NH:16][C@@H:17]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:15])=[O:11])[CH2:6][CH2:7]1
Reactant: O=C(O)CN1CCC(O)CC1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](C)N)C(=O)OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCC(O)CC2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2-(4-hydroxypiperidin-1-yl)acetic acid (0.41 g, 2.6 mmol) and (S)-benzyl 2-((S)-2-aminopropanamido)-3-(4-methoxyphenyl)propanoate (HCl salt, 0.93 g, 2.6 mmol) in dichloromethane (30 mL) at 0° C. was added HATU (1.1 g, 2.9 mmol) followed by N-methylmorpholine (1.05 g, 10.4 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (30 mL) was added and the resulting mixture was extracted with dichloromethane (30 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/dichloromethane=5:1 to 1:1) to afford (S)-benzyl 2-((S)-2-(2-(4-hydroxypiperidin-1-yl)acetamido)propanamido)-3-(4-methoxyphenyl)propanoate (1.1 g, 87% yield) as a colorless solid.
Reaction SMILES: FC(F)(F)S(O[CH:7]([CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:8]([F:10])[F:9])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.O>[N:25]([CH:7]([CH:8]([F:10])[F:9])[CH2:11][NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NCC(OS(=O)(=O)C(F)(F)F)C(F)F)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CNC(=O)OCc1ccccc1)C(F)F
Reaction time: 3 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-1,1-difluoropropan-2-yl trifluoromethanesulfonate (580 g, 1.54 mol) in DMF (3000 mL) was added sodium azide (240 g, 3.69 mol). After 3 hours, the reaction mixture was diluted with water (3000 mL) and extracted with diethyl ether (3×1500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford benzyl (2-azido-3,3-difluoropropyl)carbamate. The material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Cl[C:16]1[N:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1>>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:21][CH:20]=1)[CH3:23]
Reactant: CCc1cnc(Cl)nc1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: CCc1cnc(C#Cc2c(-c3ccccc3)noc2C)nc1
Yield: 28 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloro-5-ethylpyrimidine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 40 mg, 28%) which was obtained as a brown oil. MS: m/e=290.1 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCC.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N+:36]([C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH:41]=[O:42])([O-:38])=[O:37]>O1CCCC1>[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]([CH:41]([OH:42])[C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[N+:36]([O-:38])=[O:37])[C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C1CCN(Cc2ccccc2)CC1)C(O)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Diisopropylamine (24.87 mmoles; 3.50 mL) was dissolved in tetrahydrofuran (30.00 mL). Mixture was cooled to −78° C. 2.5 M butyllithium in pentane (24.50 mmoles; 9.80 mL) was added to the mixture drop-wise. Reaction was stirred at −78° C. for 15 minutes. A solution of methyl 2-(1-benzylpiperidin-4-yl)acetate (22.24 mmoles; 5.50 g) in 8 mL THF was then added to the mixture dropwise over 20 minutes. Reaction stirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde (24.48 mmoles; 3.70 g) in 5 mL THF was then added to the mixture dropwise over 15 minutes. Reaction was stirred at −78° C. for 30 minutes. Reaction was quenched with saturated aqueous ammonium chloride. Mixture was warmed to room temperature. Extracted from the mixture 2× EtOAc. Combined organics were dried (magnesium sulfate), filtered, then concentrated. Silica gel chromatography afforded the desired product in 89% yield as light yellow foam. MS m/e (M+H)+=399.3.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1Cl>CO.O>[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1[S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
71.6 g (0.58 mol) of benzyl mercaptan are dissolved in 2.9 l of methanol/water (8:2), and 79.8 g (0.58 mol) of potassium carbonate are added. At 0°-5° C., 170 g (0.58 mol) of 5-bromo-2-chloro-3-nitrobenzoic acid methyl ester are added in portions over a period of 2.5 hours with stirring. Stirring is then continued for a further 2 hours and the internal temperature is then raised to 20° C. The resulting precipitate is then isolated by filtration, washed with a small amount of water and subsequently with 500 ml of methanol/water. After drying, 208 g (94%) of pale yellow product are obtained. Recrystallisation from 400 ml of methanol gives 190 g (86% of the theoretical yield) of product having a melting point of 65°-66° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][OH:12])[CH:7]=[CH:8][C:9]=1[F:10].Cl[C:14]1[CH:15]=[C:16]2[N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:11][O:12][C:14]1[CH:15]=[C:16]2[NH:23][CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E65 using sodium hydride (44.2 mg, 1.104 mmol) in THF (5 mL), (3,4-difluorophenyl)methanol (106 mg, 0.736 mmol) and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (100 mg, 0.368 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([N+:12]([O-])=[O:13])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[Al]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[N:12][OH:13])[CH3:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=C(C)[N+](=O)[O-])cc1
Agent: [Al]
Solvent: C1CCOC1
Product: CCc1ccc(CC(C)=NO)cc1

Procedure:
1-(4-Ethylphenyl)-2-nitroprop-1-ene (prepared in the manner described in Preparation 7), (13.6 g) in tetrahydrofuran was added to aluminium amalgam (prepared from aluminium foil (10.7 g) and mercuric chloride (7.3 g) in tetrahydrofuran and the reaction temperature kept to 35°. The reaction mixture was left for 1h at room temperature, filtered, the solvent dried (MgSO4) and evaporated to give 4-ethylphenylacetone oxime (10.2 g) as a brown oil. This was dissolved in methanol and heated under reflux with a solution of sodium metabisulphite (44 g) in water for 6h. Concentrated hydrochloric acid was added to the cooled solution and left at room temperature for 2h. Extraction with chloroform and distillisation gave 4-ethylphenyl acetone, 6.02 g, bp 45/1 mm.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[CH3:26][N:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:32]([C:30]5[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=5)=[O:33])[CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25]
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Reactant: Cn1cc(C(=O)O)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCN(C(=O)c5cnn(C)c5)C4)c3)ccc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (0.04 g, 0.111 mmol, example 60), 1-methyl-1H-pyrazole-4-carboxylic acid (0.021 g, 0.167 mmol) and Hunig's base (0.036 g, 0.278 mmol) in EtOAc (2 mL) was added propylphosphonic acid anhydride (cyclic trimer) solution (50% in EtOAc, 0.177 mL, 0.25 mmol) dropwise and the reaction mixture was stirred at room temperature over night. The mixture was diluted with EtOAc, poured into a sat. NaHCO3 solution (5 mL) and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give the title compound (0.036 g, 75.1%) as a colorless amorphous solid. MS: 432.4 (M+H+).