Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH2:20][OH:21])[CH:17]([CH3:19])[CH3:18].C(O)(=O)C.C([BH3-])#N>CO>[CH3:18][CH:17]([CH3:19])[C@@H:16]([NH:15][CH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1)[CH2:20][OH:21]
Reactant: O=Cc1cccc(-c2ccccc2)n1
Reactant: CC(C)[C@@H](N)CO
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccccc2)n1
Reaction time: 0.08 h
Yield: 58.4 %

Procedure:
To a solution of 6-phenylpicolinaldehyde (Tetrahedron Lett. 2010, 51, 5621-5623; 0.391 g, 2.133 mmol) in methanol (4 mL) at ambient temperature was added D-valinol (0.22 mL, 1.9 mmol) followed by acetic acid (0.4 mL, 8 mmol). After 5 min, MP-cyanoborohydride (2.5 mmol/g, 500 mg) was added and stirring continued overnight. The mixture was filtered and the filtrate partitioned between 1N NaOH and CH2Cl2. The organic phase extracted with 1N aqueous HCl. The organic layer was discarded and the aqueous phase was made basic with 1N NaOH and extracted with EtOAc. The organic extract dried, filtered and concentrated to provide 300 mg (57%) of the title compound. MS (DCI30 ) m/z 271 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.04-7.93 (m, 2H), 7.73 (t, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.53-7.35 (m, 3H), 7.21 (d, J=7.5 Hz, 1H), 4.06 (s, 2H), 3.72 (dd, J=11.0, 4.0 Hz, 1H), 3.52 (dd, J=11.0, 6.9 Hz, 1H), 2.55 (td, J=6.7, 4.0 Hz, 1H), 1.91 (td, J=13.6, 6.8 Hz, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C>O>[Cl:1][C:2]1[N:9]=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(F)cnc1Cl
Yield: 51.2 %

Procedure:
Into a 50 mL round bottomed flask, 2,6-dichloro-5-fluoronicotinonitrile (1 g), acetic acid (5 mL) and water (0.5 mL) were charged, and reacted and post-treated in the same manner as in Example 1 and then purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to obtain the title compound (420 mg, yield: 52%). As a result of the HPLC analysis, the purity was 100%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@H:4]1[F:36].[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[C@H:4]([F:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@H](F)C1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@H]1F

Procedure:
Starting from N-[(1S*,3R*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f72) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Br[CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[O:12][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]([OH:6])[C:4]=2[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)c(O)c1Cl
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2c(ccc(OC)c2Cl)C1O
Yield: 79.6 %

Procedure:
To a solution of (14h) (69.91 g., 0.375 mol) and diethyl bromomalonate (79.9 ml., 0.468 mol) in 2-butanone (400 ml.) was added freshly powdered anhydrous potassium carbonate (51.78 g.). The suspension was stirred vigorously and heated at reflux for 4.5 hours, then filtered and evaporated to dryness. The oil obtained was redissolved in carbon tetrachloride and filtered, then evaporated and recrystallized from chloroform with hexane to yield 79.6% of (15h), m.p. 115.5°-117° C. Analysis (C15H17ClO7) C,H.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[CH2:5]([CH:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C=O.C(O)(=O)C>C(#N)C>[CH3:1][N:14]1[CH2:15][CH2:16][CH2:17][CH:13]1[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [BH3-]C#N
Reactant: c1ccc(CCC2CCCN2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCCC1CCc1ccccc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Sodium cyanoborohydride (17.4 mg, 0.27 mmol) was added portion-wise to a stirred solution of 2-phenethyl pyrrolidine (30 mg, 0.17 mmol) and 37% aqueous formaldehyde (0.07 mL, 0.87 mmol) in 1.5 mL acetonitrile at 25° C. The mixture was stirred for 15 min, acetic acid was added dropwise until the reaction was neutral, and the mixture was stirred for an additional 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 10 mL diethyl ether and the ethereal solution was washed with 10 mL of saturated Na2CO3 and extracted twice with 5 mL of 1N HCl. The combined HCl solutions were then basicified with saturated Na2CO3 to obtain a pH=10 and extracted three times with 10 mL dichloromethane. The combined dichloromethane layers were washed with 10 mL of saturated NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on thin layer chromatography to give 1-methyl-2-phenethyl pyrrolidine free base; 18 mg, 55% yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([NH2:22])[CH:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[CH3:23][O:24][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([NH2:22])[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N)nc(C#Cc2ccccc2)c1-c1cncnc1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-6-(2-phenylethynyl)-5-pyrimidin-5-ylpyridin-2-amine C3c (400 mg, 1.3 mmol), sodium methoxide (a solution of 2.61 mmol in 0.29 ml MeOH) and MeOH (2 ml) is stirred for 20 minutes at 100° C. and 10 minutes at 110° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over Na2SO4, concentrated in vacuo and the product purified by NP chromatography. Yield: 228 mg (58%). HPLC-MS: M+H=303.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH2:24])=[O:23]>>[C:22]([CH2:21][C:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:26])[CH3:25])(=[O:23])[NH2:24]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CC(N)=O
Agent: Cl
Product: CC(C)(CC(N)=O)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 3-amino-3-methyl-butanamide hydrochloride (1:1) (CAN 173336-86-2, 35.8 mg, 0.235 mmol) as starting materials and isolated (56 mg, 79%) as light yellow solid; LC-MS (UV peak area, ESI) 100%, 333.1926 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:18])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[N:19]([O-])=[O:20].[Na+]>C(O)(=O)C.O>[OH:20][N:19]=[C:4]([C:3]([CH2:2][Cl:1])=[O:18])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(CCl)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)C(=NO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
In 100 ml of acetic acid is dissolved 50 g (0.184 mol, uncorrected for purity) of the crude p-nitrobenzyl γ-chloroacetoacetate obtained in 1), and the solution is cooled to 5° C. or lower, and a solution of 12.7 g (0.184 mol) of sodium nitrite in 50 ml of water is added dropwise thereto at 5° C. or lower over a period of an hour. After completion of the addition, the mixture is stirred for 30 minutes and poured into 600 ml of ice water and extracted with 300-ml and 200-ml portions of ethyl acetate. The organic layers are combined and washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to dryness to give 54.0 g of p-nitrobenzyl α-hydroxyimino-γ-chloroacetoacetate as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:26][NH:25][C:23](=[O:24])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[CH:8]=[C:3]([CH2:2][O:1][S:35]([CH3:34])(=[O:37])=[O:36])[N:4]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)Nc1ccc(-c2nc(CO)cc(N3CCOC[C@@H]3C)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2nc(COS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methyl-urea (1.24 g) was partially dissolved in DCM (30 mL) and triethylamine (0.724 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.405 mL) and the reaction was stirred for 15 minutes at RT then concentrated in vacuo to give the desired material.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=4[O:37][CH3:38])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:39])[N:15]=1)=[O:13])[CH3:2].[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:24]2[N:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]4[C:14]([C:12]([NH:11][C:4]5[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=5[CH2:1][CH3:2])=[O:13])=[N:15][N:16]([CH3:39])[C:17]=4[C:26]=3[N:25]=2)=[C:29]([O:37][CH3:38])[CH:30]=1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc([N+](=O)[O-])cc3OC)nc1-2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(N)cc3OC)nc1-2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(2,6-diethylphenyl)-8-[(2-methoxy-4-nitrophenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (1.4 g, 2.656 mmol) in 27 ml of dioxane, zinc (695 mg, 10.624 mmol) and ammonium chloride (1.4 g, 26.56 mmol) in 2.7 ml of water were added and heated at 100° C. under stirring for 8 h. The mixture was cooled, the insoluble material filtered off and washed with ethyl acetate, the combined organic solutions are washed with aqueous citric acid solution, dried on Na2SO4 and evaporated in vacuo leaving a pink foam as crude title product that has been used without any further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[S:22][CH:21]=[N:20][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH2:3][CH2:2]1.N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C>[Si:32]([O:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:8]3[S:22][CH:21]=[N:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1)([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(-c2nc(N3CCOCC3)c3scnc3n2)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2nc(N3CCOCC3)c3scnc3n2)c1
Temperature: 70 °C

Procedure:
3-(7-morpholinothiazolo[4,5-d]pyrimidin-5-yl)phenol (1.0 eq.) was dissolved in DMF (5 ml). To this imidazole (8.0 eq.) and TBDMSCl (3.5 eq.) were added and the mixture was heated at 70° C. for 5 h. DMF was evaporated under reduced pressure and purification by flash chromatography (hexane:ethyl acetate, gradient from 100%-50% hexane in EtOAc) yielded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:36]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:35])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:34])[C:20]=2[C:21]2[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH:26]=2)[N:13]=1.Cl>CO.O1CCOCC1>[NH2:36][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:34])[C:20]=1[C:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=1)=[O:35]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1=CCNCC1

Procedure:
tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.10 g, 0.16 mmol) was dissolved in MeOH (3 mL) and HCl in 1,4-dioxane (4.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:34](=[CH:35][CH:36]=1)[C:12]1[N:13](COCC[Si](C)(C)C)[C:14]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([CH2:37][C:38]([OH:41])([CH3:40])[CH3:39])=[CH:6][C:5]2=1>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:34](=[CH:35][CH:36]=1)[C:12]1[NH:13][C:14]([C:16]3[C:17]([C:18]#[N:19])=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]#[N:25])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([CH2:37][C:38]([OH:41])([CH3:39])[CH3:40])=[CH:6][C:5]2=1
Reactant: CC(C)(O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1[nH]c(-c3c(C#N)cccc3C#N)nc21
Yield: 33.2 %

Procedure:
2-(9-chloro-6-(2-hydroxy-2-methylpropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (1.94 g) from Step 3 above was dissolved in TBAF (1 M in THF, 20 mL). The mixture was heated at reflux for 5 h and then quenched with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography on silica (50% ethyl acetate in hexanes) to provide 2-[9-chloro-6-(2-hydroxy-2-methylpropyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile (500 mg) as a yellow solid. 1H NMR δ (ppm) (400 MHz, Acetone-d6): 13.13 (1H, bs), 8.87 (1H, s), 8.77 (1H, s), 8.58 (1H, m), 8.43 (1H, m), 8.35 (2H, d, J=7.9 Hz), 7.99 (1H, t, J=7.9 Hz), 7.73 (2H, dd, J=1.9, 8.6 Hz), 3.51 (1H, bs), 3.08 (2H, s), 1.26 (6H, s).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:13]([C@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Di-isopropylazodicarboxylate (5.7 mL, 29.38 mmol) was added to an ice-cooled solution of (R)-(−)-N-boc-3-pyrrolidinol (5 g, 26.71 mmol), phenol (2.51 g, 26.71 mmol) and triphenyl phosphine (7.71 g, 29.38 mmol) in tetrahydrofuran (70 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was twice triturated with diethyl ether and filtered. The filtrate was washed with 1N sodium hydroxide solution (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 90:10 to 83:17, afforded the title compound as a colourless oil in 75% yield, 5.27 g.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[CH3:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(-c2ccccc2)c1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2ccccc2)c1NC(N)=S

Procedure:
A mixture of N-benzoyl-N'-(3-methyl-2-biphenylyl)-thiourea (16.2 g), sodium hydroxide (2 g) and ethanol was heated under reflux for two hours to give N-(3-methyl-2-biphenylyl)thiourea as a foamy solid.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:7]([C:12]([OH:14])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:43][NH:44][O:45][CH3:46]>CN(C=O)C>[CH3:46][O:45][N:44]([CH3:43])[C:12]([C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:4][CH:3]=[C:2]([CH3:1])[N:11]=2)=[O:14]
Reactant: CNOC
Reactant: Cc1ccc(Sc2ccccc2)c(Nc2c(C(=O)O)cnc3nc(C)ccc23)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnc2nc(C)ccc2c1Nc1cc(C)ccc1Sc1ccccc1
Reaction time: 24 h

Procedure:
The product from Example 11a (50.5 mg, 0.125 mmol) was reacted with 1,1′-carbonyldiimidazole (40.8 mg, 0.215 mmol) in 2 mL of DMF under an atmosphere of N2 for 30 min. Added N,O-dimethylhydroxylamine hydrochloride (25 mg, 0.215 mmol) and stirred ate room temperature for 24 h. The solvent was concentrated under vacuum giving the title compound. After purification of the crude product by HPLC with AA the product was isolated as the free base (12 mg, 21%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.23 (s, 3H) 2.67 (s, 3H) 2.89 (s, 3H) 3.39 (s, 3H) 6.86 (s, 1H) 6.91-7.04 (m, 1H) 7.15-7.35 (m, 7H) 7.44 (d, J=8.46 Hz, 1H) 8.34 (d, J=8.09 Hz, 1H) 8.67 (s, 1H); MS (ESI+) m/z 445 (M+H)+, 467 (M+Na)+, MS (ESI−) m/z 443 (M−H)−.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[NH:8][C:7]([C:9]([O:11]C)=[O:10])=[C:6](/[CH:13]=[CH:14]/[O:15][CH3:16])[N:5]=1.Cl>O.O1CCCC1>[Br:3][C:4]1[NH:8][C:7]([C:9]([OH:11])=[O:10])=[C:6](/[CH:13]=[CH:14]/[O:15][CH3:16])[N:5]=1
Reactant: CO/C=C/c1nc(Br)[nH]c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C/c1nc(Br)[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2.20 g lithium hydroxide in 175 ml of water is added to a solution of 3.50 g methyl 2-bromo-5-(trans-2-methoxy-vinyl)-3H-imidazole-4-carboxylate in 140 ml of tetrahydrofuran. The solution is stirred for 4 h at ambient temperature. Then 92 ml aqueous 1 M hydrochloric acid are added, and the solution is cooled in the ice bath. The precipitate is separated off, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:33])CC>ClCCl>[F:33][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C)(O)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C)(F)CC3)c(F)c2)C(=O)O1
Yield: 66 %

Procedure:
The title compound was prepared by stirring (S)—N-{3-[4-(4-methyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.36 mmol) with DAST (1.64 mmol) in dichloromethane (10 ml) at a temperature 0° C. for half hour and by purifying the compound by silica gel column chromatography in 66% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1.[H-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:25]4[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Oc4ncccc4[N+](=O)[O-])cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
3-(N-t-Butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-5-hydroxy-1H-indole and 2-chloro-3-nitropyridine were used. Sodium hydride (60% in oil) was the base, tetrahydrofuran was the reaction solvent, the reaction was stirred at room temperature for 3 hours, and the chromatographic solvent system was diethyl ether/hexanes [gradient 1:1 to 4:1] to afford the title compound (62%) as a yellow solid: top, 206.0°-208.0° C. with effervescence; 1H NMR (DMSO-d6) δ8.53 (dd, J=1.8 and 8.3 Hz, 1H), 8.33 (dd, J=1.8 and 4.4 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.50 (br s, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.30 (dd, J=4.4 and 8.3 Hz, 1H), 6.94 (dd, J=2.0 and 8.6 Hz, 1H), 6.05-6.01 (m, 1H), 4.02-3.94 (m, 2H), 3.54 (br t, J=5.6 Hz, 2H), 2.54-2.45 (m, 2H), 1.42 (s, 9H); TLC [methylene chloride/hexanes, 1:1]: Rf =0.2; TLC [diethyl ether]: Rf 32 0.3.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[C:20]([CH:25]=O)=[N:21][CH:22]=[CH:23][CH:24]=1)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[C:20]([CH2:25][NH:11][CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C=O
Reactant: NC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccnc1CNC1CCCc2cccnc21

Procedure:
Using General Procedure B: Reaction of 5,6,7,8-tetrahydro-quinolin-8-ylamine in CH2Cl2 with (2-formyl-pyridin-3-yl)-carbamic acid tert-butyl ester and NaBH(OAc)3 gave {2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-pyridin-3-yl}-carbamic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.51 (s, 9H), 1.85-1.94 (m, 2H), 1.98-2.08 (m, 2H), 2.78-2.84 (m, 2H), 3.82-3.86 (m, 1H), 4.19 (s, 2H), 7.11-7.19 (m, 2H), 7.42 (d, 1H, J=7.1 Hz), 8.15-8.17 (m, 1H), 8.28 (d, 1H, J=8.0 Hz), 8.44 (d, 1H, J=3.0 Hz), 10.17 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:23]N>CCO>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[NH:23][N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Reactant: NN
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccn[nH]1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 350 mg, 1.09 mmol, 1 eq.) in EtOH (5 mL) was added hydrazine (140 mg, 4.36 mmol, 4 eq.). The mixture was heated at 80° C. for 2 h, cooled, concentrated, and purified on silica gel using EtOAc as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1H-pyrazol-5-yl)pyridine (282 mg, 90%) as a white solid. LRMS (M+H+) m/z 290.1