Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCOCC2)ccc1Br
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-3-methylbenzoic acid (5.00 g) in dry THF (60 ml) was added dropwise at -5° to +5° to 1,1'-carbonylbis[1H-imidazole](4.90 g) and stirred under nitrogen over 10 min. Stirring was continued at +23° for 4 h, and morpholine (6.1 ml) added dropwise over 1 min. After 16 h the solution was evaporated, treated with aqueous 2M hydrochloric acid (80 ml), and extracted with ethyl acetate (4×75 ml). The combined, dried organic extracts were washed with aqueous saturated sodium bicarbonate (100 ml), dried and evaporated. A solution of the residual oil in dichloromethane (60 ml) was adsorbed onto silica gel (Merck 7734) and the mixture applied as a plug to a flash column of silica gel (Merck 9385). Gradient elution with ethyl acetate:hexane (3:7→6:4) afforded the title compound as a cream solid (5.75 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:23]=[C:24]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([N:38]5[CH2:42][CH2:41][CH2:40][CH:39]5[CH3:43])[N:33]=4)[C:25]4[N:26]([CH:28]=[CH:29][N:30]=4)[N:27]=3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>ClCCl>[ClH:44].[CH3:43][CH:39]1[CH2:40][CH2:41][CH2:42][N:38]1[C:34]1[N:33]=[C:32]([NH:31][C:24]2[C:25]3[N:26]([CH:28]=[CH:29][N:30]=3)[N:27]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:17]=3)[CH:23]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)c3)nn3ccnc23)n1
Agent: Cl
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CNC4CCNCC4)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109 %

Procedure:
tert-Butyl-4-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzylamino)piperidine-1-carboxylate (35 mg, 0.06 mmol) was dissolved in HCl gas in dichloromethane (5 mL). The solution was stirred at room temperature for 2 h. The solvent was concentrated in vacuo to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-((piperidin-4-ylamino)methyl)phenyl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (35 mg, 109%) as a yellow solid. 1H NMR (300 MHz, DMSO+D2O): δ 9.18 (s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.99 (d, 1H, J=7.5 Hz), 7.80 (d, 1H, J=7.5 Hz), 7.68 (t, 1H, J=7.5 Hz), 7.53 (t, 1H, J=7.8 Hz), 6.60 (d, 1H, J=7.5 Hz), 6.19 (d, 1H, J=8.4 Hz), 4.28-4.21 (m, 3H), 3.53-3.38 (m, 5H), 2.95 (t, 2H, J=12.3 Hz), 2.31-2.28 (m, 2H), 2.07-1.68 (m, 6H), 1.06 (d, 3H, J=6.0 Hz). LC/MS: 486 [M+H]+, tR=0.85 min. HPLC: 100% at 214 nm, 99.89% at 254 nm, tR=4.58 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:5].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(O)(C)C>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]2=3)=[O:5])[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: O=C1Nc2ccccc2N(C(=O)CCCl)c2ccccc21
Solvent: CC(C)O
Product: O=C1Nc2ccccc2N(C(=O)CCN2CCOCC2)c2ccccc21

Procedure:
6.0 gm (0.02 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 10 gm (0.11 mol) of morpholine were refluxed in 200 ml of isopropanol for 2 hours. The solvent was distilled off, the residue was dissolved in methylene chloride, and the solution was washed with water. After distilling off the solvent, the residue was recrystallized from isopropanol.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:22]1([CH2:34][C:35]([NH2:37])=[O:36])[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1>>[C:22]1([C:34]2[C:35](=[O:36])[NH:37][C:3](=[O:2])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]4[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=4)=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2cc(-c3ccncc3)ccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(-c3ccncc3)ccc12

Procedure:
Beginning with (6-(pyridin-4-yl)indol-3-yl)oxoacetic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [OH:1][CH:2]([CH2:29][CH2:30][CH3:31])[C:3]#[C:4][C:5]1[C:6]([F:28])=[C:7]([F:27])[C:8]([F:26])=[C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:10]=1.[H][H]>[C].[Pd].C(O)C>[OH:1][CH:2]([CH2:29][CH2:30][CH3:31])[CH2:3][CH2:4][C:5]1[C:6]([F:28])=[C:7]([F:27])[C:8]([F:26])=[C:9]([C@H:11]2[CH2:12][CH2:13][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[CH:10]=1
Reactant: CCCC(O)C#Cc1cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)c(F)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC(O)CCc1cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)c(F)c(F)c1F
Reaction time: 8 h

Procedure:
To 20 g of 5-(3-hydroxy-1-hexynyl)-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl) cyclohexyl]benzene which was dissolved into 80 mL of ethanol, 2 g of 5% palladium carbon (50% in water) was added, stirred for 6 hours at a hydrogen pressure of 0.5 MPa, and was then left to stand overnight. After palladium carbon was removed by filtration, the solvent was evaporated under a reduced pressure to obtain 10 g of 5-(3-hydroxy-1-hexyl)-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>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.COCCOC>[Br:10][C:8]1[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#Cc1cc(Br)cc(-c2ccccc2)c1
Temperature: 95 °C

Procedure:
A mixture of 3,5-dibromobenzonitrile (0.58 g, 2.2 mmol), phenylboronic acid (0.24 g, 2.0 mmol), Pd(PPh3)4 (0.23 g, 0.1 mmol), K2CO3 (3 mL 2 M aqueous solution) and DME (3 mL) was degassed and heated to 95° C. for 12 hr under argon. The reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried (MgSO4) and concentrated to give the crude product which was purified with chromatography on silica gel (EtOAc/hexanes) to afford 5-bromobiphenyl-3-carbonitrile.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([CH3:28])=[N:17][N:18]([C:20]4[N:25]=[C:24](Br)[C:23]([CH3:27])=[CH:22][N:21]=4)[CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCOC(C)=O.[CH3:35][N:36](C=O)C>[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([CH3:28])=[N:17][N:18]([C:20]4[N:25]=[C:24]([C:35]#[N:36])[C:23]([CH3:27])=[CH:22][N:21]=4)[CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CN(C)C=O
Reactant: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C#N
Temperature: 25 °C

Procedure:
A solution of 1-(4-bromo-5-methyl-pyrimidin-2-yl)-3-methyl-1H-pyrazole-4-carboxylic acid (adamantan-1-ylmethyl)-amide (1.05 g, 2.4 mmol), zinc cyanide (328 mg, 2.8 mmol) and Pd(PPh3)4 (240 mg) in DMF (12 mL) is heated at 90° C. for 12 h. The mixture is cooled to RT and EtOAc and brine are added. The mixture is filtered through Celite, and the organic layer is separated, washed with brine, dried and evaporated. Purification by flash chromatography, eluting with a mixture of 5% MeOH and 1% TEA in DCM, affords the title compound. MS (M+1)=391.27; RT=1.34 min. *IC50.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:43][O:44][CH2:45][C:46]1[NH:47][CH:48]=[C:49]([OH:53])[C:50](=[O:52])[N:51]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH2:45][C:46]2[NH:47][CH:48]=[C:49]([OH:53])[C:50](=[O:52])[N:51]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(/C(=N/OCc2nc(=O)c(O)c[nH]2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 14 h
Yield: 104.6 %

Procedure:
(6R, 7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (125 mg) (0.2 mmol), 41 mg (0.26 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 50 mg (0.26 mmol) of p-toluenesulphonic acid hydrate are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 14 hours the mixture is concentrated in a high vacuum at room temperature and the residue is treated with water. The product is filtered off and washed in succession with water, ethanol and diethyl ether. There are obtained 160 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:15]1[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21]
Reactant: O=N[O-]
Reactant: c1ccc(-c2cn3cccnc3n2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c(-c2ccccc2)nc2ncccn12
Temperature: 5 °C
Yield: 65.3 %

Procedure:
A mixture of 20 g of 2-phenylimidazo(1,2-a)pyrimidine, 200 ml of glacial acetic acid and 20 ml of water is warmed with stirring until the solids are completely dissolved. The solution is next cooled to 5° C. in an ice/salt bath. A solution of 15 g of NaNO2 in 50 ml of water is added dropwise to the cooled acetic acid solution while the solution is kept between 0°-5° C. throughout the addition of NaNO2 solution and three hours thereafter. The reaction mixture is further stirred for 12 more hours at room temperature. The green precipitate is filtered and washed thoroughly with water on a glass filter. The residue is recrystallized once from 2-propanol to yield about 15 g of 3-nitroso-2-phenylimidazo(1,2-a)pyrimidine, m.p. 223°-225° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([CH:38]([F:40])[F:39])=[N:11][CH:12]=[C:13]([C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:30]=[CH:31][N:17]3[N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][CH:38]([F:39])[C:10]1[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][C:13]([C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3=[C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:30]=[CH:31][N:17]3[N:16]=2)=[CH:12][N:11]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cnc1C(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cnc1C(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
N-(tert-Butyl)-2-(difluoromethyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino) pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.520 g, 0.923 mmol) was dissolved in CH2Cl2 (4 mL). Then TFA (1.0 0 mL, 13.0 mmol) was added and stirred at RT for 16 h. The volatile components were removed under reduced pressure and the resulting residue was diluted with 10% NaHCO3 (25 mL). The reaction mixture was extracted with EtOAc (2×25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition B-96 as described in general methods) to afford 2-(difluoromethyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.140 g, 29.9%) as a pale yellow solid. LCMS Condition B-78: retention time 2.29 min, [M+1]=508.2. HPLC Condition B-31: retention time 8.65 min, purity 98.6%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.95 (d, J=4.8 Hz, 2H), 6.87 (d, J=2.8 Hz, 1H), 7.28-7.62 (m, 9H), 7.75-7.82 (m, 1H), 7.99 (d, J=2.4 Hz, 1H), 8.17 (s, 2H), 8.38-8.40 (m, 1H), 9.09 (d, J=1.6 Hz, 1H), 9.67 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][CH:12]([CH3:20])[C:13](=O)[C:14](OCC)=[O:15]>C(O)C(F)(F)F>[CH:12]([C:13]1[C:14](=[O:15])[O:10][CH2:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)([CH3:20])[CH3:11]
Reactant: CCOC(=O)C(=O)C(C)C
Reactant: N[C@@H](CO)c1ccccc1
Solvent: OCC(F)(F)F
Product: CC(C)C1=N[C@H](c2ccccc2)COC1=O
Yield: 35.6 %

Procedure:
(R)-2-phenylglycinol (4) (2.00 g, 14.6 mmol, 1.0 equiv.) and ethyl 3-methyl-2-oxobutyrate (2.20 mL, 14.6 mmol. 1.0 equiv.) were refluxed in trifluoroethanol (30 mL) over activated 4 molecular sieves (7.0 g) for 24 hours. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo generated the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (4:1) to furnish the title compound as a colourless oil (1.13 g, 36%); v(max)(film) 2965 (C—H), 1740 (C═O), 1638 (C═N) cm−1; δH (250 MHz, CDCl3) 7.45-7.32 (5H, m, Ph), 4.90-4.83 (1H, m, PhCH), 4.55 (1H, dd, J 4.4 Hz, T 11.5 Hz, 6β-H), 4.13 (1H, dd/10.9 Hz, T 11.4 Hz, 6α-H), 3.32 (1H, m, CH(CH3)2), 1.25 (3H, d, J 5.0 Hz, CH(CH3)2×3), 1.22 (3H, d, /5.0 Hz, CH(CH3)2×3); δc (62.5 MHz, CDCl3) 167.7, 155.7, 137.5, 129.3, 128.6, 127.4, 71.7, 59.7, 32.7, 20.7, 19.9: m/z (CL, NH3), 220 (100%), 218 (MH+, 17%), 217 (27%), and 216 (25%); HRMS for C13H16NO2 requires 218.1177 found 218.1181. [α]D20 −207.5 (c 1.17 CHCl3).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[C:14](=[O:15])[NH:13][C@H:12]1[C:16](OC)=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].OCC1CCN1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[N-:37]=[N+:38]=[N-:39].[Na+]>>[N:37]([CH2:16][C@H:12]1[C@@H:11]([NH:10][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[C:14](=[O:15])[NH:13]1)=[N+:38]=[N-:39]
Reactant: COC(=O)[C@@H]1NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: OCC1CCN1
Agent: [BH4-]
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CN=[N+]=[N-]

Procedure:
Sodium borohydride reduction of methyl cis-3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate as described in Preparation 3, followed by conversion of the 2-hydroxymethylazetidine product to the p-toluene-sulfonate derivative, mp 160°-162°(d), and reaction of the derivative with sodium azide as described in Preparation 4 gives the title compound.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[NH:2]2.[CH3:15][C:16]1[S:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:11][C:10]([F:12])([F:13])[C:9]([NH:8][CH2:7][C@@H:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[N:2]1[C:21]([C:19]1[N:20]=[C:16]([CH3:15])[S:17][C:18]=1[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)=[O:22])=[O:14]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (acidic): tR=0.99 min; [M+H]+=424.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([N+:19]([O-])=O)[C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.Cl>C1COCC1.CO.[Pd]>[NH2:19][C:11]1[C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]=1
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reaction time: 48 h

Procedure:
A mixture of methyl 5-[(4-fluorophenyl)methyl]-3-nitro-2-pyridinecarboxylate (200 g, 0.66 mol) and Degussa 10% Pd on carbon (50% by weight water, 20 g) in THF (1.5 L) was stirred under an atmosphere of H2 for 2 d. The mixture was filtered through celite and the filtrate was re-subjected to similar hydrogenation conditions with 10% Pd on carbon (30 g) at 45° C. for 7 d. During this time, conc. HCl (14 mL, 0.17 mol) in MeOH (75 mL) and 10% Pd on carbon (18 g) were added in approximately three portions each. The mixture was filtered through celite, concentrated at reduced pressure, reconstituted in CH2Cl2 and washed with saturated NaHCO3 solution. The organic phase was concentrated and the resulting material was triturated with EtOAc to provide the product as an off-white solid: 1H NMR (CDCl3) δ 7.94 (1H, d, J=1.5 Hz), 7.11 (2H, m), 6.98 (2H, m), 6.72 (1H, 1.5 Hz), 5.67 (2H, br s), 3.95 (3H, s), 3.89 (2H, s); ES+ MS: 261 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cc2Cl)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 4-(5-carboxy-3-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (a) above (1.1 g, 3.22 mmol) and K2CO3 (0.67 g, 4.83 mmol) in DMF (10 mL) was added dropwise MeI (0.3 mL, 4.83 mmol) with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 h, quenched with 20 mL of satd. aq. solution of NaHCO3 and extracted with EtOAc (50 mL). The organic extract was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (gradient 30% to 50% EtOAc in hexane) to give the title compound as white solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10](S(C)(=O)=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[CH:28][O:29][CH2:30][F:31])[C:24]([O:26][CH3:27])=[O:25].[H-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[N:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[CH:28][O:29][CH2:30][F:31])[C:24]([O:26][CH3:27])=[O:25])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)ns1
Reactant: COC(=O)C(=COCF)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=COCF)c1ccccc1Oc1nc(-c2ccccc2)ns1
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A solution of 3.2 g (0.005 mol) of 3-phenyl-5-methanesulphonyl-1,2,4-thiadiazole and 2.3 g of methyl 2-(2-hydroxyphenyl)-3-fluoromethoxy-acrylate in 10 ml of dry dimethylformamide is treated at 0° C. with 0.2 g (0.005 mol) of 80% strength sodium hydride in mineral oil. The mixture is stirred for 4 hours at this temperature, and for a further 18 hours without cooling, and then concentrated. The residue is taken up using ethyl acetate, the solution is washed with water, and the organic phase is dried over sodium sulphate and concentrated again. The crude product is chromatographed on silica gel using hexane/acetone (7:3). 1.3 g (67% of theory) of methyl 2-[2-(3-phenyl-1,2,4-thiadiazol-5-yloxy)-phenyl]-3-fluoromethoxy-acrylate are obtained as a yellow, highly viscous oil.
Reaction SMILES: CB1OB(C)OB(C)O1.[C:10](=O)([O-])[O-].[K+].[K+].Br[C:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=2)[N:19]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[N:18]=1.O>O1CCOCC1.Cl[Pd]Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:34][O:33][CH2:32][CH2:31][CH2:30][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=2)[C:17]([CH3:10])=[N:18]1
Reactant: O=C([O-])[O-]
Reactant: COCCCn1nc(Br)c2ccc(C(=O)OC)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Solvent: O
Product: COCCCn1nc(C)c2ccc(C(=O)OC)cc21
Temperature: 110 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
Trimethylboroxin (513 μL), potassium carbonate (1.27 g) and bis(diphenylphosphino)ferrocene dichloropalladium (224 mg) were added to a solution of methyl 3-bromo-1-(3-methoxypropyl)-1H-indazol-6-carboxylate (1.0 g) in 1,4-dioxane (15 ml) under argon atmosphere and the mixture was stirred at 110° C. for 6 hours. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=4/1 to 3/2) to give methyl 1-(3-methoxypropyl)-3-methyl-1H-indazol-6-carboxylate (705 mg) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[N:6]([C@H:13]3[O:25][C@@H:24]([CH2:26][O:27]C(=O)C)[C@H:19]([O:20]C(=O)C)[C@@H:14]3[O:15]C(=O)C)[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[N:6]([C@H:13]3[O:25][C@@H:24]([CH2:26][OH:27])[C@H:19]([OH:20])[C@@H:14]3[OH:15])[C:7]([NH:9][CH:10]([CH3:11])[CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 84 %

Procedure:
5,6-Dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (7.50 g, 14.93 mmol), sodium carbonate (1.72 g, 16.23 mmol), water (29 mL), methanol (100 mL) and ethanol (100 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 55:45 dichloromethanelmethanol to afford 4.72 g (84%) of a white foam. Analytical data were consistent with the assigned structure.