Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[CH:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:4]1[CH:3]=[C:2]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)[CH:7]=[CH:6][N:5]=1)([O-:22])=[O:21]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Into a 30-mL round bottom flask, was placed a solution of 4-fluoro-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridine (500 mg, 1.66 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), (3-(trifluoromethyl)benzylamine (581 mg, 3.32 mmol, 2.00 equiv), and potassium carbonate (985 mg, 7.14 mmol, 4.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of brine and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/hexane (1:1). The product was obtained as 500 mg (66%) of a yellow oil.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([CH:9]([C:11]2[N:12]=[C:13](OS(C(F)(F)F)(=O)=O)[C:14]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16][C:15]=3[N:28]=2)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC#N>[CH3:1][NH:2][C:13]1[C:14]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16][C:15]=2[N:28]=[C:11]([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:10])[N:12]=1
Reactant: CC(c1ccccc1)c1nc2c(c(OS(=O)(=O)C(F)(F)F)n1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN
Solvent: CC#N
Product: CNc1nc(C(C)c2ccccc2)nc2c1CCN(C(=O)OC(C)(C)C)CC2
Yield: 90 %

Procedure:
A solution of methylamine (2.0M, 0.65 mL, 1.30 mmol) was added to a solution of Tert-butyl 2-(1-phenylethyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate of preparation 2, step B (130 mg, 0.26 mmol) in MeCN (4.0 mL) at room temperature with stirring. The mixture was stirred at room temperature for 20 h. The solvent was evaporated in vacuo to provide the crude title compound as a yellow gum. The crude material was purified by flash column chromatography eluting with CH2Cl2:ethyl acetate (100:0 to 50:50) to yield the desired product as a white crystalline solid (89 mg, 90% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO.O>[OH:5][C:4]1[CH:3]=[N:2][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=2[N:6]=1
Reactant: O=C1CCCCC1=O
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1cnc2c(n1)CCCC2
Temperature: -30 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
11.05 g (0.1 mol) of glycinamide hydrochloride was dissolved in 200 ml of methanol. To the resultant solution was added a solution of 13.44 g (0.12 mol) of cyclohexane-1,2-dione in 30 ml of methanol under cooling to -30° C. or lower and then, 20 ml of an aqueous 12.5 N NaOH solution was dropwise added thereto. Subsequently, the resultant mixture was stirred at -30° C. or lower for 30 minutes and further stirred at room temperature for 3 hours to effect a reaction. To the resultant reaction mixture was added 25 ml of concentrated hydrochloric acid, followed by stirring for 10 minutes and then, 15 g of sodium hydrogencarbonate was added thereto. The solvent of the reaction mixture was distilled off in vacuo to thereby obtain a residue. Water was added-to the obtained residue, followed by extraction with chloroform three times to obtain an extract. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was recrystallized from acetone, to thereby obtain 9.36 g of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline (yield: 62.4%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH:13]=[N: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>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([CH3:10])[N:12]=[CH:13]3)[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Cn1ncc2cc(B(O)O)ccc21
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+]
Product: COc1ccnc(-c2ccc3c(cnn3C)c2)n1
Temperature: 185 °C

Procedure:
2-chloro-4-methoxypyrimidine (100.0 mg, 0.69 mmol), 1-methyl-1H-indazol-5-ylboronic acid (133.9 mg, 0.76 mmol), Pd(PPh3)4 (79.9 mg, 0.069 mmol), and K2CO3 (286.8 mg, 2.075 mmol) were taken in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed toluene (2.5 mL) and DMF (0.28 mL). The reaction mixture was heated in a microwave at 185° C. for 30 min, diluted with ethyl acetate, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.56 (dd, J=8.9, 1.3 Hz, 1H), 8.52 (d, J=5.8 Hz, 1H), 8.10 (s, 1H), 7.47 (d, J=8.9 Hz, 1H), 6.64 (d, J=5.8 Hz, 1H), 4.14 (s, 3H), 4.12 (s, 3H). LCMS-ESI+: calc'd for C13H13N4O: 241.1 (M+H+); Found: 241.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1)#[N:23]>>[C:22]([C:24]1([C:27]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:16][CH:17]=2)=[O:28])[CH2:26][CH2:25]1)#[N:23]
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1ccc(CCCCCCOCC2CCCCC2)cc1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCOCC3CCCCC3)cc2)CC1
Yield: 99.2 %

Procedure:
General procedure E was used to convert 1.30 mmol of 13b and 1.95 mmol of 1-cyanocyclopropanecarboxylic acid to 1.29 mmol (99%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH3:23])([CH3:22])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:21])[CH2:9][CH:10](O)[CH2:11][C:12]([CH:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)=[O:13].[CH3:24]O>>[CH3:24][O:13][C:12](=[C:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)/[CH:11]=[CH:10]/[CH2:9][CH:8]([CH3:21])[CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])([CH3:23])[CH3:22]
Reactant: CO
Reactant: COC(C)(C)CCCC(C)CC(O)CC(=O)C1COC(=O)C1
Agent: Cl
Product: COC(/C=C/CC(C)CCCC(C)(C)OC)=C1COC(=O)C1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
1 ml of methanol saturated with hydrochloric acid is added to a solution of 1.05 g (0.0033 moles) of 3-(9-methoxy-3-hydroxy-5,9-dimethyl-decanoyl)-4-butyrolactone in 10 ml of dry methanol, and the mixture is allowed to stand at room temperature overnight. The solvent is distilled off in vacuo, the residue is dissolved in ether, the etheral solution is washed with distilled water, dried, the solvent is distilled off, and the residue is purified by column chromatography (adsorbent: Kieselgel 60, solvent: a 10:0.1 mixture of benzene and methanol). 0.54 g (52.1%) of the aimed compound are obtained; Rf =0.8 (developed with a 10:0.2 mixture of benzene and methanol).
Reaction SMILES: CS(C1C=CC(/C=C/C)=C(C=1)N)(=O)=O.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-])=O)([CH3:17])=[CH2:16]>>[C:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][C:19]=1[NH2:28])([CH3:17])=[CH2:16]
Reactant: C=C(C)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: C/C=C/c1ccc(S(C)(=O)=O)cc1N
Product: C=C(C)c1ccc(S(C)(=O)=O)cc1N

Procedure:
Following the general method as outlined in Intermediate 60, starting from 1-isopropenyl-4-(methylsulfonyl)-2-nitrobenzene (Intermediate 88), the title compound was obtained as an orange solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:11]([OH:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9]#[N:10])=[CH:4][CH:3]=1.ClC(Cl)C.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29]>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:11]([O:22][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:20])([F:21])[F:19])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: N#CC(=C(O)c1ccccc1C(F)(F)F)c1ccc(Br)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)OC(=C(C#N)c1ccc(Br)cc1)c1ccccc1C(F)(F)F

Procedure:
60 mg of triethylamine was added to a mixture comprising 0.20 g of α-(4-bromophenyl)-β-hydroxy-β-(2-trifluoromethylphenyl)acrylonitrile and 6 ml of dichloroethane. Then, a mixture comprising 77 mg of n-propanesulfonyl chloride and 2 ml of dichloroethane, was dropwise added thereto. After completion of the dropwise addition, the mixture was reacted for 15 hours at room temperature.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[N+:20]([O-])([OH:22])=[O:21].[K+].[Br-]>C(O)(=O)C>[OH:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19]
Reactant: CC1(C)Oc2ccsc2C(N2CCCCC2=O)C1O
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(N2CCCCC2=O)C1O

Procedure:
The title compound was prepared as described in Example 5 starting with 5,6-dihydro-6-hydroxy-5,5-dimethyl-7(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran (1.5 g, 5.33 mmol) and 90% nitric acid (2.5 mL) in acetic acid (25 mL) to give the product, 0.837 g (48%), as a yellow solid: mp 210°-211° C.; IR (KBr): 3231, 1613, 1515 and 1492 cm-1 ; MS: m/z 327 (MH+); 1H NMR (CDCl3): δ 1.32 (s, 3H), 1.51 (s, 3H), 1.84 (m, 4H), 2.55 (m, 2H), 3.20 (m, 2H), 3.84 (d, J=9.5 Hz, 1H), 4.78 (bs, 1H, exchanges with D2O), 5.86 (d, J=9.5 Hz, 1H) and 7.40 (s, 1H). Anal. Calcd. for C14H18N2O5S: C, 51.52; H, 5.56; N, 8.58; S, 9.86.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][NH:10][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][CH2:16]1
Reactant: N#Cc1ccccc1F
Reactant: NCCCN1CCOCC1
Product: N#Cc1ccccc1NCCCN1CCOCC1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and 4-(3-aminopropyl)morpholine.
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[S:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([SH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:9][CH:8]=1)(=[O:12])[CH3:11]
Reactant: Cc1ccc(C=S)cc1
Reactant: CC(=O)Cl
Product: CC(=O)[SH]=Cc1ccccc1

Procedure:
Two other S-protected p-thiobenzaldehydes were obtained as shown in Scheme 2 (FIG. 15). The thiocyanato-benzaldehyde 8 was prepared according to a general procedure (Suzuki and Abe (1996) Synth. Commun., 26: 3413-3419) in 20% yield. All attempts to improve the yield by replacement of DMF with 1,3-dimethyl-2-imidazolidinone, increasing the temperature, or prolonging the reaction time were unsuccessful. S-Acetylthiobenzaldehyde 9 was prepared in a two-step one-flask procedure. Cleavage of the methyl group of 4-methylthiobenzaldehyde according to a general procedure (Tiecco et al. (1982) Synthesis, 478-480) followed by trapping of the resulting anion with acetyl chloride afforded the desired S-acetylthiobenzaldehyde 9 in 55% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]2=[O:30])[CH2:15][CH2:14]1>C(O)(C)C>[OH:12][CH:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][N:6]=1)[CH2:11][N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20]2=[O:30])[CH2:17][CH2:18]1
Reactant: Clc1nccnc1OCC1CO1
Reactant: O=C1N(c2ccccc2)CCN1C1CCNCC1
Solvent: CC(C)O
Product: O=C1N(c2ccccc2)CCN1C1CCN(CC(O)COc2nccnc2Cl)CC1

Procedure:
7.27 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine and 7.35 g of 1-(4-piperidyl)-3-phenyl-2-imidazolidinone in 120 ml of isopropanol are stirred for 24 hours at approx. 20° C. The reaction mixture is then concentrated in a water jet vacuum. The residue crystallises from ether and yields 1-{1-[2-hydroxy-3-(3-chloro-pyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenylimidazolidin-2-one with a melting point of 122°-124° C. The starting material can be prepared as follows: 9.8 g of N-phenylethylenediamine and 13.9 g of 1-benzyl-4-piperidone are dissolved in 200 ml of methanol and, with the addition of 0.7 g of a 5% platinum on charcoal catalyst, hydrogenated at room temperature and under normal pressure. The calculated amount of hydrogen is taken up after approx. 3 hours. The reaction mixture is filtered to remove the catalyst and concentrated in a water jet vacuum. The residue crystallises from methanol/water to yield 21.4 g of 1-benzyl-4-(2-phenylamino-ethylamino)-piperidino with a melting point of 78°-81° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.BrCCCCO[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C@@H:26]3[C@@H:21]([CH2:22][CH:23]=[CH:24][CH2:25]3)[C:20]2=[O:39])=CC=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:35][C:32]1[CH:31]=[CH:30][C:17]([CH2:16][N:19]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[C@@H:26]3[C@@H:21]([CH2:22][CH:23]=[CH:24][CH2:25]3)[C:20]2=[O:39])=[CH:18][CH:13]=1
Reactant: COc1ccc(C2=NN(c3ccc(OCCCCBr)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: BrCCCCBr
Product: COc1ccc(C2=NN(Cc3ccc(OCCCCBr)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from compound 7b and 1,4-dibromobutane as described for compound 6a. M. p. 42-46° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([CH3:41])(=[O:40])=[O:39]>>[F:16][C:17]1[C:18]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3S(C)(=O)=O)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: CS(=O)(=O)c1ccccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 32.6 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-(2-fluoro-2′-(methanesulfonyl)biphenyl-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (105 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(6-fluoro-2′-methanesulfonylbiphenyl-3-yl)-2-trifluoromethyl[1,8]-naphthyridine (32 mg, 33%). δH (360 MHz, CDCl3) 2.97 (3H, s), 7.38-7.46 (2H, m), 7.54-7.74 (5H, m), 7.87 (1H, d, J 8.4), 8.26 (1H, dd, J 1.2 and 7.9), 8.79 (1H, d, J 8.4), 9.27 (1H, d, J 4.2). m/z (ES+) 447 [MH]+.
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3][OH:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].C(N(CC)CC)C>C1COCC1.CN(C)C1C=CN=CC=1.CC(OC)(C)C.O>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([O:4][CH2:3][C:2]([F:6])([F:1])[CH3:5])(=[O:18])=[O:17])=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC(F)(F)CO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(F)(F)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 28 h
Yield: 46.9 %

Procedure:
2,2-Difluoropropan-1-ol (383 mg, 3.99 mmol) was combined with THF (3 mL). The solution was stirred at room temperature as 4-nitrobenzene-1-sulfonyl chloride (931 mg, 4.20 mmol) was added followed by triethylamine (0.611 mL, 4.39 mmol). After about 28 hours, the reaction mixture was diluted with THF (2 mL) and 4-dimethylaminopyridine (23 mg, 0.188 mmol) was added. After 16 hours the reaction mixture was diluted with 12 mL MTBE and 5 mL water and stirred for 5 minutes before the layers were separated. The organic layer was extracted with 1 M HCl (3 mL), 5% sodium carbonate (3 mL), brine (3 mL), and then water (3 mL). The organic layer was diluted with another 10 mL MTBE and extracted three times with 1 M NaOH (5 mL) and then water (5 mL). The organic layer was dried over sodium sulfate, filtered, concentrated on a rotovap, and dried under vacuum to give 2,2-difluoropropyl 4-nitrobenzenesulfonate (526 mg) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.C(N(CC)CC)C.[CH3:21][NH:22][CH2:23][CH2:24][OH:25]>C(#N)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][OH:25])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CNCCO
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CN(C)CCO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 5 mL round bottom flask was charged with 4-(bromomethyl)-1-methoxy-2-nitrobenzene (0.6 g, 2.44 mmol) and acetonitrile (2 mL). The solution was treated with triethylamine (1 mL, 7.32 mmol) and 2-(methylamino)ethanol (0.585 mL, 7.32 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to provide the title compound. MS (DCI+) m/e 241.1 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:21][CH:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23]>>[CH3:21][CH:22]([S:24]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:5]=[CH:6][C:7]([S:10][CH3:11])=[CH:8][CH:9]=1)(=[O:26])=[O:25])[CH3:23]
Reactant: CSc1ccc(C(C#N)=NO)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CSc1ccc(C(C#N)=NOS(=O)(=O)C(C)C)cc1
Yield: 67.6 %

Procedure:
Analogously to the preparation of Example 3.4, 9.6 g (0.5 mol) of α-hydroxyimino-4-methylthiobenzyl cyanide are reacted, in the presence of 7.6 g (0.075 mol) of triethylamine, with 7.85 g (0.055 mol) of 2-propanesulfonyl chloride. After working-up, the crude product is recrystallised from acetic acid acetate/hexane. 11.1 g (83%) of α-(2-propylsulfonyloxyimino)-4-methylthiobenzyl cyanide are obtained in the form of beige crystals having a melting point of 83-87° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 350 nm (ε=14660) that extends to 435 nm. Elemental analysis: C12H14N2O3S2 (266.32)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:30]1([CH2:36][CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH3:20][O:19][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:14]([CH3:18])[C:15](=[O:17])[NH:38][CH2:37][CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: NCCc1ccccc1
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: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)NCCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To #11 (22 g, 77 mmol, 1 eq.) in dichloromethane (383 mL, 0.2 M) and N,N-dimethylformamide (30 mL) were added diisopropylethylamine (26.9 mL, 153 mmol, 2 eq.), 2-phenylethylamine (11.6 mL, 91.9 mmol, 1.2 eq.) and HATU (39.0 g, 99.5 mmol, 1.3 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (700 mL) and washed sequentially with 1 M aqueous hydrochloric acid solution (2×200 mL) and brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was taken up in dichloromethane and filtered. The filtrate was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #20 (24 g, 80%) as an off-white solid. LC-MS: m/z 392.2 [M+2H+], 291.1 [(M−Boc)+H+], retention time=0.88 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.80-7.89 (br m, 1H), 7.23-7.29 (m, 2H), 7.15-7.23 (m, 3H), 3.72-3.82 and 3.55-3.62 (2 br m, total 1H), 3.45-3.55 (br m, 1H), 3.31-3.44 (br m, 2H), 3.29 (s, 3H), 3.12-3.25 (br m, 1H), 2.98-3.12 (br m, 1H), 2.71 (t, J=7.1 Hz, 2H), 2.09-2.19 (m, 1H), 1.71-1.83 (br m, 2H), 1.60-1.70 (br m, 1H), 1.49-1.60 (br m, 1H), 1.41 (s, 9H), 1.03 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH2:15]([OH:20])[CH2:16][CH2:17][C:18]#[CH:19]>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:19]#[C:18][CH2:17][CH2:16][CH2:15][OH:20])[N:7]=1
Reactant: COC(=O)CCc1nc(I)ccc1O
Reactant: C#CCCCO
Product: COC(=O)CCc1nc(C#CCCCO)ccc1O
Yield: 28 %

Procedure:
Under the conditions of example 5 A, 5 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 1.37 g of 4-pentyn-1-ol, worked up, and the crude product is chromatographed on silica gel with hexane/0-4% methanol. 1.2 g of 3-[3-hydroxy-6-(5-hydroxy-1-pentynyl)-2-pyridyl]-propionic acid methyl ester is obtained as colorless oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:13][C@H:14]([CH3:30])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)=[O:12])[N:10]=1)(=[O:5])[CH3:4]>C(O)C>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@H:14]([NH:13][C:11]([C:9]3[N:10]=[C:6]([CH:3]([OH:5])[CH3:4])[S:7][CH:8]=3)=[O:12])[CH3:30])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CC(=O)c1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
Sodium borohydride (29.3 mg, 0.773 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (R)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (160 mg, 0.387 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted to 6 and the mixture was evaporated. DCM and a few drops of methanol were added and the crude product was washed with 1M Na2CO3 and with water. The product was triturated using diethyl ether and DCM and heptane. Yield 33.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.09-1.17 (m, 3H), 1.45 (t, 3H), 2.38-4.53 (m, 3H), 4.92-5.02 (m, 1H), 6.23 (dd, 1H), 6.96 (dd, 1H), 7.85 (dd, 1H), 7.92-7.97 (m, 2H), 8.07-8.09 (m, 1H), 8.10 (d, 1H), 8.33-8.39 (m, 1H).