Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])=[CH:5][CH:6](Br)[CH3:7].C(N(CC)CC)C.[CH3:18][N:19]([CH3:27])[C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])=[CH:5][CH:6]([S:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]([CH3:27])[CH3:18])=[CH:21][CH:22]=1)[CH3:7]
Reactant: COC(=O)C(C)=CC(C)Br
Reactant: CN(C)c1ccc(S)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)=CC(C)Sc1ccc(N(C)C)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 4-bromo-2-methylpent-2-enoic acid methyl ester (0.414 g, 2.0 mmol) in dry benzene (4 mL) under an atmosphere of argon was added a solution of triethylamine (0.28 mL, 2.0 mmol) and 4-dimethylamino-benzenethiol (0.306 g, 2.0 mmol) in dry benzene (2 mL). The mixture was stirred at 20° C. for 2 hours (TLC monitoring). The solvent was then removed under reduced pressure to give a yellow oil that was purified by column chromatography (20:79:1 diethyl ether:60-80° C. petroleum ether:triethylamine) to give the title compound (0.53 g, 95%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH:5]([NH:22][C:23]([C:25]1([NH:30][C:31](=[O:40])[CH:32]([S:36][C:37](=[O:39])[CH3:38])[CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[CH:11][CH:12]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:41])[CH:5]([NH:22][C:23]([C:25]1([NH:30][C:31](=[O:40])[CH:32]([S:36][C:37](=[O:39])[CH3:38])[CH:33]([CH3:35])[CH3:34])[CH2:26][CH2:27][CH2:28][CH2:29]1)=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(-c2cccc([N+](=O)[O-])c2)nc1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(-c2cccc(N)c2)nc1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Reaction time: 18 h

Procedure:
A suspension of 2-{[1-(2-acetylthio-3-methyl-butanoylamino)-cyclopentanecarbonyl]-amino}-3-[6-(3-nitro-phenyl)-pyridin-3-yl]-propanoic acid ethyl ester (110 mg) and 25 mg of 10% Pd/C in 10 mL of EtOH is stirred under a H2 atmosphere for 18 h. The catalyst is filtered off, and the reaction mixture is concentrated in vacuo. The residue is purified by chromatography on silica gel (50% EtOAc/hexane) to produce yellow product; 1H NMR (250 MHz, CDCl3) δ8.39 (d, 1H), 7.60 (s, 2H), 7.10-7.36 (m, 3H), 6.71 (d, 1H), 6.34 (d, 1H), 4.76 (app q, 1H), 4.15 (q, 2H), 3.62 (dd, 1H), 3.05-3.25 (m, 2H), 2.35, 2.32 (two s, 3H), 1.55-2.40 (m, 9H), 1.19 (t, 3H), 0.92-1.06 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:38][N:39]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:39][CH3:38])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NC
Yield: 77 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (68c) (100 mg, 0.20 mmol), methylamine hydrochloride (45 mg, 0.67 mmol), WSC hydrochloride (117 mg, 0.61 mmol) and HOBT (23 mg, 0.17 mmol), to obtain 78.6 mg of the title compound as a white solid (77%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)[CH2:4][CH2:3]1
Reactant: CC1CCC(N)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: CC1CCC(Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1
Yield: 30.2 %

Procedure:
Using the procedure of example 1, 4-methylcyclohexylamine (92 mg) was reacted with compound 1f (100 mg) to provide compound 17 (25 mg, 30%) as a mixture of cis- and trans-isomers. 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=8.0 Hz, 1H), 8.92 (d, J=8.0 Hz, 1H), 8.28 (m, 2H), 8.20 (s, 1H), 8.19 (s, 1H), 8.14 (d, J=5.2 Hz, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.25 (m, 2H), 7.03 (d, J=5.6 Hz, 1H), 7.00 (d, J=5.6 Hz, 1H), 4.15 (m, 1H), 3.83 (m, 1H), 2.15 (m, 2H), 1.89-1.14 (m, 16H), 1.01 (d, J=6.4 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].C(N(CC)CC)C>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)OCC(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 110.5 g of o-nitrobenzenesulfonyl chloride and 50.0 g of 2,2,2-trifluoroethanol in 600 ml of diethyl ether was added 52.0 g of triethylamine at 5°-15° over a 45 minute period. The reaction mixture was stirred at 25° for 1 hour then washed with water, dried over MgSO4, and stripped in vacuo to give 2,2,2-trifluoroethyl 2-nitrobenzenesulfonate as an oil weighing 110.3 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[C:12]([NH2:15])(=[S:14])[CH3:13].[OH-].[Na+]>O1CCOCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:15]=[C:12]([CH3:13])[S:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(Br)cc2)cs1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
To a stirred solution of 2,4′-dibromoacetophenone (5 g, 18 mmol) in dioxane (180 ml) was added thioacetamide (6.76 g, 90 mmol), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (4.73 g, 99% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: Fc1ccccc1CCCBr
Reactant: CCc1ccncc1
Product: CC(CCCc1ccccc1F)c1ccncc1
Yield: 71.9 %

Procedure:
1.62 g (15.1 mmol) of 4-ethylpyridine and 3.3 g (15.1 mmol) of 1-bromo-3-(2-fluorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.64 g of the desired compound (yield: 71.6%). The resulting compound was identified as 1-(2-fluorophenyl)-4-(4-pyridyl)-pentane (hereinafter referred to as compound 40) by the following analytical results.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=1[F:33])#[N:16]>>[F:29][C:28]1[C:27]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:26][CH:25]=[C:24]([F:33])[C:23]=1[C:18]1[C:17]([C:15]#[N:16])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1-c1c(F)ccc(B(O)O)c1F
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1c(F)ccc(-c2cnc3nc(C(F)(F)F)ccn23)c1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine and 2′-cyano-2,6-difluorobiphenyl-3-boronic acid were coupled using the procedure described in Example 1 to give 2′,6′-difluoro-3′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white solid: δH (360 MHz, CDCl3) 7.30-7.34 (2H, m), 7.59-7.68 (3H, m), 7.75-7.79 (1H, m), 7.88 (1H, dd, J 7 and 1), 8.13 (1H, s), 8.78 (1H, dd, J 7 and 4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=O)=[CH:23]3)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N1CCCCC1>C(O)C>[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=[C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]2=[O:10])=[CH:23]3)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
A mixture of 2-oxindole (29 mg, 0.22 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (60 mg, 0.22 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 81 mg (95%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10]C(=O)C)[O:7][C@@H:6]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[S:19])[NH:17][C:15]2=[O:16])[CH2:5]1)=[N+:2]=[N-:3]>O1CCOCC1.[NH4+].[OH-].CCOCC>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[S:19])[NH:17][C:15]2=[O:16])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=S)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=S
Reaction time: 18 h

Procedure:
3'-Azido-3'-deoxy-5'-O-acetyl-4-thiothymidine (0.25 g; 0.76 mMol, Example 21) was dissolved in a mixture of 5 mL of dioxane and 5 mL of conc. NH4OH and stirred for 18 hrs. The solvent was removed in vacuo and the residue applied to a silica gel column followed by elution with CHCl3 /EtOAc (3:1 v/v). The appropriate fractions were combined and the solvent removed in vacuo to yield a yellow oil which was dissolved in Et2O, forming crystals upon concentration: 0.16 g (0.56 mMol; 74%); m.p.=116°-118° C.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:4]=1.[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.20) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 526.2 [(M−H)−]; mp 231° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](=[NH:29])[NH2:28])[CH3:23]>C(O)C>[CH2:22]([O:24][C:25]([C:26]1[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:4]([OH:3])=[O:21])=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:28][C:27]=1[NH2:29])=[O:30])[CH3:23]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=C(C(=O)O)C1c1ccccc1
Yield: 48 %

Procedure:
Upon boiling a solution of 14.0 g of benzylidenebenzoylacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-4,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester of melting point 183°C (ethanol) is obtained.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)Cl>C(Cl)(Cl)Cl>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:29])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: O=C(Cl)N1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)N4CCCCC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.075 g, 0.25 mmol, Preparation #9) and TEA (0.041 mL, 0.29 mmol) in CHCl3 (1.2 mL) to give a brown suspension. Piperidine-1-carbonyl chloride (0.040 g, 0.27 mmol) was added and the reaction was stirred at ambient temperature for about 3 h. The reaction mixture was heated to about 45° C. for about 16 h. The mixture was cooled to ambient temperature, DCM (25 mL) was added, and the solution was washed with water and brine (about 5 mL each). The layers were separated and the organic solution was dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)piperidine-1-carbohydrazide (0.11 g, 100%): LC/MS (Table 2, Method a) Rt=2.09 min; MS m/z: 415 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.[CH3:30][S:31][CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl>[CH3:29][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH2:15][NH:34][CH2:33][CH2:32][S:31][CH3:30])[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CSCCN
Reactant: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CSCCNCC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,1-dimethyl-2-oxo-ethyl)-phenyl]-amide (as prepared in the previous step, 60.0 mg, 0.154 mmol) and 2-methylsulfanyl-ethylamine (84 mg, 0.92 mmol) in 2 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (49.0 mg, 0.231 mmol). After stirring at RT for 3 h, the mixture was treated with EtOAc (40 mL) and washed with aqueous saturated NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1-3% MeOH/DCM) to afford the title compound (45.0 mg, 63%) as a white solid. 1H-NMR (1:1 CD3OD/CDCl3; 400 MHz): δ 8.22 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.27 (dd, 1H, J=8.6, 2.0 Hz), 7.14 (d, 1H, J=2.0 Hz), 5.73 (m, 1H), 2.77 (s, 2H), 2.68 (t, 2H, J=6.3 Hz), 2.55 (t, 2H, J=6.3 Hz), 2.27 (m, 2H), 2.06 (m, 2H), 1.92 (s, 3H), 1.57 (t, 2H, J=6.3 Hz), 1.35 (s, 6H), 1.07 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H35N5OS, 466.3 (M+H). found 466.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([C:11]([OH:13])=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([C:11]([O:13][CH3:24])=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)=C(C(=O)O)C1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 153 mg of 1-(t-butoxycarbonyl)-4-phenyl-1,2,5,6-tetrahydronicotinic acid in 1 mL of THF and 1 mL of MeOH was added 0.6 mL of TMSCHN2 (2M in hexanes). The reaction was stirred at room temperature for 2 h and concentrated under vacuum. The residue was purified by flash chromatography eluting with 20% EtOAc in hexanes to provide 116 mg of the title compound: 1H NMR (300 MHz, CDCl3): δ1.5 (s, 9H), 2.5-2.6 (m, 2H), 3.5 (s, 3H), 3.6 (t, 2H), 4.2-4.3 (m, 2H), 7.1-7.2 (m, 2H), 7.2-7.4 (m, 3H). RF : 0.68 (50% EtOAc in hexanes).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:27][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]1[N:37]2[CH:38]=[C:39]([O:42][C@@H:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C@@H:45]([NH2:52])[CH2:44]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:52][C@@H:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:43]([O:42][C:39]3[CH:40]=[CH:41][C:36]4[N:37]([C:33]([C@@H:29]5[CH2:30][CH2:31][CH2:32][N:28]5[CH3:27])=[N:34][N:35]=4)[CH:38]=3)[CH2:44]2)=[O:24])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@H]3C[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12

Procedure:
A solution of Intermediate 33a (190 mg, 0.454 mmol), Intermediate 37a (132 mg, 0.378 mmol) and DIPEA (132 μL, 0.756 mmol) in anhydrous DMF (3 mL) was stirred at 100° C. for 3 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and then extracted into EtOAc (3×50 mL). The combined organics were washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as give an off-white solid after freeze-drying (143 mg, 61%). LCMS (Method 5): Rt 3.23, m/z 621 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.22 (9H, s), 1.95-1.97 (3H, m), 2.07 (3H, s), 2.20-2.23 (3H, m), 2.52-2.53 (1H, m), 3.10 (1H, m), 3.92 (1H, t, J 8.1), 4.51 (2H, d, J 5.6), 5.25-5.27 (2H, m), 5.83 (1H, d, J 5.8), 6.25 (1H, s), 6.99 (1H, d, J 7.9), 7.18 (1H, dd, J 9.9, 2.2), 7.24-7.32 (2H, m), 7.35-7.41 (6H, m), 7.67 (1H, d, J 9.9), 8.10 (1H, s), 8.20 (1H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=2[C:22]2[N:26]([CH3:27])[C:25]([CH2:28][CH3:29])=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([Cu])#[N:31].CN(C=O)C>CCOC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:30]#[N:31])=[CH:17][C:16]=2[C:22]2[N:26]([CH3:27])[C:25]([CH2:28][CH3:29])=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCc1nnc(-c2cc(I)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nnc(-c2cc(C#N)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-iodo-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C, 18 mg, 0.034 mmol), CuCN (15 mg, 0.17 mmol), and DMF (500 μL). The reaction was then heated to 100° C. and stirred for 48 hours. The solution was then diluted with EtOAc and washed with an aqueous solution of EDTA (5% wt/wt). The organic layer was then concentrated and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-cyano-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide as a white solid: MS (ES) M+H expected 424.2, found 424.4.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH2:25]>ClCCl>[CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([NH:25][NH:24][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:9]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1scnc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1scnc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methyl-1,3-thiazole-4-carboxylic acid (500 mg, 3.49 mmol) in dry dichloromethane (DCM) (17.500 ml) was stirred at room temperature under an atmosphere of argon. EDC (736 mg, 3.84 mmol) and HOBt (267 mg, 1.746 mmol) were added to the stirred solution and the resulting solution was stirred at room temperature for ½ hour. After this time, 1,1-dimethylethyl hydrazinecarboxylate (554 mg, 4.19 mmol) was added and the solution was stirred for a further 16 hours (overnight) at room temperature. The solution was diluted with DCM (approx. 50 ml) and washed with water (2× approx. 25 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oily solid. The residue was chromatographed [SiO2, MeOH in DCM 0-5%] to give a pale yellow coloured solid of desired material in 544 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].I([O-])(=O)(=O)=[O:16].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:16])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: C=Cc1ccc(NS(C)(=O)=O)c(F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of N-(2-Fluoro-4-vinylphenyl)methansulfonamide (20-2, 1.076 g, 5 mmol) in acetone and water (1:1, 20 mL) was treated with a catalytic amount of osmium tetroxide (4 wt % solution in hydroxyperoxide) and sodium periodate (2.139 g, 10 mmol). After being stirred at room temperature for 1 h, the mixture was concentrated into a small volume in vacuo. The residue was treated with aqueous sodium thiosulfate solution and then extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant to afford N-(2-Fluoro-4-formylphenyl)methanesulfonamide (20-3, LJO-326, 0.521 g, 48%) as a white solid.
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][N:24]([CH3:39])[CH2:25][CH2:26][N:27]([S:35]([CH3:38])(=[O:37])=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH3:23][N:24]([CH3:39])[CH2:25][CH2:26][N:27]([C:28]1[CH:29]=[CH:30][C:31]([NH:34]/[C:3](=[C:10]2\[C:11](=[O:22])[NH:12][C:13]3[C:18]\2=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=3)/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:32][CH:33]=1)[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3cc4c(cc32)OCO4)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine