Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][C:32]1[C:36]([CH2:37][NH:38][CH3:39])=[C:35]([CH3:40])[NH:34][N:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:31][C:32]1[C:36]([CH2:37][N:38]([CH2:26][C:24]2[S:23][CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:11][CH2:10]3)[CH:25]=2)[CH3:39])=[C:35]([CH3:40])[NH:34][N:33]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CNCc1c(C)n[nH]c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5c(C)n[nH]c5C)c4)cc23)CC1
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (45 mg, 100 μmol) in dimethyl sulfoxide (1.0 mL) was added 1-(3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (320 μmol) and 2 to 3 drops of glacial acetic acid. The resulting mixture is agitated overnight. After 18 h, sodium triacetoxyborohydride (200 mg, 1000 μmol) is added. This mixture is agitated for 1.5 h followed by purification by Gilson Preparatory HPLC to give 6.24 mg of the title compound (11.0%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=S)[CH:16]=[CH:17][CH:18]=1>CO.O=[Hg]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[O:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: NNC(=O)c1ccc(O)cc1
Agent: O=[Hg]
Solvent: CO
Product: Oc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Mercury (II) oxide yellow (6.38 g, 29.47 mmol) was suspended in ca. 100 mL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (4.48 g, 29.47 mmol) was added to this bright-orange suspension, followed by 3-chlorophenylisothiocyanate (5.0 g, 29.47 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite. Then it was purified by silica gel chromatography using 0% to 20% methanol gradient in EtOAc. Solvent was removed in vacuo and the resulting grey precipitate was re-crystallized from ca. 50 mL of EtOAc. The formed white crystalline solid was filtered, washed with a small amount of EtOAc, anhydrous Et2O and dried in vacuo to give the title product as a white powder (7.606 g). Yield 89.7%.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].Cl[C:16]1[N:21]=[C:20]([C:22]2[CH:34]=[CH:33][C:25]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=3[CH:23]=2)[CH:19]=[CH:18][N:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([C:16]1[N:21]=[C:20]([C:22]2[CH:34]=[CH:33][C:25]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=3[CH:23]=2)[CH:19]=[CH:18][N:17]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N(C)S(=O)(=O)c4ccc(C)cc4)n3)cc2s1
Reaction time: 0.5 h

Procedure:
A microwave vial equipped with a stir bar was charged with N-methyl-p-toluenesulfonamide (0.23 g, 1.2 mmol) in DMF (3 mL). NaH (0.12 g, 4.9 mmol) was added to the mixture and allowed to stir for 30 minutes. Then, palladium (II) acetate (0.011 g, 0.049 mmol), N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.150 g, 0.492 mmol), and Xantphos (0.010 g) were added to the mixture. The vial was capped and placed into a microwave for 10 minutes at 100° C. The mixture was then added to a RBF, diluted with water (150 mL), and allowed to stir overnight. The resulting precipitate was collected by filtration and washed with hexane and 1:1 hexanes/ethyl ether to provide N-(6-(2-(N,4-dimethylphenylsulfonamido)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide as a tan solid. MS (ESI pos. ion) m/z: 454 (MH+). Calculated exact mass for C21H19N5O3S2: 453. 1H NMR (400 MHz, DMSO-d6): 12.52 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.10 (d, J=5.0 Hz, 1H), 7.93 (s, 2H), 7.83 (s, 1H), 7.71 (s, 1H), 7.40 (s, 2H), 3.70 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)n1nc2c(c1-c1ccc(C(C)(C)C)cc1)CCNCC2
Yield: 17.9 %

Procedure:
The title compound (28 mg) was prepared according to Example 189 using 215 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 268 mg of 4-tert-butylphenylboronic acid. MS (ESI): exact mass calculated for C20H29N3, 311.24; found, m/z 312.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.61-7.59 (m, 2H), 7.27-7.25 (m, 2H), 4.40 (m, 1H), 3.43-3.40 (m, 2H), 3.19-3.17 (m, 2H), 2.79-2.77 (m, 2H), 1.50-1.25 (m, 15H).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[C:38]([NH:40][CH:41]([CH3:43])[CH3:42])[N:37]=[C:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:35]=2)[CH:31]=[N:32][CH:33]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]([C:28]3[CH:29]=[C:30]([C:34]4[CH:39]=[C:38]([NH:40][CH:41]([CH3:43])[CH3:42])[N:37]=[C:36]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)[CH:35]=4)[CH:31]=[N:32][CH:33]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: CC(C)Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)Nc1cc(-c2cncc(-c3cccc(CN4CCN(C(C)(C)C)CC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of 3-(4-tert-Butyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B11) (1.1 eq, 0.149 mmol, 41 mg) and 2M Na2CO3 (2.0 eq, 0.270 mmol, 0.14 ml) in DME (1 ml) are added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-isopropyl-amine (Example 2.46, step1) (1 eq, 0.135 mmol, 50 mg) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.0135 mmol, 9.9 mg). The reaction mixture is heated using microwave radiation at 90° C. for 3 hours. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The residue is purified by reverse phase chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 521.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)[S:15][CH:16]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[S:15][CH:16]=1
Reactant: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)cc1
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To the compound (300 mg, 0.759 mmol) obtained in Example 186b were added ethanol (4 mL), tetrahydrofuran (2 mL) and 2N aqueous sodium hydroxide solution (0.76 mL, 1.52 mmol), and the mixture was stirred overnight. The reaction mixture was extracted with water, and washed with ether. The aqueous layer was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate), and recrystallized from ethanol-hexane to give the title compound (186 mg, 64%) as colorless crystals.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:12]=2[N+:25]([O-])=O)[CH2:7][CH2:6][N:5]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:3])[CH3:2]>C1COCC1.CO.[Ni]>[NH2:25][C:12]1[CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:4]([CH:1]([CH3:2])[CH3:3])[C:9]1=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 1 L round-bottom flask containing (R)-tert-butyl 2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylsulfonyl)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate (26.3 g, 0.0526 mol) in THF (200 mL) and methanol (200 mL) was added Raney Nickel (in H2O, 4 g). The mixture was stirred under H2 (30 psi) at rt overnight. The mixture was filtered and concentrated under vacuum to give (R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (24.7 g, 100% yield) as a yellow solid. The residue was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].[CH3:17][C:18]1[CH:22]=[CH:21][O:20][C:19]=1[C:23]([NH:25][C:26]1[CH:27]=[C:28]([C:32]#[C:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:42]=2)[C:39](O)=[O:40])[CH:29]=[CH:30][CH:31]=1)=[O:24]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=1)(=[N:4][C:39]([C:38]1[CH:37]=[N:36][CH:35]=[C:34]([C:33]#[C:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:23]([C:19]3[O:20][CH:21]=[CH:22][C:18]=3[CH3:17])=[O:24])[CH:27]=2)[CH:42]=1)=[O:40])=[O:3]
Reactant: COC(=O)CCc1ccc(S(C)(=N)=O)cc1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)O)c2)c1
Product: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4occc4C)c3)c2)cc1
Yield: 94.6 %

Procedure:
In a manner similar to that described in Example 480 (step 6), Methyl 3-(4-(S-methylsulfonimidoyl)phenyl)propanoate (0.25 g, 1.037 mmol) and 5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinic acid (0.326 g, 0.943 mmol) reacted to give the title compound (0.508 g, 86%).
Reaction SMILES: [C:1]([O:7][CH:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.O([Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:1]([O:7][CH:8]1[CH2:9][CH:10]([O:12][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:11]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC1CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC1CC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 2 h

Procedure:
To a stirred mixture of 3-hydroxycyclobutyl pivalate (16.60 g, 96.4 mmol) and diea (25.2 ml, 145 mmol) in DCM (100 ml) at 0° C. was added tert-butyldimethylsilyl triflate (31.0 ml, 135 mmol) dropwise. The reaction was stirred for 2 h, then quenched with H2O. The layers were separated, and the organic layer was washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated to give the title compound as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH2:34][N:33](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:32][CH2:31][C:22]=1[NH:23]2.CCOC(C)=O.Cl>CO>[CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH2:34][NH:33][CH2:32][CH2:31][C:22]=1[NH:23]2
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC4)cccc1-n1cnc2ccccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A suspension of 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (248.5 mg, 0.359 mmol) in methanol (4 mL) was treated with EtOAc (less than 1 mL) to form a clear solution. This was treated with 1 M aqueous HCl (3 mL), forming a cloudy mixture which was stirred at room temperature. After 30 min, the mixture was concentrated under vacuum, treated with NaHCO3 (aq) and EtOAc and stirred at room temperature for about 1 h. The precipitate was collected by filtration, washed with water, then with EtOAc, and dried under vacuum to provide the desired product as a white solid (145 mg, 90% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:18]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(CCc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1cn(CCc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of ethyl [1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (440 mg), 1 N aqueous sodium hydroxide solution (2 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1 N hydrochloric acid. The obtained crystals were collected by filtration, and [1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid was obtained (350 mg, yield: 85%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 199–200° C.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1)=[O:10]
Reactant: Nc1ccccc1C(=O)O
Reactant: N#CC1(c2ccc(N)cc2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: N#CC1(c2ccc(NC(=O)c3ccccc3N)cc2)CCC1

Procedure:
A mixture of anthranilic acid (1.4 g) and 1-(4-aminophenyl)cyclobutane-carbonitrile (1 eq) and TEA (1.2 eq) in dichloromethane (80 ml) was stirred with EDCI (1.25 eq) and HOBt (1 eq) at RT overnight. The reaction was washed with sat. NaHCO3, H2O followed by brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give (2-aminophenyl)-N-[4-(cyanocyclobutyl)phenyl]-carboxamide.
Reaction SMILES: [OH:1][C:2]([C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:11][CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].[Br:20]N1C(=O)CCC1=O>CN(C=O)C.O.C(OCC)(=O)C>[Br:20][C:6]1[S:5][C:4]([C:2]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:13][CH2:14]2)([OH:1])[CH3:3])=[N:8][CH:7]=1
Reactant: CC(O)(c1nccs1)[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)(c1ncc(Br)s1)[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Temperature: 50 °C

Procedure:
To a solution of N-{trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexyl}methanesulfonamide (178 mg, 0.59 mmol) in DMF (4.0 mL) was added N-bromosuccinimide (104 mg, 0.585 mmol) and the reaction was heated at 50° C. for one hour. The reaction was then cooled to room temperature and another portion of N-bromosuccinimide (52 mg, 0.292 mmol) was added. The reaction was then heated at 50° C. for one hour. The solution was then cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford N-{trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexyl}methanesulfonamide. MS ESI calc'd. for C12H20N2O3S2 [M+H]+ 383, 385. found 383, 385. 1H NMR (500 MHz, DMSO-d6) δ 7.73 (s, 1H), 6.91 (d, J=7.4, 1H), 5.95 (s, 1H), 2.99-2.87 (m, 1H), 2.54 (s, 3H), 1.94-1.72 (m, 4H), 1.52 (t, J=11.9, 1H), 1.47-1.39 (m, 4H), 1.30-0.92 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:19])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[BrH:26]>O>[Br:26][C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:19])[N:3]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)nc2Cl)cc1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2ccc(O)cc2)c(Br)n1
Temperature: 110 °C
Yield: 62 %

Procedure:
2-Chloro-3-(4-methoxybenzenesulfonyl)-6-methylpyridine (4.74 g, 15.92 mmol) was suspended in HBr (84 mL, 48%). The orange reaction mixture was heated at 110° C. for 24 h. The reaction mixture was cooled to rt, diluted with H2O, and was treated with Na2CO3 until neutral. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford a colorless solid (3.22 g, 62% yield) which was used without further purification: mp 99–102° C.; 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=7.7 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.0 Hz, 1H), 6.95 (d, J=9.1 Hz, 2H), 2.63 (s, 3H); LRMS (APCI) m/z 328.0 [(M+H)+, calcd for C12H11NO3BrS, 328.0].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[O:21]1[C:25]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[CH:24][N:23]=[CH:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([C:25]4[O:21][CH:22]=[N:23][CH:24]=4)=[CH:34][CH:33]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(-c2cnco2)cc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-4-oxazol-5-yl-benzamide was prepared starting from intermediate D and 4-oxazol-5-yl-benzoic acid. MS calcd. for C26H18ClN3O3 [(M+H)+] 455.9, obsd. 456.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH:12]1[S:17][CH2:16][CH2:15][CH2:14][S:13]1.O1CCCC1>C(O)(=O)C.C(OCC)C.[Fe]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([CH:12]2[S:17][CH2:16][CH2:15][CH2:14][S:13]2)[CH:4]=1
Reactant: O=[N+]([O-])c1cc(C2SCCCS2)c(Cl)cc1F
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1cc(C2SCCCS2)c(Cl)cc1F
Temperature: 50 °C
Yield: 75.2 %

Procedure:
To a stirred mixture of 20.0 g (0.0681 mole) of 2-(2-chloro-4-fluoro-5-nitrophenyl)-1,3-dithiane in 150 mL of acetic acid was added 75 mL of tetrahydrofuran. Iron powder (15.8 g, 0.269 mole) was added portionwise. Upon complete addition, the reaction mixture was heated to about 50° C. for approximately 30 minutes. The reaction mixture was cooled in an ice bath and was diluted with diethyl ether. The resultant mixture was filtered through a pad of Celite® filter aid. Water was added to the filtrate, and the organic phase was removed. An aqueous, sodium bicarbonate solution was added to the organic phase with vigorous stirring until the mixture was slightly basic. The aqueous phase was allowed to separate from the organic phase and was removed. The aqueous phase was extracted with diethyl ether, and the extracts were added to the organic phase. This organic solution was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 13.5 g of 2-(5-amino-2-chloro-4-fluorophenyl)-1,3-dithiane as a solid, m.p. 112°-115° C.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[SH-:16].[Na+]>O>[CH2:14]([O:13][C:11]([C:4]1[CH:3]=[C:2]([SH:16])[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[N:5]=1)=[O:12])[CH3:15]
Reactant: [SH-]
Reactant: CCOC(=O)c1cc(Cl)n2cnnc2n1
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(S)n2cnnc2n1
Yield: 75.8 %

Procedure:
The product obtained in Step 1 (6 g) was added all at once under ice cooling to a solution of sodium hydrosulfide (5.5 g) in 100 ml of water, with stirring in nitrogen, and the mixture was stirred at room temperature for two hours. After filtering off the insoluble matters, the yellow filtrate was acidified to pH 2.0 with 6N hydrochloric acid, and the formed crystals were collected by filtration, washed with 20 ml of water and air-dried, affording 4.5 g of the objective compound as faint yellow crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14][CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1>CO.[Pd]>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:28])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Agent: [Pd]
Solvent: CO
Product: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCNCC2
Reaction time: 3 h

Procedure:
200 mg of Pd/C was added a solution of benzyl 2-(cis-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (2.13 g, 0.00551 mol) in methanol (50 mL) under nitrogen. The reaction mixture was stirred under an atmosphere of hydrogen for 3 hrs. The mixture was filtered, and the filtrate was concentrated to give 2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (1.29 g, 93%).