Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>C(Cl)Cl>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Solvent: ClCCl
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of (3S)-1-Cbz-3-(cyclohexylamino)pyrolidine (4.75 g, 15.1 mmol) and TEA (4.26 mL, 30.2 mmol) in DCM (50 mL) was added dropwise isobutyryl chloride (1.15 mL, 60.3 mmol). The reaction mixture was stirred at rt for 12 h and quenched with 1N HCl solution. The organic material was extracted with DCM (50 mL×2) followed by EtOAc (50 mL×2), and the extracts were washed with a saline, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/3) to give the title compound (5.40 g, 96.7%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:23]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[N:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:23](=[O:24])[N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:31][CH2:30]2)[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CC(C)(C)OC(=O)Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1

Procedure:
37.3 Using general procedure C, (2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid was coupled with 1-(pyrrolidinocarbonylmethyl)piperazine to give (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester. White solid. MS 460.4 ([M+Na]+)
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1[CH:35]=[C:34](Br)[C:33]([Br:37])=[CH:32][CH:31]=1>>[Br:37][C:33]1[CH:34]=[C:35]([C:25]([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:30]=[CH:31][CH:32]=1
Reactant: Brc1ccccc1Br
Reactant: CC(C)C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 76.5 %

Procedure:
By the reaction in the same manner as in Example 1-(ii) using 1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanone (34.90 g) and O-dibromobenzene (50.7 g), the title compound (37.7 g) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:21][C:22]6[O:26][C:25]([C:27]7[C:28]([O:33]C)=[N:29][CH:30]=[CH:31][CH:32]=7)=[C:24]([C:35]([NH:37][CH3:38])=[O:36])[C:23]=6[CH:39]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[Na+].[I-]>CC(O)=O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:21][C:22]6[O:26][C:25]([C:27]7[C:28]([OH:33])=[N:29][CH:30]=[CH:31][CH:32]=7)=[C:24]([C:35]([NH:37][CH3:38])=[O:36])[C:23]=6[CH:39]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2cccnc2OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CNC(=O)c1c(-c2cccnc2O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 23.3 %

Procedure:
A mixture of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(2-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (45 mg, 0.07 mmol) and NaI (54 mg, 0.36 mmol) in HOAc (1 mL) was stirred at 100° C. under N2 for 5 h. After the reaction, it was extracted with EtOAc (10 mL×3) and Na2CO3 (a.q., 5 mL). The organic layer was washed with brine (5 mL×3), dried over aq. Na2SO4 and concentrated. The residue was purified by prep-HPLC to give 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(2-hydroxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (10 mg, yield: 23%). 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 8.11 (s, 1H), 7.97 (d, J=5.2 Hz, 1H), 7.96 (s, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.55 (m, 2H), 7.23 (s, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.85 (s, 1H), 6.60 (t, J=6.8 Hz, 1H), 6.01 (s, 2H), 5.30 (s, 1H), 3.41 (s, 3H), 2.96 (d, J=4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)+: 614.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C>C1COCC1>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(N2CCCC2)s1
Yield: 108.4 %

Procedure:
4 batches of 2,5-dibromo-1,3-thiazole (250 mg, 1.029 mmol), pyrrolidine (0.089 mL, 1.081 mmol) and DIPEA (0.225 mL, 1.286 mmol) in THF (2.5 mL) were heated in a microwave at 120° C. for 15 minutes. All 4 batches were combined and evaporated to dryness. The residues were purified on silica eluting with cyclohexane and ethyl acetate (0-100%). The appropriate fractions were combined and evaporated to dryness producing the title compound (260 mg). LCMS (A): m/z (M+H)+ 233/235, C7H9BrN2S requires 232/234 (acidic).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:7]1[C:6]2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: Clc1cccc(CBr)c1
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3cccc(Cl)c3)c12
Yield: 86 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-chlorobenzyl bromide as starting materials, the title compound was obtained in a yield of 86% as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.CN([CH:18]=[O:19])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C([Li])(C)(C)C>[CH:18]([C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12)=[O:19]
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CN(C)C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)CCc2c(C(=O)O)sc(C=O)c2C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
To a cooled (−78° C.) solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.00 g, 9.51 mmol) in THF (40 mL), tert.-butyllithium (15.8 mL, 1.5 M in pentane) is added. The mixture is stirred at −30° C. for 30 min and cooled again to −78° C. before DMF (2 mL, 27.4 mmol) is added. Stirring is continued for 5 min. The reaction mixture is poured onto 10% aq. citric acid solution and extracted twice with EA. The combined organic extracts are washed with brine, dried over Na2SO4 and evaporated go give crude 3-formyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.30 g) as a brownish foam, LC-MS: tR=0.92 min, [M+1+CH3CN]=280.22; 1H NMR (CDCl3): δ 10.06 (s, 1H), 4.02 (s br, 1H), 3.06 (t, J=6.7 Hz, 2H), 2.84 (s, 2H), 1.63 (t, J=6.7 Hz, 2H), 1.03 (s, 6H).
Reaction SMILES: C[N:2]1C(=O)CCC1.N.Br[C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][CH3:21])[N:15]=2)[CH:11]=1>C(OCC)(=O)C.[Cu](I)I>[CH2:20]([N:14]1[CH:13]=[C:12]2[C:16]([C:17]([CH3:19])=[CH:18][C:10]([NH2:2])=[CH:11]2)=[N:15]1)[CH3:21]
Reactant: CCn1cc2cc(Br)cc(C)c2n1
Reactant: CN1CCCC1=O
Agent: I[Cu]I
Agent: N
Solvent: CCOC(C)=O
Product: CCn1cc2cc(N)cc(C)c2n1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Copper oxide (I) (60 mg), NMP (2 mL), and concentrated aqueous ammonia (2 mL) were added to 5-bromo-2-ethyl-7-methyl-2H-indazole obtained in the above-described Step 1 (446 mg), and the reaction solution was stirred in a microwave reactor at 100° C. for 10 hours. The reaction solution was cooled to room temperature, and diluted with ethyl acetate. Thereafter, the reaction solution was washed successively with water four times and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-ethyl-7-methyl-2H-indazol-5-amine.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[S:31])[CH:24]=1>>[CH3:32][C:23]1[CH:24]=[C:25]([NH:29][C:30]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:31])[CH:26]=[CH:27][CH:28]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: Cc1cccc(N=C=S)c1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(C)c4)CC3)nc21

Procedure:
Pipemidic acid (54 mg, 0.177 mmol) and m-tolylisothiocyanate (20 μL, 0.148 mmol) were used. Purification on silica yielded compound 13 in Table 1, below (67 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.68 (s, 1H), 7.34-7.32 (m, 1H), 7.05-6.94 (m, 3H), 4.33 (q, J=7.10 Hz, 2H), 4.24-3.87 (m, 8H), 2.35 (s, 3H), 1.49 (t, J=7.19 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH:5]([CH2:11][C:12]([F:43])([F:42])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[Cl:47]N1C(=O)CCC1=O>C(COC)OC>[CH2:1]([O:3][C:4](=[O:44])[C:5]([Cl:47])([CH2:11][C:12]([F:42])([F:43])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Reactant: O=C1CCC(=O)N1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cl)(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
The diester (9) (700 mg, 1.125 mmol) was treated with sodium hydride (39 mg, 1.625 mmol) in dimethoxyethane (20 ml) at room temperature under argon atmosphere for 1 hr. Then, to this solution N-chlorosuccinimide (180 mg, 1.35 mmol) was added and the mixture was stirred at room temperature for 1 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (20 g). Elution with n-hexane-ether (10:1) provided the chlorodiester (10) (730 mg, 99%), glass. 1H-NMR: 0.72 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 1.30 (6H, t, J=7.5 Hz, --CO2CH2CHHD 3), 2.95 (2H, t, J=15 Hz, 24-H2), 3.52 (2H, m, THP), 3.88 (1H, m, 3-H), 4.32 (4H, q, J=7.5 Hz, --CO2CO2CH3), 4.72 (1H, m. THP), 5.38 (1H, m, 6-H). MS m/z: 554, 520.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCCl>[C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:4]([O:3][CH3:2])=[O:10])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of 3.00 g (18.1 mmol) of L-proline methyl ester hydrochloride, 5.05 g (18.1 mmol) of trityl chloride and 10 mL of triethylamine in 40 mL of 1,2-dichloroethane is stirred at 22° C. After a few minutes, a thick precipitate began to form. An additional 20 mL of 1,2-dichloroethane is added and the mixture is heated to 60° C. and stirred for 3 hrs. The reaction mixture is partitioned between water (100 mL) and CH2Cl2 (100 mL). The organic layer is washed with satd. NaHCO3 (50 mL), dried (MgSO4) and evaporated. The residue is recrystallized from hexane/EtOAc to give 5.76 g of 1-trityl-pyrrolidine-2-carboxylic acid, methyl ester as a white crystalline solid which is used directly in the next step.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1>C(O)C>[C:15]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)[CH:16]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cccc(-c3ccccc3)c2)[nH]c1=O
Temperature: 80 °C

Procedure:
The mixture of ethyl 2-(methylthio)-6-oxo-1,6-dihyropyrimidine-5-carboxylate (319 mg, 1.491 mmol) and [1,1′-biphenyl]-3-amine (252 mg, 1.491 mmol) were dissolved in 10 mL of ethanol and heated at 80° C. overnight. After heating, the solution was run on thin layer chromatography and filtered. The precipitate was collected and stored. 1H-NMR confirmed the product (246 mg, 49.2%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:19])=[O:18]
Reactant: OCc1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
2-Pyridylcarbinol(0.19 ml, 1.71 mmol) was dissolved in methylene chloride(2 ml), triethylamine(0.59 ml, 4.27 mmol) was added thereto, and the mixture was stirred for 10 minutes at 0° C. Then, methanesulfonyl-chloride(0.26 ml, 3.41 mmol) was added and the resulting mixture was stirred for 10 minutes at the same temperature. The reaction solution was sequentially washed with saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to give 2-(methanesulfonyloxymethyl)pyridine(315 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][N:12]=1)[CH3:2].[NH:28]1[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.ClCCl.O.CC(O)=O>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29]4)[CH:7]=[CH:6][CH:5]=3)=[N:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3,4-thiadiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D27) (31 mg) and methyl 3-azetidinecarboxylate (62.6 mg) in ethanol (10 mL) stirred at room temperature was added sodium acetate (33.9 mg) and AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. The residue was dissolved in dichloromethane (DCM) (10 mL), sodium triacetoxyborohydride (52.5 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford methyl 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)methyl]-3-azetidinecarboxylate (D29) (39 mg). MS (ES): C27H30N4O2S requires 474. found 475.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.[Br:17]Br>C(O)(=O)C.C1(C)C=CC=CC=1>[Br:17][CH2:15][C:14]([C:4]1[CH:5]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[3-Bromo-5-(pentafluorosulfanyl)phenyl]ethanone (50 mg) was initially charged dissolved in glacial acetic acid (3 ml), and bromine (50 μl of a solution of 475 mg of bromine in 1 ml of glacial acetic acid) was slowly added dropwise. After stirring at RT for 30 min, the mixture was heated to 60° C. for 3 h and then a further 15 μl of the bromine solution were added. After 2 h, the mixture was left to stand overnight, then heated again to 60° C., and a further 10 μl of the bromine solution were added. After 1 h, the mixture was diluted with toluene and dried. The residue was purified by means of preparative HPLC, and the product-containing fractions were combined, freed of the acetonitrile, alkalized with saturated sodium hydrogencarbonate solution and extracted three times with EA. The combined EA phases were dried over magnesium sulfate, filtered and concentrated. 16 mg of the title compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]([C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=O)(C)(C)C.C(=O)(O)[O-].[Na+].C(#N)C>ClCCl.FC(F)(F)C(O)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[C:26]([N:14]([CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:37]
Reactant: COc1ccc(C(=O)N(Cc2ccc3ccccc3c2)CC2CCCN2C(=O)OC(C)(C)C)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(C(=O)N(Cc2ccc3ccccc3c2)C[C@@H]2CCCN2)cc1OC
Reaction time: 1 h

Procedure:
In 20 mL mixture of dichloromethane and trifluoroacetic acid 30%, was dissolved 2-{[(3,4-Dimethoxy-benzoyl)-naphthalen-2-ylmethyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester 1.1 g (2.18 mmol). After 1 hour at room temperature, saturated solution of sodium bicarbonate was added until basic pH, the mixture was extracted with dichlorometane, dried over magnesium sulfate, filtered and concentrated under vacuum, yield to 0.88 g. LC-MSD, m/z for: C25H28N2O3 [M+H]: 404.2. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 7 minutes: 1.37 min.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[C:8](=[O:21])[C:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=1[C:15]2=[O:20])([O-])=O.[H][H]>[Pd].COCCO>[NH2:3][C:6]1[C:7]2[C:8](=[O:21])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:20])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 110.8 %

Procedure:
0.026 Gram of a 5% palladium on carbon catalyst and 3.0 grams of a 20% aqueous sodium hydroxide solution were added to a mixture of 2.6 grams of 5-nitrotetrahydroanthraquinone and 101 grams of methyl cellosolve, into which was fed hydrogen for having hydrogen absorbed at room temperature under normal pressure in the 5-nitro compound in an amount of 1.1 mols per mol of the 5-nitro compound. A small amount of reddish brown crystals were precipitated. The reaction solution was subjected to filtration, followed by washing with methyl cellosolve. The filtrate and washings were combined together and neutralized with dilute sulfuric acid. Then, the resultant solution was concentrated under reduced pressure to obtain crystals which were separated by filtration, washed with methanol and then with water, and dried to obtain 2.5 grams of 1-aminoanthraquinone. The purity was 97.8% and the yield was 93.3%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23]>>[CH3:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: Cc1ccc(C)c(Br)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cc(C)ccc2C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 2-bromo-1,4-dimethylbenzene (0.08 mL, 0.60 mmol) according to the general procedure IF to give 123 mg (84%) of a clear oil after purification by flash chromatography (SiO2, EtOAc:PE, 1:8): Rf=0.21 (EtOAc:PE, 1:8); 1H NMR (CDCl3) δ 7.46-7.43 (m, 2H), 7.31 (s, 1H), 7.19-7.17 (m, 2H), 7.11-7.10 (m, 1H), 7.04-7.02 (m, 1H), 3.67 (s, 3H), 2.96 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.45 (s, 3H), 2.30 (s, 3H); 13C NMR (CDCl3) δ 173.5, 140.8, 137.2, 135.2, 132.4, 131.8, 129.5, 129.3, 128.5, 123.0, 121.7, 93.0, 88.4, 51.8, 35.6, 31.0, 20.9, 20.3; ESI-MS m/z 315.1 (M+Na+).
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=2)[C:19]([N:21]=[C:22]([NH2:24])[NH2:23])=[O:20])[CH:13]=[CH:14][CH:15]=1)=[O:10])C1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>CO.[C].[Pd]>[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=2)[C:19]([N:21]=[C:22]([NH2:23])[NH2:24])=[O:20])[CH:13]=[CH:14][CH:15]=1)([OH:10])=[O:8]
Reactant: NC(N)=NC(=O)c1cccc(-n2cccc2C(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(N)=NC(=O)c1cccc(-n2cccc2C(=O)O)c1
Yield: 45.5 %

Procedure:
10% Palladium-carbon (0.2 g) was added to a mixture of 2-[3-(2-benzyloxycarbonylpyrrol-1-yl)benzoyl]guanidine (1.2 g) in methanol and the mixture was hydrogenated at ambient temperature under an atmospheric pressure. After the mixture was added to water, and the mixture was adjusted to pH 10 with potassium carbonate. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate and the separated aqueous layer was adjusted to pH 5 with 6N-hydrochloric acid. The isolated precipitate was collected by filtration and the precipitate was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-[3-(2-carboxypyrrol-1-yl) benzoyl]guanidine (0.41 g).