Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.[CH3:14][NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClC(Cl)C>[C:9]([O:8][CH2:7][CH:6]([N:15]([CH3:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: CNCC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCC(COC(C)=O)N(C)CC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of 3-(acetyloxy)-2-oxopropyl acetate (4.54 g, 26 mmol) in dichloroethane (75 ml) was added tert-butyl 2-(methylamino)acetate HCl. After stirring for 10 minutes sodium triacetoxyborohydride (8.3 g, 39 mmol) was added and stirring was continued for 18 hours and monitored by TLC (1:1heptane:EtOAc). The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and the crude product was extracted into dichloromethane. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 0-20% EtOAc:Hept to yield the title compound (1.32 g, 17% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ 4.07-4.33 (4H, m), 3.34 (2H, s), 3.23 (1H, t, 5.9 Hz), 2.49 (3H, s), 1.99-2.19 (6H, m), 1.33-1.55 (9H, m).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.Cl>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
Acryloylchlorid (0.8 ml, 9.8 mmol, 1 eq) was added dropwise to a stirred ice-cold solution of piperazine 1-carboxylic acid tert butyl ester (2 g, 9.8 mmol, 1 eq) and triethylamine (1.4 ml, 9.8 mmol, 1 eq) in dichloromethane (50 mL) at 0° C. The mixture was then stirred and allowed to come to room temperature over 2 hours. 1M Hydrochloric acid solution (50 mL) was added to the mixture, and the two layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution (2×50 ml) and saturated sodium chloride solution (50 ml) and dried over MgSO4. After filtration, the solvent is evaporated. The residue was purified by chromatography (ethyl acetate/n-hexane 1/1) to give the product (1.26 g, 49%) as a white solid.
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(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:26]([C:21]1[CH:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
To a solution of 24.8 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5 mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered, and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 36.8 g (0.15 mol) of 3,5-dichlorobenzenesulfonyl chloride in 70 mL of CH2Cl2 dropwise quickly over five minutes. The addition funnel was rinsed with an additional 30 mL of CH2Cl2, and the cloudy yellow mixture was allowed to warm to room temperature with stirring overnight. The mixture was washed twice with 400 mL of 1 N HCl, twice with 400 mL of 1 N NaOH, then brine, then dried (MgSO4), filtered, and concentrated to a yellow oil which crystallized on standing. The material was recrystallized three times from ethyl acetate/hexanes to give 39.3 g (0.116 mol, 77%) of N-(3,5-dichlorobenzenesulfonyl)-Proline methyl ester (MW=338) as white needles (TLC on silica vs. 2:1 hexanes/ethyl acetate, Rf=0.51). M/z=339.3 (M+H+).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:34][O:35][CH2:36][CH2:37][CH2:38][NH:39]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:32](=[O:33])[N:15]3[C:16]([C:29]([OH:31])=[O:30])=[C:17]([CH2:20][S:21][C:22]4[N:26]([NH2:27])[C:25]([CH3:28])=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:47]>CO>[ClH:47].[ClH:47].[ClH:47].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:34][O:35][CH2:36][CH2:37][CH2:38][NH2:39])[C:10]([NH:12][CH:13]2[C:32](=[O:33])[N:15]3[C:16]([C:29]([OH:31])=[O:30])=[C:17]([CH2:20][S:21][C:22]4[N:26]([NH2:27])[C:25]([CH3:28])=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOCCCNC(=O)OC(C)(C)C)c4csc(NC=O)n4)[C@H]3SC2)n1N
Agent: Cl
Solvent: CO
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOCCCN)c4csc(N)n4)[C@H]3SC2)n1N
Yield: 85.8 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-(4-amino-5-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.45 g.), and conc. hydrochloric acid (1.1 g.) in methanol (10.2 ml.) was treated in a similar manner to that of Example 8-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)acetamido]-3-(4-amino-5-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid trihydrochloride (syn isomer, 1.21 g.)
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30](C(OCC)=O)[CH:29]=[CH:28]3)(=[O:24])=[O:23])[CH:3]=1.C1([OH:45])C=CC=CC=1>>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([S:22]([C:4]3[CH:3]=[C:2]([OH:45])[C:7]4[O:8][C:9]5[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C:10]=5[C:6]=4[CH:5]=3)(=[O:24])=[O:23])=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(Cl)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Reactant: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(S(=O)(=O)c4ccc5[nH]ccc5c4)cc3c2C1
Yield: 65 %

Procedure:
The product of step A was converted to the phenol derivative using the procedure of Example 54, step A. Purification by flash column chromatography (SiO2, 3:7 hexane/ethyl acetate) provided tert-butyl 8-((1H-indol-5-yl)sulfonyl)-6-hydroxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (90 mg, 65%) as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 8.98 (s, 1H), 8.22 (s, 1H), 7.77-7.17 (m, 4H), 6.51 (s, 1H), 4.49 (s, 2H), 3.80-3.67 (m, 2H), 2.80-2.63 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([N:25]([CH3:41])[C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.CC[O:53]CC.CN(C=O)C>C(O)(=O)C>[NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([N:25]([CH3:41])[C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17]([CH3:18])=[O:53])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N(C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reactant: CCOCC
Agent: OO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 0.17 h

Procedure:
In 3 ml of acetic acid is dissolved 0.35 g of BOC-Tyr-(D)-Met-Gly-MePhe-NHNHCONH2 followed by addition of 0.082 ml of 30% aqueous H2O2. The solution is stirred for 10 minutes, treated with 100 ml of ether and filtered to obtain a powder. Yield 0.35 g (88%); m.p. 110°-115° C.; [α]D24 -35.1° (c=1.04, DMF); Rf1 0.05.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[OH:40][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Example 5) according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.65 (m, 2 H), 1.95–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 5 H), 3.55–3.70 (m, 2 H), 3.80–3.90 (m, 1 H), 4.05–4.20 (m, 1 H), 5.70 (brs, 1 H), 6.67 (d, J=9.0 Hz, 2 H), 6.76 (d, J=9.0 Hz, 2 H), 6.78 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 7.58 (d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H), 8.97 (s, 1 H), 10.37 (s, 1 H); MS (ES) m/z: 555.1 (MH+); HRMS Calcd. for C28H35N4O6S (MH+): 555.2277. Found: 555.2267.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Br)cc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1Br

Procedure:
5.8 g of 2-bromo-4-fluoro-5-methylsulphonylbenzoic acid are stirred, at room temperature for 12 h, in 20 ml of DMF together with 3.7 ml of methyl iodide and 8.3 g of potassium carbonate. The reaction mixture is then concentrated and 50 ml of water are added to it. The resulting precipitate is filtered off with suction and dried. Methyl 2-bromo-4-fluoro-5-methylsulphonylbenzoate is obtained, m.p. 126°.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[CH:3]=1.[C:12]1([S:18]([N:21]2[C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[C:23](I)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:21]2[C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[C:23]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[N:4]([CH3:11])[CH:3]=3)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccncc21
Reactant: Cn1cc(I)c2cccnc21
Product: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cnccc23)c2cccnc21

Procedure:
Analogously to Example 5, 3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine is reacted with 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-c]pyridine to give 1-benzenesulfonyl-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrolo-[2,3-c]pyridine.
Reaction SMILES: [C:1]([C:6]1[CH:47]=[C:46]([C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH:45]=[CH:44][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:25]=[C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[C:32]([N+:40]([O-])=O)[CH:31]=2)(=[O:29])=[O:28])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[OH:43])=[O:15])([CH2:4][CH3:5])([CH3:3])[CH3:2]>O1CCCC1.[Pd]>[NH2:40][C:32]1[CH:31]=[C:30]([S:27]([NH:26][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([OH:43])=[C:16]([C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:44]=[CH:45][C:46]([C:48]([CH2:51][CH3:52])([CH3:49])[CH3:50])=[CH:47][C:6]=3[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])=[O:15])[CH:25]=2)(=[O:28])=[O:29])[CH:35]=[CH:34][C:33]=1[C:36]([O:38][CH3:39])=[O:37]
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(NS(=O)(=O)c3ccc(C(=O)OC)c([N+](=O)[O-])c3)c3ccccc3c2O)c(C(C)(C)CC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(NS(=O)(=O)c3ccc(C(=O)OC)c(N)c3)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
Intermediate (C) (10.0 g, 13.9 mmoles) was reduced in tetrahydrofuran (100 ml) using Pd/C catalyst at 60 pounds pressure (H2 gas). The temperature rose to 30° C. The catalyst was removed by filtration; the filtrate was concentrated to dryness. Trituration of the residue with methanol produced a solid; yield, 8.3 g (84.9 percent).
Reaction SMILES: [CH3:1][CH:2]([C:4](=O)[C:5](=O)[CH:6]([CH3:8])[CH3:7])[CH3:3].[CH:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH2:17].O>C(O)(=O)C>[CH:2]([C:4]1[C:5]([CH:6]([CH3:8])[CH3:7])=[N:18][C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:17]=1)([CH3:3])[CH3:1]
Reactant: NC1CCCCC1N
Reactant: CC(C)C(=O)C(=O)C(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1nc2c(nc1C(C)C)CCCC2

Procedure:
8.7 g of 2,5-dimethyl-3,4-hexanedione and 11.2 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 30 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 6.8 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](F)(F)F)[CH:5]=[CH:6][C:7]=1[Cl:8].[Al+3].[Cl-:14].[Cl-:15].[Cl-:16]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:16])=[C:2]([Cl:1])[CH:7]=2)([Cl:15])[Cl:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [Cl-]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Solvent: Clc1ccccc1Cl
Product: Clc1ccc(C(Cl)(Cl)c2ccc(Cl)c(Cl)c2)cc1Cl

Procedure:
reacting 3,4-dichlorobenzotrifluoride with 1,2-dichlorobenzene and AlCl3 to form bis(3,4-dichlorophenyl) dichloromethane;
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20]C)=[C:14]([O:22][CH3:23])[CH:13]=3)=[CH:8][CH:9]=2)[C:4]([C:24]#[N:25])=[CH:3]1.C[Si](I)(C)C.O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:13]=[C:14]([O:22][CH3:23])[C:15]([OH:20])=[C:16]([O:18][CH3:19])[CH:17]=3)=[CH:8][CH:9]=2)[C:4]([C:24]#[N:25])=[CH:3]1
Reactant: COc1cc(Oc2ccc3c(c2)c(C#N)cn3C)cc(OC)c1OC
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClCCl
Product: COc1cc(Oc2ccc3c(c2)c(C#N)cn3C)cc(OC)c1O
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-3-cyano-5-(3,4,5-trimethoxyphenoxy)-1H-indole (500 mg; 1.47 mmol) in CH2Cl2 (10 ml) was added trimethylsilyl iodide (831 μl; 5.84 mmol). After stirring at room temperature under argon atmosphere for 2 h30, the mixture was poured into cold water, extracted with ethyl acetate. The organic phase was evaporated and the residue was purified by flash chromatography on silica gel, eluting with CH2Cl2/Et2O 1:1 to give 1-methyl-3-cyano-5-(4-hydroxy-3,5-dimethoxyphenoxy)-1H-indole: (244 mg)
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])=[C:5]([C:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:18]=1)[C:6]([O:8]CC1C=CC=CC=1)=[O:7])#[N:2].CO>[Pd].C1COCC1>[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([C:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:17][CH:18]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: Cc1c(C#N)ccc(NS(=O)(=O)c2ccccc2)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C#N)ccc(NS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
A mixture of Example 108C (140 mg, 0.34 mmol), 10% Pd/C (73 mg, 0.03 mmol), methanol (4 mL), and THF (8 mL) was stirred under a hydrogen atmosphere for 45 minutes and filtered. The filtrate was concentrated to an oil which was triturated with diethyl ether to provide the desired product. MS (ESI(−)) m/e 315 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.80 (m, 2H), 7.56 (m, 4H), 7.22 (d, 1H), 3.32 (br s, 2H), 2.56 (s, 3H).
Reaction SMILES: [C:1]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CO.Cl>C1COCC1>[C:1]([NH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@H]1CC[C@@H](O)CC1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
This ketone (2.36 g, 9.55 mmol) in THF (5 mL) was added dropwise to a stirred solution of L-selectride in THF (1M, 19.1 mL, 9.55 mmol) under N2 at -78° C. The reaction mixture was stirred at -78° C. for 3 hours, methanol (0.5 mL) was added, and the reaction mixture was allowed to warm to room temperature. 1N hydrochloric acid (5 mL) was added and the mixture stirred overnight. The reaction mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo to yield 2.73 g crude oil. The crude product was purified by MPLC on silica gel (70-230 mesh, 1.5×45 cm column) using a 1:1 hexane/ethyl acetate, 2:1 hexane/ethyl acetate, and ethyl acetate step gradient. Fractions containing pure product were pooled and concentrated in vacuo to give a clear oil (cis-N-Cbz-4-aminocyclohexanol) (1.35 g, 57% yield): 1H NMR (300 MHz) δ 7.35 (m, 5H), 5.10 (s, 2H), 4.74 (br, 1H), 3.91 (br, 1H), 3.62 (br, 1H), 1.18 (m, 8H); MS: (M+H)+ =250, (M+H+NH3)+ =267.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCOCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CC2CCOCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.57 g (3.32 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoate (racemate) in 25 ml of dichloromethane and 5.12 ml (66.4 mmol) of TFA were reacted according to General Method 6A. Yield: 1.60 g (quant.)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.[CH:14]1([NH:17][C:18](=[O:35])[NH:19][C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1([NH:17][C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:3]=3)=[CH:22][CH:21]=2)=[O:35])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: Clc1ccnc(N2CCOCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2ccnc(N3CCOCC3)n2)cc1)NC1CC1
Yield: 5.7 %

Procedure:
To a solution of 4-(4-chloropyrimidin-2-yl)morpholine (80 mg, 0.40 mmol) and (4-(3-cyclopropylureido)phenyl)boronic acid pinacol ester (145 mg, 0.48 mmol) in dioxane (2 mL) was added Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and Cs2CO3 (2M aq solution, 0.3 mL). The reaction mixture was then heated to reflux for 16 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with aqueous NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (0-5% EtOAc/MeOH) to yield a white solid (7.8 mg, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH3:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CO.I([O-])(=O)(=O)=[O:22].[Na+]>O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:16])=[O:22])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
4-chloro-4'-methylthiomethylbenzophenone (4.2 g) was added to methanol (150 ml). Sodium periodate (3.6 g) dissolved in water (20 ml), was added to this solution, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated, and water was added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with n-hexane to obtain the desired product (4.1 g, melting point: 116° to 118° C., yield: 93%).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[C:5]1([CH:11]([CH3:14])[CH:12]=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)C>CO>[CH3:3][C:2](=[CH:12][CH:11]([CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:1]=[O:4]
Reactant: CC(C=O)c1ccccc1
Reactant: CCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C=O)=CC(C)c1ccccc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
192 g of propionaldehyde are added dropwise to a solution of 402 g of 2-phenylpropan-1-al and 12 g of sodium hydroxide in 1 l of methanol in the course of 6 hours. Stirring is continued for one hour, after which the mixture is neutralized with glacial acetic acid (pH=6), stirred overnight and evaporated down, the residue is taken up with CH2Cl2 /H2O, and the solution is extracted with CH2Cl2. The organic phase is washed with water, dried over Na2SO4, evaporated down again and distilled to give 178 g of 2,4-dimethyl-4-phenylbut-2-en-1-al of boiling point 108°-120° C./0.5 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.Cl.[CH2:17]([O:19][NH2:20])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:20][O:19][CH2:17][CH3:18])[CH2:8]2
Reactant: CCON
Reactant: COc1ccc2c(c1OC)CCC(=O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCONC1CCc2c(ccc(OC)c2OC)C1
Temperature: 10 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
5,6-Dimethoxy-3,4-dihydro-1H-naphthalen-2-one (1.5 g, 7.5 mmol), prepared as described in J Med. Chem. 1977, 20, 1111-1116, was dissolved in water (15 ml) and a solution of O-ethylhydroxylamine hydrochloride (1 g, 10 mmol) and Na2CO3 (0.53 g, 5 mmol) in water (10 ml) was added dropwise under stirring at 10° C. The reaction was left at room temperature overnight and then extracted with diethyl ether. The ether solution was evaporated to dryness under vacuum. The residue was dissolved in 20 ml of ethanol and concentrated hydrochloric acid (1 ml) and hydrogenated at 3,6×106 Pa (50 psi) using PtO2 as catalyst. The solvent was removed under reduced pressure, water was added and the aqueous phase was treated with NaHCO3 and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated to dryness under vacuum. The crude residue was purified by chromatography, to afford 0.85 g of the title compound.