Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Yield: 42 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-phenyloxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenyloxazole. The yield was 42%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 111-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:14](OCC)=O)[N:8]2[CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(OCC)(=O)C>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[CH2:14][NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc2ccc(Br)cc2n1CC#N
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Brc1ccc2cc3n(c2c1)CCNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
Ethyl 6-bromo-1-cyanomethylindole-2-carboxylate (3.1 g, 10 mmol) was added portionwise over 2–3 min to a stirred suspension of lithium aluminium hydride (0.95 g, 25 mmol) in ether (100 mL) at room temperature under Ar. The reaction was then heated to reflux and stirred for 18 h. After allowing to cool to room temperature the mixture was poured slowly into stirred saturated aqueous sodium potassium tartrate solution (300 mL). The mixture was stirred for 10 min and ethyl acetate (200 mL) was added. The mixture was then filtered through celite and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine (150 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; methanol-ethyl acetate-ammonium hydroxide (1:9:0)→(9:90:1)] to give the product as a yellow oil (1.1 g, 44%). IR νmax (Nujol)/cm−1 3310, 2925, 2855, 2725, 1886, 1666, 1604, 1563, 1535, 1458, 1411, 1378, 1366, 1340, 1321, 1301, 1278, 1242, 1217, 1201, 1169, 1139, 1128, 1114, 1048, 1000, 945, 924, 876, 844, 835, 812, 792, 751, 730, 699, 648, 619, 590, 562, 523 and 490. NMR δH (400 MHz; CDCl3) 7.42 (1H, m), 7.39 (1H, d, J 8.7 Hz), 7.19 (1H, dd, J 8.7 Hz, 2 Hz), 6.17 (1H, m), 4.20 (2H, d, J 0.8 Hz), 3.97 (2H, t, J 5.8 Hz), 3.35 (2H, t, J 5.8 Hz), 1.63 (1H, br. s).
Reaction SMILES: [OH-].[Na+].C([O:11][CH:12]([C:14]1[S:15][C:16]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=2)=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[N:18]=1)[CH3:13])(=O)C1C=CC=CC=1>CO.O1CCCC1>[OH:11][CH:12]([C:14]1[S:15][C:16]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=2)=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[N:18]=1)[CH3:13]
Reactant: CCC(=O)Nc1cc(-c2sc(C(C)OC(=O)c3ccccc3)nc2-c2cccc(C)c2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)Nc1cc(-c2sc(C(C)O)nc2-c2cccc(C)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
An 1N aqueous sodium hydroxide solution was added dropwise to a solution of 1-[4-(3-methylphenyl)-5-(2-propionylamino-4-pyridyl)-1,3-thiazol-2-yl]ethyl benzoate (1.63 g, 3.46 mmol) in methanol (5 mL) and tetrahydrofuran (20 mL) at 0° C. and the reaction mixture was allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 30 minutes and the solvent was removed under reduced pressure. The residue was treated with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extracts were washed with aqueous sodium hydrogen carbonate solution and brine. The resulting solution was dried, and concentrated under reduced pressure. The obtained crude crystal was recrystallized from ethyl acetate-hexane to give a title compound (1.12 g, yield 89%).
Reaction SMILES: B.O1[CH2:6][CH2:5][CH2:4]C1.[C:7]([NH:11][C:12](=O)[C:13]([CH2:16]C(C)C)([CH3:15])C)([CH3:10])([CH3:9])[CH3:8].Cl.[OH-].[Na+].O1CCC[CH2:25]1>O>[C:7]([N:11]([CH2:25][CH:5]([CH3:4])[CH3:6])[CH2:12][CH:13]([CH3:15])[CH3:16])([CH3:8])([CH3:9])[CH3:10]
Reactant: C1CCOC1
Reactant: CC(C)CC(C)(C)C(=O)NC(C)(C)C
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)CN(CC(C)C)C(C)(C)C

Procedure:
Isobutyryl chloride (10.90 g, 0.1 mol) was added to a solution of tert-butylisobutylamine (25.85 g, 0.2 mol) in tetrahydrofuran (150 ml) at room temperature and stirred for 1 h. Solids were filtered off and washed with tetrahydrofuran ( 2×25 ml). N, N-tert-butylisobutyl-2-methylpropionamide was isolated by distillation to yield 18.50 g, (90%), bp 59-60° C./1.3 mm Hg. A 1 M borane-tetrahydrofuran solution (100 ml, 0,10 mol) was added dropwise to a solution of the amide (17.95 g, 90 mmol) in tetrahydrofuran (50 ml) at room temperature and the mixture refluxed for 1 h. Water (5 ml) was added after cooling, followed by a slow addition of 6 M hydrochloric acid (60 ml). Tetrahydrofuran was distilled off and solid sodium hydroxide (20.00 g, 0.5 mol) was added. The organic layer was separated and the aqueous solution was extracted with n-pentane (50 ml). The organic solutions were combined, dried over anhydrous magnesium sulfate, and the product was isolated by distillation to yield 14.24 g, (85%), bp 34-35° C./1.5 mm Hg; 1H NMR (CDCl3) δ0.84 (d, J=6.6 Hz, 12H, CH3), 1.01 (s, 9H, CH3), 1.58 (nonet, J=6.6 Hz, 2H, CH), 2.14 (d, J=6.6 Hz, 4H, CH2),
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]1([C:15]#[N:16])C(OCC)=O.[OH-].[K+]>>[CH3:17][C:2]1([CH3:1])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]1[C:15]#[N:16]
Reactant: CCOC(=O)C1C(C)(C)C1(C#N)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C1C(C#N)C1(C)C
Temperature: 130 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
A mixture of 2 g of ethyl 2,2-dimethyl-3-ethoxycarbonyl-1-cyano-cyclopropane-1-carboxylate and 4.71 g of 10% ethanolic potassium hydroxide was stirred under an inert atmosphere for 15 hours and the ethanol was evaporated under reduced pressure. The resulting potassium salt was washed with ether and added to 5.2 g of dimethylformamide and 0.128 g of water. The mixture was heated at 130° C. under an inert atmosphere for 5 hours and the mixture was cooled and poured into a stirred mixture of 25 g of ice and 200 ml of ether. The decanted aqueous phase was extracted with ether. The combined ether phases were washed with aqueous sodium chloride solution, dried and evaporated to dryness to obtain 1.23 g of 2,2-dimethyl-3-ethoxycarbonyl-cyclopropane-1-carbonitrile in the form of a mixture of 90% of the cis isomer and 10% of the trans isomer which could be separated as in Example 2.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH:18]1([N:22]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([CH:18]2[CH2:19][CH2:20][CH2:21]2)[CH2:23][CH2:24]1)=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C1CC(N2CCCNCC2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of N-Boc-trans-4-hydroxy-L-proline (1.0 g, 4.32 mmol), 1-cyclobutyl-[1,4]diazepane hydrochloride (981 mg, 4.32 mmol), EDC (869 mg, 4.54 mmol) and HOBt (583 mg, 4.32 mmol) in DMF (22 mL) was added Et3N (1.2 mL, 8.64 mmol). The solution was allowed to stir overnight at room temperature (rt). The mixture was diluted with 5% aqueous (aq.) NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. Purification by FCC provided the desired product (897 mg, 56%). MS (ESI): mass calcd. for C19H33N3O4, 367.25; m/z found, 368.6 [M+H]+. 1H NMR (CDCl3): 4.81-4.67 (m, 1H), 4.59-4.48 (m, 1H), 3.79-3.42 (m, 6H), 2.92-2.80 (m, 1H), 2.63-2.30 (m, 4H), 2.26-2.07 (m, 2H), 2.07-1.97 (m, 3H), 1.91-1.75 (m, 4H), 1.73-1.54 (m, 2H), 1.48-1.39 (m, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[O:5][CH2:6][C:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:11]=2[CH3:12])[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Reactant: CCOC(=O)CCc1ccc(O)cc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.50 g), ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate (0.31 g), anhydrous potassium carbonate (0.18 g) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[2-ethoxy-4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as a colorless oil (0.62 g, 93%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:55][S:56]([C:59]1[CH:67]=[CH:66][C:62]([C:63](O)=[O:64])=[CH:61][CH:60]=1)(=[O:58])=[O:57]>C(Cl)Cl>[NH2:55][S:56]([C:59]1[CH:60]=[CH:61][C:62]([C:63]([N:24]2[CH2:25][C@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:22]([CH2:21][N:13]([C@@H:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]2)=[O:64])=[CH:66][CH:67]=1)(=[O:57])=[O:58]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(S(N)(=O)=O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of 100 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate, 53 mg of WSC hydrochloride, 37 mg of HOBt and 1.5 ml of methylene chloride was mixed with 51 mg of 4-(aminosulfonyl)benzoic acid and stirred at room temperature for 3Hours. The reaction solution was washed with water and then concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 120 mg of tert-butyl ({(3R,4S)-1-[4-(aminosulfonyl)benzoyl]-4-phenylpyrrolidin-3-yl}methyl)[(1R)-1-(1-naphthyl)ethyl]carbamate as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][C:3]=1[NH:4][S:5]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].S([O-])(O[CH3:27])(=O)=O>[OH-].[Na+]>[NH2:1][C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH3:22])=[CH:15][C:3]=1[N:4]([CH3:27])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[CH:13][CH:14]=1)(=[O:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C)cc([N+](=O)[O-])c2N)cc1
Reactant: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)N(C)c2cc(C)cc([N+](=O)[O-])c2N)cc1
Temperature: 10 °C

Procedure:
0.246 mol (79 g) of 2-amino-3-nitro-5-methyl-N-tosylaniline is dissolved in 260 ml of normal sodium hydroxide solution at 40° C. 0.286 mol (30 ml) of methyl sulphate is added gradually in the course of 3 hours, the temperature being kept at about 40° C. Towards the end of the addition of the methyl sulphate, the pH of the reaction medium is kept alkaline by simultaneously adding 20 ml of normal sodium hydroxide solution. After cooling to about 10° C., the expected product which has precipitated is filtered off. It is washed with a normal sodium hydroxide solution and then with water and recrystallised from acetic acid. After drying in vacuo, it melts at 208° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH:24]=[O:25])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[BH4-].[Na+].CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(C=O)c2)Cc2ccccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(CO)c2)Cc2ccccc2C1
Reaction time: 1 h

Procedure:
The compound of step 1 (0.500 g, 1.42 mmol) was dissolved in THF (5 ml) and cooled in an ice bath. Sodium borohydride (0.164 g, 4.25 mmol) was added. Subsequently methanol (2 ml) was added dropwise. After 1 h, the volatiles were evaporated, the residue was partitioned between diethyl ether and a saturated sodium hydrogencarbonate solution, and the aqueous phase extracted with diethyl ether. The combined organic phases were dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:24]([C@@H:26]2[C@H:29](OC(=O)C)[N:28]([NH2:34])[C:27]2=[O:35])=[O:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:24]([C@@H:26]2[CH:29]([O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:28]([NH2:34])[C:27]2=[O:35])=[O:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)CCc2ccccc2)C(=O)N1N
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: NN1C(=O)[C@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)CCc2ccccc2)C1OCc1ccccc1
Yield: 23 %

Procedure:
A mixture of (3S,4S)-3{N-(3-phenylpropionoyl)-β-(2-naphthyl)-L-alanyl}-amino-4-acetoxy-azetidin-2-one (236 mg, 0.5 mmol), benzyl alcohol (54 mg, 0.5 mmol), and zinc acetate dihydrate (110 mg, 0.5 mmol) in benzene (20 ml) and toluene (20 ml) was refluxed for 5 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate, containing a small volume of acetone, and water. The organic layer was washed with water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:1) as eluent and the title compound was obtained.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.OS(O)(=O)=O.C1C(=O)N([Br:25])C(=O)C1>O>[Br:25][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([CH:2]([F:12])[F:1])[CH:8]=1
Reactant: O=[N+]([O-])c1cccc(C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
1-(Difluoromethyl)-3-nitrobenzene (866 mg, 5.00 mmol) was added to cold conc. H2SO4 and then NBS (890 mg, 5.00 mmol) was added. The mixture was warmed to room temperature for 30 minutes then 50-60° C. for 1 h. The mixture was then poured in water and ice and extracted diethyl ether twice. The organic layer was washed with dilute aqueous NaHCO3 and brine. Purification by chromatography on silica gel (0-15% ethyl acetate in hexanes) yielded 1-bromo-3-(difluoromethyl)-5-nitrobenzene (710 mg, 2.82 mmol, 56.3%).
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[K+].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:3]1[C:4](=[O:6])[CH2:5][O:1][C:2]1=[O:7]
Reactant: O=C1COC(=O)C1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COC(=O)C1CCCCCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of furan-2,4(3H,5H)-dione (500 mg, 5.0 mmol) in THE (10 ml) is added K2CO3 (2.5 g, 18.1 mmol) and the mixture is stirred at room temperature for 3 hours under nitrogen atmosphere. To the reaction mixture is added a solution of 1,5-dibromopentane (5.0 g, 21.7 mmol) in THE (10 ml), slowly over 30 minutes. It is then stirred vigorously at room temperature for one day. The reaction mixture is then partitioned between CH2Cl2 (100 ml) and saturated NH4Cl (50 ml). The organic phase is extracted with CH2Cl2 (3×50 ml), and the combined organic phase is washed with brine (50 ml), dried over MgSO4 and concentrated. The resulting crude product is purified by column chromatography over silica gel eluting with 20% ethyl acetate to give a pure product.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[CH:9]=[C:10]([F:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: I[C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.[H-].[Na+].N1C=CC=C1C(OC)=O.C([Si](Cl)(C(C)C)C(C)C)(C)C>CCCCC.O1CCCC1>[CH3:10][O:9][C:7]([C:5]1[N:4]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:3]=[CH:2][CH:6]=1)=[O:8]
Reactant: COC(=O)c1cc(I)cn1[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: COC(=O)c1ccc[nH]1
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)c1cccn1[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 73 %

Procedure:
The 3-iodo-5-methoxycarbonyl-1-triisopropylsilylpyrrole starting material can be prepared as follows. Sodium hydride (80% dispersion; 660 mg, 22 mmol) was washed with pentane and suspended in tetrahydrofuran (20 mL). A solution of methyl pyrrole-2-carboxylate (1.251 g, 10 mmol) in tetrahydrofuran (10 mL) was added and the mixture stirred at room temperature. When gas evolution ceased, triisopropylsilyl chloride (1.928 mg, 10 mmol) was added dropwise, and the mixture was stirred for 1 hour, heated at reflux overnight, and partitioned between ether and water. The ethereal layer was dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by chromatography using hexanes:ethyl acetate (8:1) to yield 2-methoxycarbonyl-1-triisopropylsilylpyrrole as an oil (2.05 g, 73%): 1H NMR (CDCl3) δ 7.12 (m, 2H), 6.26 (m, 1H), 3.78 (m, 3H), 1.76 (sept, 3H, J=7.6 Hz), 1.04 (d, 18 H, J=7.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[O:7])=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH3:25])([CH3:24])[CH2:21][CH2:22]O.CCN=C=NCCCN(C)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([O:16][CH2:22][CH2:21][Si:20]([CH3:25])([CH3:24])[CH3:19])=[O:15])=[O:7])=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)CCO
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOC(=O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.9 %

Procedure:
To a solution of trans-2-(4-bromobenzoyl)cyclohexanecarboxylic acid (5.0 g, 16.07 mmol) in DCM (80 mL) was added 2-(trimethylsilyl)ethanol (2.1 g, 17.68 mmol), N,N′-dimethylamino-pyridine (98 mg, 0.80 mmol), and EDCI (4.0 g, 20.89 mmol). The resulting reaction mixture was stirred at rt for 2 days. Water was added, and the mixture was diluted with DCM. The aqueous layer was separated and extracted with DCM. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Biotage cartridge), eluting with 10% EtOAc in hexane gave trans-(trimethylsilyl)ethyl 2-(4-bromobenzoyl)cyclohexanecarboxylate (2.44 g, 37%). 1H NMR (400 MHz, CD2Cl2) δ −0.01 (s, 9H), 0.85 (m, 2H), 1.45 (m, 3H), 1.73 (m, 2H), 1.90 (m, 2H), 2.18 (m, 1H), 2.71 (m, 1H), 3.80 (m, 1H), 4.05 (m, 2H), 7.58 (d, 2H), 7.70 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[CH:5]=[N:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8].[CH:20]([Mg]Br)=[CH2:21].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH:20]=[CH2:21])[CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=1
Reactant: CC(C)(C)[S@](=O)N=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
To a solution of (S)-N-(3-bromo-5-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (20 g, 56.1 mmol) in DCM (300 mL) was drop wise added vinylmagnesium bromide (84 mL, 1 M in THF, 84 mmol) at −60° C. The reaction mixture was stirred at room temperature for 5 h and poured into aqueous NH4Cl solution. The resulting mixture was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (12 g, yield: 56%); m/z (ES+): 384 [M+H]+.