Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(O[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)C=C.[OH-].[K+]>>[C:18]1([CH:19]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:21]=[CH:22][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccccc1O
Reactant: C=CCOc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General procedure for the synthesis of chalcone 32a-l: To a round-bottom flask was charged with 2′-hydroxyacetophenone 31 (1.0 equiv.), 4-allyloxybenzaldehyde (1.0 equiv.) and excess potassium hydroxide solution (3M solution in 96% EtOH). The mixture was stirred at room temperature for 16 h. When TLC indicated complete consumption of 2′-hydroxyacetophenone, the reaction mixture was acidified to pH 5 with 1 M HCl solution at ice-bath temperature. The mixture was continuously extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure to give a crude mixture, which was washed with 5% ethyl acetate in hexane to furnish desired chalcone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16]([O:18]N2C(=O)CCC2=O)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=2)C=CC=CC=1.[Al]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:18])[N:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:37][C:36]2[CH:35]=[CH:34][CH:33]=[CH:40][CH:39]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)ON1C(=O)CCC1=O
Reactant: NCc1ccc(-c2ccccc2)cc1
Agent: [Al]
Solvent: ClCCl
Product: O=C(Cn1cccc(OCc2ccccc2)c1=O)N(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
15 (0.5 g, 1.4 mmol) was dissolved in 50 mL of dry CH2Cl2. 4-phenylbenzylamine (0.28 g, 1.5 mmol) was dissolved in 10 mL of dry CH2Cl2 to yield an almost clear, colorless solution and was quickly added to the stirring solution of 15. The reaction flask was protected from light with aluminum foil and stirred at room temperature under a dinitrogen atmosphere for 18 h. A white solid was removed by vacuum filtration. A second crop of white precipitate was isolated after cooling the filtrate at 4° C. for 3 h. The CH2Cl2 filtrate layer was washed with 0.05 M aqueous sodium bicarbonate solution (3×25 mL). The methylene chloride layer was washed with ddH2O (1×25 mL) and then dried over anhydrous sodium sulfate. The clear, colorless solution was concentrated by rotary evaporation to yield a white solid. Yield: 55%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.33 (d, J=6.0 Hz, 2H, —CH2—), 4.61 (s, 2H, —CH2—), 5.00 (s, 2H, —CH2—), 6.12 (t, J=7.2 Hz, 1H, Ar—H), 6.91 (d, J=7.6 Hz, 1H, Ar—H), 7.22 (d, J=6.8 Hz, 1H, Ar—H), 7.39 (m, 9H, Phenyl-H, Bz—H), 7.62 (m, 5H, Bz—H), 8.70 (t, J=5.8 Hz, 1H, —NH—).
Reaction SMILES: S([O:11][C@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH2:39](O)[CH2:40][OH:41].O>O1CCOCC1>[CH3:28][CH:26]([CH2:25][CH2:24][CH2:23][C@H:22]([C@@H:21]1[C@:30]2([CH3:38])[C@H:18]([C@H:17]3[C@H:33]([CH2:32][CH2:31]2)[C@:34]2([CH3:37])[C:14]([CH2:13][C@@H:12]([O:11][CH2:39][CH2:40][OH:41])[CH2:36][CH2:35]2)=[CH:15][CH2:16]3)[CH2:19][CH2:20]1)[CH3:29])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Reactant: OCCO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 70.3 %

Procedure:
A solution of 10 g of cholesterol tosylate and 25.3 g of ethylene glycol in 180 ml of dioxan is heated to 120° C. while stirring. The mixture is then treated with 200 ml of water and extracted with ether. The ethereal phase is washed firstly with 10% sodium carbonate solution and then with water. The organic phase is dried and evaporated. The residue is chromatographed on silica gel while eluting with ether/hexane. There are obtained 5.6 g of 2-(cholest-5-en-3β-yloxy)-1-ethanol, m.p. 92°-95° C., the starting material in Example 2q.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([S:21][CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:24])[CH:10]=1.[C:31]([O:35][C:36](=[O:50])[CH2:37][CH2:38][S:39][CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([S:21][CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH:24][C:44]([C:43]2[CH:42]=[C:41]([CH:49]=[CH:48][CH:47]=2)[CH2:40][S:39][CH2:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:50])=[O:45])[CH:10]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: CCSc1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCSc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(ethylthio)phenyl)isonicotinamide (200 mg, 0.46 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (200 mg, 0.68 mmol, 1.50 equiv), EDC.HCl (190 mg, 0.99 mmol, 2.00 equiv), and 4-dimethylaminopyridine (60 mg, 0.49 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 300 mg (crude) of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(ethylthio)phenyl)carbamoyl)-benzylthio)propanoate as a yellow solid.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:31]#[N:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)CC1
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=O)=[CH:6]2.[Br-].[Cl:15][C:16]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:17]=1[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C>>[Cl:15][C:16]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:17]=1/[CH:18]=[CH:12]/[C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Reactant: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3c(Cl)cccc3Cl)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (O) was reacted with (2,6-dichlorobenzyl)(triphenyl)phosphonium bromide (511) prepared as described in example 102 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0° C., the ratio of LDA aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (512) as a yellow solid (the pure E isomer) (97%), mp 144–147° C. 1H NMR (CDCl3) δ 8.20 (br s, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.27 (m, 1H), 7.25 (d, J=16.8 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.93 (d, J=16.8 Hz, 1H), 6.88 (dd, J=8.7, 2.5 Hz, 1H), 6.61 (d, J=1.8 Hz, 1H), 3.86 (s, 3H). Found: C, 64.04; H, 4.13; N, 4.39. C17H13Cl2NO requires C, 64.17; H, 4.12; N, 4.40.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:16](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1)[CH2:4][CH3:5].N1C=CC=CC=1.[S:38](Cl)([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:16](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:17][CH2:18][O:19][S:38]([C:41]2[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[CH:11][CH:10]=1)[CH2:4][CH3:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)CCOc1ccc(/C(=C(/CCOS(=O)(=O)c2ccc(C)cc2)c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cis- or trans- N,N-diethylhydroxytamoxifen (II) (100 mg, 0.27 mmol) was dissolved in methylene chloride (2 ml) and cooled to 0° C. Pyridine (150 μl) and tosyl chloride (55 mg, 0.27 mmol) were added. After 2 hours, the reaction mixture was diluted with methylene chloride and washed with water. The methylene chloride layer was evaporated and chromatographed on a 18C column using 85:15:1 acetonitrile/water/triethylamine as eluant to yield cis (51 mg, 34%, oil) or trans tosyl analog (30 mg, 20%, oil): m/z 569(60, M+), 397(20, +OSO2PhCH3). Values for aliphatic protons are presented in Table 2.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:11]1[CH:16]=[C:15]([C:17](O)=O)[CH:14]=[N:13][CH:12]=1.N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:15]3[CH:16]=[N:11][CH:12]=[N:13][CH:14]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cncnc1
Agent: N
Product: c1cncc(-c2noc(-c3cncnc3)n2)c1

Procedure:
The titled compound was prepared according to the procedure of Method C using N′-hydroxynicotinimidamide (Tyger) and pyrimidine-5-carboxylic acid (Maybridge). 1H NMR (300 MHz, DMSO-d6) δ 7.68 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 8.48 (dt, J=7.7, 2.1 Hz, 1 H), 8.84 (dd, J=4.7, 1.7 Hz, 1 H), 9.29 (dd, J=2.4, 1.0 Hz, 1 H), 9.51 (s, 1 H), 9.56 (s, 2 H) ppm; MS (DCI/NH3) m/z=226 (M+H)+, 243 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)C=O.[H-].[Na+]>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Clc1cc(Cl)nc(OCc2ccccc2)n1

Procedure:
4, 6-Dichloro-2-(methysulfonyl)pyrimidine (Compound III-5) (21.3 g, 93.8 mmol) and benzyl alcohol (Compound II-64) (10.1 g, 93.8×1.0 mmol) were introduced into a 500 ml eggplant type flask, to which dimethylformamide (150 ml) was added to form a solution. While stirring in ice bath, 60% sodium hydride (3.94 g, 93.8×1.05 mmol) which had been washed with hexane was added. After bubbling was ceased, ice bath was removed and the reaction solution was stirred for 2 hours at room temperature. The reaction mixture was poured onto ice and the separated organic matter was extracted with ethyl acetate. The organic phase was washed successively with diluted hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and thereafter, the solvent was distilled off. The residue was purified on silica gel column chromatography (Wakogel C300, ethyl acetate/hexane=1/50(v/v)) to obtain the compound (I-173) as an oily product.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].[Na].Br[CH2:7][C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:29])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1>CC(O)C.C1(C)C=CC=CC=1>[OH:29][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[C:24](=[O:28])[CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C:8](=[O:30])[CH2:7][S:4][CH:2]([CH3:3])[CH3:1])[CH2:17]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CC(C)S
Agent: [Na]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)SCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
Propane-2-thiol (1.3 ml.) was added to a warm solution of sodium (0.6 g.) in a mixture of propan-2-ol (25 ml.) and toluene (30 ml.). 21-Bromo-3α-hydroxy-5α-pregnane-11,20 -dione (0.7 g.) was then added and the mixture was gently refluxed for 2 hr. The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na2SO4) and evaporated. The residual foam was purified by preparative t.l.c. (CHCl3) to give title compound (0.2 g.) as a white foam, [α]D + 67° (c 1.3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:39]5[CH2:40][CH2:41][CH2:42][C@H:38]5[CH3:37])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:35][CH2:36]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Product: C[C@@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)CC1

Procedure:
The title compound was synthesized in the same manner as Example 13 by condensing 2-[2-fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) with (R)-2-methyl-pyrrolidine (101.2 mg, 1.19 mmol) to obtain 45 mg (67% yield) of the compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[CH:6][C:5]=1[OH:12].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][C:5]=1[OH:12]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Br)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1O
Temperature: 70 °C
Yield: 45.5 %

Procedure:
To a solution of 5-Bromo-2,4-dihydroxy-benzoic acid methyl ester (1.0 g, 4.04 mmol) in DMF (7 mL) was added Cs2CO3 (1.58 g, 4.85 mmol) and benzylbromide (0.69 g, 4.04 mmol) and heated at 70° C. for 6 h. Reaction mixture was diluted with EtOAc (10 mL) and filtered, filtrate was washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography (EtOAc:Hex, 1:3) gave pure 4-benzyloxy-5-bromo-2-hydroxy-benzoic acid methyl ester (0.62 g).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([C:10]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8]>C(OCC)(=O)C>[C:1]([NH:5][S:7]([C:10]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
206 g of tert-butylamine are added dropwise to a solution of 384 g of methyl 2-chlorosulfonyl-4-nitro-benzoate (Example b) in 1500 ml of ethyl acetate at 0° C. The reaction mixture is then allowed to warm up to room temperature and is stirred at this temperature for 1 hour. After washing with dilute hydrochloric acid and water, the organic phase is dried over MgSO4 and concentrated. The residue is extracted by stirring with diisopropyl ether; Yield of sulfonamide: 377.6 g; m.p.: 122-124° C.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=2)=O)[CH2:3][CH2:2]1.Cl.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([N:25]1[C:6]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=2)=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)C#CC2CC2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(C3CC3)nn2Cc2ccccc2)s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 5-(3-cyclopropylpropioloyl)thiophene-2-carboxylate (100 mg, 0.427 mmol) was dissolved in N,N-dimethylformamide (2 mL), and the solution was cooled to 0° C. Benzylhydrazine hydrochloride (74.5 mg, 0.470 mmol) was added followed by potassium carbonate (77 mg, 0.555 mmol). The mixture was stirred at 0° C. until the ice bath melted and was stirred overnight at room temperature. The solution was partitioned between water and ethyl acetate. The organic extract was dried with sodium sulfate, filtered, concentrated and purified by normal phase chromatography to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:17]1([N:23]2[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:27]4[N:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:24]=[N:25][N:26]=4)[CH2:29][CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Reactant: O=C(O)C(=O)c1c[nH]c2c(Br)ncc(F)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (5.0 g, 17.5 mmol) was dissolved in DMF (100 mL) and treated with 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.0 g, 17.5 mmol), Hunig's base (9.2 mL, 52.6 mmol) and TBTU (5.6 g, 17.5 mmol) and the reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A white solid precipitated out and it was collected by filtration and recrystallized twice with MeOH to afford the title compound (4.58 g) as a white solid. The mother liquid was concentrated and purified using silica gel (CH2Cl2 to 5% MeOH/CH2Cl2) to afford more title compound (1.8 g). 1HNMR (500 MHz, DMSO) δ 8.47 (s, 1H), 8.16 (s, 1H), 7.70-7.59 (m, 5H), 3.67 (m, 2H), 3.44 (m, 2H), 3.37 (m, 2H), 3.20 (m, 2H). LCMS: m/e 499 (M+H)+, ret time 1.50 min (method 1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[CH3:11][O:12][NH2:13].[C:14]1(=[O:21])[CH:20]=[CH:19][CH2:18][CH2:17][CH:16]=[CH:15]1>C(O)(C)C>[CH3:11][O:12][N:13]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][C:14](=[O:21])[CH2:20]2
Reactant: CON
Reactant: O=C1C=CCCC=C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CON1C2CCC1CC(=O)C2
Reaction time: 6 h
Yield: 20 %

Procedure:
N,N-Diisopropylethylamine (14.5 ml) was added dropwise to a stirred suspension of O-methylhydroxylamine hydrochloride (2.32 g) in isopropyl alcohol (25 ml). After 30 minutes cyclohepta-2,6-dienone (3.0 g) in isopropyl alcohol (5 ml) was added dropwise. After 24 hours N,N-diisopropylethylamine (4.9 ml) was added. After 6 hours the mixture was allowed to stand at room temperature overnight. The mixture was evaporated under reduced pressure, diethyl ether added and the resulting mixture extracted with 2M hydrochloric acid (×3). The combined aqueous fractions were washed with diethyl ether (×3), neutralised with sodium hydroxide and extracted with diethyl ether (×3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Kugelrohr distillation gave 8-methoxy-8-azabicyclo[3.2.1]octan-3-one (0.86 g).
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[CH:11]1([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:14])=[O:2])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)Cc1ccc(C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
Methyl(4-cyclopropylphenyl)acetate (710 mg, 3.73 mmol) was dissolved in 5 mL THF, 5 mL MeOH, and aqueous 1N NaOH (7.46 mmol) and the resulting mixture was heated at 45° C. overnight. After cooling to ambient temperature, the reaction was concentrated in vacuo and the residue was diluted with water (50 mL). The aqueous material was acidified with 1N HCl to pH˜3. A light brown precipitate formed which was collected by filtration and dried in a vacuum oven for 3 days to give (4-cyclopropylphenyl)acetic acid (SM-1ag, 395 mg, 60%). MS (ES−) 175.2 (M−H). 1H NMR (DMSO-d6) δ 0.57-0.61 (m, 2H), 0.86-0.91 (m, 2H), 1.81-1.88 (m, 1H), 3.45 (s, 2H), 6.97 (d, 2H), 7.08 (d, 2H), 12.20 (br s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH2:13][CH:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([O:17][CH:12]1[CH2:11][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:15][C:14](=[O:16])[CH2:13]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CC(=O)OC(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
To 6-t-butyldimethylsilyloxymethyl-4-hydroxytetrahydropyran-2-one (0.50 parts) in dichloromethane (10 parts) at ambient temperature was added pyridine (0.20 parts) followed by a solution of acetylchloride (0.20 parts) in dichloromethane (2 parts). After 1 hour at 20°-25° C. less than 2% starting material remained by GLC analysis. The reaction mixture was then washed with water, dried over magnesium sulphate and evaporated to give 4-acetoxy-6-t-butyldimethylsilyloxymethyltetrahydro pyran-2-one (0.6 parts).