Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:43])([F:42])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([CH2:37]OS(Cl)=O)=[CH:29][N:28]=2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:37][C:30]2[C:31]([C:33]([F:36])([F:34])[F:35])=[N:32][C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][C:19]([F:42])([F:43])[F:18])=[CH:22][CH:23]=3)=[N:28][CH:29]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: O=S(Cl)OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with chlorosulfurous acid 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-ylmethyl ester (example 111F]) to give 2-methyl-2-{2-methyl-4-[2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-ylmethoxy]-phenoxy}-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as a white powder of mp. 153.5–154.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
(S)-1-Benzyl-3-hydroxypyrrolidine (20.2 g, 114 mmol) was dissolved in toluene (200 mL). To this stirred solution, triethylamine (20 mL, 142 mmol) was added followed by methanesulfonyl chloride (10.5 mL, 136 mmol) during a period of 40 min at 0° C. The resultant slurry was allowed to stir for two hours at 0° C. and 7% sodium bicarbonate (200 mL) was added to the reaction mixture. Organic layer was separated, and the aqueous layer was extracted with toluene (3×100 mL). The combined organic layers were washed with saturated sodium bicarbonate (3×200 mL), dried over Na2SO4 and concentrated under reduced pressure to give (S)-methanesulfonic acid 1-benzyl-pyrrolidin-3-yl ester as a yellow oil (28 g, 96%). The material was used directly for next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.34-7.17 (m, 5H), 5.24-5.18 (m, 1H), 3.71 (d, JAB=13.0 Hz, 1H), 3.64 (d, JAB=13.0 Hz, 1H), 3.01 (s, 3H), 2.89-2.80 (m, 3H), 2.56-2.50 (m, 1H), 2.38-2.31 (m, 1H), 2.14-2.07 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>CCOC(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:7]=[CH:6][C:5]([C:8]4([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: OC1(c2ccc(I)cc2)CCNCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Solvent: CCOC(C)=O
Product: OC1(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)CCNCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 4-(4-iodophenyl)piperidin-4-ol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.78 g (61% of theoretical); C24H21ClN2O (M=388.889); calc.: molpeak (M+H)+:389/391 (Cl); found: molpeak (M+H)+:389/391 (Cl); Rf value: 0.86 (silica gel, EtOAc/cyc 4:1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([CH:12]3[C:21](=[O:22])[CH2:20][CH2:19][C:14]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:13]3)=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O-:23][CH2:24][CH3:25].[Na+]>C(O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][C:14]1([CH2:13][CH2:12][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[O:11])[O:18][CH2:17][CH2:16][O:15]1)[CH3:25]
Reactant: CC[O-]
Reactant: O=C1CCC2(CC1C(=O)c1ccc3ncsc3c1)OCCO2
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC1(CCC(=O)c2ccc3ncsc3c2)OCCO1
Reaction time: 12 h

Procedure:
Under a nitrogen atmosphere, 7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (271 mg, 0.85 mmol) was dissolved in ethanol (1 mL). 2.43 M sodium ethoxide solution (0.01 mL, 0.03 mmol) was added. After 12 hrs, reaction was concentrated in vacuo. The residue was diluted with 10 mL EtOAc/5 mL 10% citric acid. The layers were separated. The aqueous layer was further extracted with EtOAc (3×3 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column (40% EtOAc/hexanes) to yield 3-[2-(3-Benzothiazol-6-yl-3-oxo-propyl)-[1,3]dioxolan-2-yl]-propionic acid ethyl ester (100 mg, 38%, light yellow oil).
Reaction SMILES: S(C)C.[C:4]([NH:7][C:8]1[C:18]2[NH:17][C:16](=O)[CH2:15][N:14]3[C:20]4[CH:21]=[C:22]([C:33]([O:35]C)=[O:34])[CH:23]=[CH:24][C:25]=4[C:26]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[C:13]3[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=O)[CH3:5]>C1COCC1>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([OH:35])=[O:34])=[CH:21][C:20]=3[N:14]3[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]4[N:7]=[C:4]([CH3:5])[N:17]([C:18]=24)[CH2:16][CH2:15]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Nc1c(NC(C)=O)cccc1-3
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1nc2cccc3c2n1CCn1c-3c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reaction time: 0.75 h
Yield: 36 %

Procedure:
Me2S complex (2M in THF) (20 eq) was added to a stirred solution of methyl 4-(acetylamino)-13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate in anhydrous THF (0.02 M) at RT under N2. After 45 min further BH3.Me2S complex (2M in THF) (5 eq) were introduced and the reaction left to stir for 1 h. The reaction was quenched by cautious addition of 1N HCl (aq) and MeOH before partitioning between saturated NaHCO3 (aq) and EtOAc. The organics were washed with water, brine before being dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude product. Purification by flash chromatography (3% MeOH/CH2Cl2) afforded the title compound (36%). MS (ES+) m/z 414 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:36][NH2:37]>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:37][N:36]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)OC[C@H]2C)n1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-2-morpholinecarboxamide (302 mg, 0.66 mmol) and hydrazine monohydrate (0.41 mL, 13.18 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. in a sealed tube for 18 hours. The reaction mixture was cooled and concentrated in vacuo, and the residue was purified by flash chromatography (60 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (239 mg) as a light yellow solid. LC-MS (ES) m/z=473 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (d, J=6.6 Hz, 3H), 2.77-3.02 (m, 4H), 3.78 (d, J=11.2 Hz, 1H), 3.88 (d, J=11.1 Hz, 1H), 4.02 (dd, J=11.2, 2.9 Hz, 1H), 4.27-4.41 (m, 2H), 4.41-4.85 (bs, 2H), 5.39 (s, 2H), 6.51-6.72 (m, 2H), 7.19-7.38 (m, 5H), 7.62 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.99 (s, 1H), 8.54 (t, J=6.2 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[CH:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([C:29]([NH2:31])=[O:30])[CH:22]=1>[OH-].[K+].CCO>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:27][C:26]2[CH:25]=[CH:24][C:23]([C:29]([NH2:31])=[O:30])=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Reactant: NC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc(C=C2CCc3cc(OCCc4c[nH]cn4)ccc3C2=O)cc1

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with benzamide-4-carboxaldehyde (0.178 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.197 (42%) of the title compound as an off-white powder, mp dec. >230° C.: CI-MS m/e 388 (M+ +1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](Cl)[C:8]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][CH:6]=1)[CH3:2].[CH2:18]([Zn]CC)[CH3:19]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH2:18][CH3:19])[C:8]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(N(CC)CC)c(Cl)c1
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N(CC)CC)c(CC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloro-6-diethylamino-nicotinic acid ethyl ester (2.96 g, 11.5 mmol) in dioxane (50 mL), Pd(dppf) (470 mg, 0.576 mmol) is added under argon. To this mixture, diethyl zinc (8.53 g, 69.1 mmol, as a 1.1 M solution in toluene) is added dropwise. The mixture is stirred at 75° C. for 16 h before another portion of Pd(dppf) 94 mg, 0.115 mmol) and diethyl zinc (1.42 g, 11.5 mmol, as a 1.1 M solution in toluene) is added. Stirring is continued at 75° C. for 24 h. The reaction mixture is cooled to rt and carefully quenched with water. The mixture is filtered over celite and the filtrate is extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC (heptane:EA 9:1) to give 6-diethylamino-5-ethyl-nicotinic acid ethyl ester (2.40 g) as a colourless oil; LC-MS: tR=0.78 min, [M+1]+=251.19; 1H NMR (CDCl3): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t, J=7.3 Hz, 3H), 1.40 (t, J=7.3 Hz, 3H), 2.65 (q, J=7.5 Hz, 2H), 3.36 (q, J=7.0 Hz, 4H), 4.37 (q, J=7.0 Hz, 2H), 7.99 (d, J=2.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2-fluoro-4-iodophenylamine (1.50 g) was dissolved in dichloromethane (40 ml) and to the solution were added pyridine (1.02 ml) and methanesulfonylchloride (700 μl). The mixture was stirred at room temperature for 1 hour and 1.5 N aqueous hydrochloric acid was added thereto to quench the reaction. The resulting mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was column-chromatographed (ethyl acetate/hexane=1/1) to yield the compound 3-2 (1.89 g, 95%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:38]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C@@H:16]([CH2:18][CH3:19])[CH3:17])[C:11]=1[O:20]C(=O)N[C@@H](C1C=CC=CC=1)C)(CC)C.[OH-].[Na+]>C(OC)(C)(C)C>[C@H:3]([C:13]1[C:12]([C@@H:16]([CH2:18][CH3:19])[CH3:17])=[C:11]([OH:20])[CH:10]=[CH:15][CH:14]=1)([CH2:4][CH3:5])[CH3:2]
Reactant: CC[C@@H](C)c1cccc([C@H](C)CC)c1OC(=O)N[C@H](C)c1ccccc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC[C@@H](C)c1cccc(O)c1[C@H](C)CC
Temperature: 57.5 °C

Procedure:
To a 100-ml three-necked flask equipped with a magnetic stirrer, a reflux condenser, a thermocouple and an N2 inlet, was added tetrahydrofuran (THF) (9 ml), (R,R,R)-1-phenylethylcarbamic acid-2,6-di-sec-butylphenyl ester (1 g, 2.8 mmol), and 1.0 M sodium hydroxide (11.4 ml, 11.4 mmol). The resulting clear mixture was heated under N2 at 55-60° C. using a heating mantle and continued to stir at this temperature while monitoring the progress of the reaction by HPLC. After the reaction was finished (6-8 h) as judged by HPLC, the reaction mixture was cooled to 15° C. and filtered to remove precipitated urea. The filtered cake was washed with cold THF (5 ml). The filtrate and the wash were combined, acidified to pH 2-3 with 3.0 M hydrochloric acid (HCl) (3.5 ml). After stirring for 10 minutes (min), ether (10 ml) was added and then resulting mixture was vigorously stirred for 15 min after which layers were separated. The organic layer was washed with 3.0 M HCl (3 ml), brine (5 ml), dried magnesium sulfate (MgSO4), filtered to remove the drying agent, and then concentrated on a rotavap to give a semi solid yellow residue which was stirred with methyl tertiary butyl ether (MTBE) (3 ml) for 15 min and then filtered. The filtered cake was washed with MTBE (2 ml). The filtrate and the wash were combined, and then concentrated on a rotavap to give the title compound as a yellow oil (0.6 g, 100% crude yield) that was found to be greater than 93 A % pure by HPLC. The 1H NMR (DMSO-d6) was found to be consistent with the structure.
Reaction SMILES: Br[C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.[C:10]([O:16][CH3:17])(=[O:15])[CH2:11]C(C)=O>>[C:7]([C:3]1[C:2]([CH2:11][C:10]([O:16][CH3:17])=[O:15])=[CH:6][S:5][CH:4]=1)([OH:9])=[O:8]
Reactant: O=C(O)c1cscc1Br
Reactant: COC(=O)CC(C)=O
Product: COC(=O)Cc1cscc1C(=O)O

Procedure:
Methyl (4-carboxy-3-thienyl)acetate was prepared from 4-bromothiophen-3-carboxylic acid and methyl acetoacetate by the method described by D. E. Ames and O. Ribeiro, J Chem.Soc., Perkin I, 1975, 1390, for the preparation of the corresponding ethyl ester. It is a solid which, after crystallisation from aqueous methanol, had mp 121°-122° C., 1H nmr: delta 3.72 (3H, s), 3.95 (2H, s), 7.18 (1H, d J 3 Hz), 8.27 (1H, d J 3 Hz) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[O:2].[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Product: CC(C)(C)OC(=O)c1ccc(C=O)cc1

Procedure:
The starting 4-formylbenzoic acid t-butyl ester was prepared from 4-formylbenzoic acid chloride by esterification with t-butanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[CH3:9].[H-].[Na+].I[CH3:13]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:13])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(S)ccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Br)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a solution of 4-bromo-3-methylbenzenethiol (5.47 g, 26.9 mmol) in DMF (25 mL) was added NaH (0.743 g, 32.3 mmol) at RT. After 15 minutes at RT, the solution was cooled to 0° C. and iodomethane (2.02 ml, 32.3 mmol) was added. The cooling bath was removed and the mixture was allowed to warm up to RT. After 1 hour, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 5.81 g of (4-bromo-3-methylphenyl)(methyl)sulfane as a pale yellow oil.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:11][CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Nc1ccc(S(=O)(=O)Cl)cn1
Temperature: 150 °C
Reaction time: 7 h
Yield: 32.2 %

Procedure:
To 123.8 g (1.06 mol) of chlorosulfonic acid was added 10.00 g (0.106 mol) of 2-aminopyridine by portions under ice-cooling. Thionyl chloride (50.56 g, 0.425 mol) was added thereto, followed by heating under reflux for 2.5 hours and further stirring at 150° C. for 7 hours. The reaction solution was poured onto ice water, neutralized by adding sodium bicarbonate thereto and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution, water and brine successively, dried over magnesium sulfate and then concentrated to dryness. The resulting residue was suspended in ethyl ether and the insoluble matters were filtered off. The filtrate was concentrated to dryness and the resulting residue was recrystallized from ethyl ether-hexane to give 6.58 g of the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:21]>[Cu]Br>[Br:21][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Amino-5-(pentafluorosulfanyl)benzoic acid (1.1 g; example 2a) was dissolved in 24% hydrogen bromide solution (40 ml). While stirring and cooling, sodium nitrite solution (290 mg dissolved in 20 ml of water) was added dropwise, in the course of which the temperature was not to exceed 5° C. On completion of formation of the diazonium salt, copper(I) bromide solution (720 mg dissolved in 15 ml of 48% hydrobromic acid) was cooled to 0° C. while stirring and the above diazonium salt solution was slowly added dropwise. Then the cooling bath was removed and the mixture was stirred at RT for 3 h. Thereafter, the reaction mixture was diluted with water and extracted repeatedly with EA. The combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in 500 ml of EA and filtered through a glass frit filled with a 10 cm silica gel layer. The filter layer was washed thoroughly with EA. The clear filtrate was concentrated, and solvent residues were drawn off under high vacuum. 800 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=O.[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[NH:1][C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Nc1cccnc1Cl
Solvent: ClCCl
Product: Clc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
A mixture of 23.2 g (0.10 mole) of 2-amino-4'-chlorobenzophenone and 14.7 g (0.11 mole) of 3-amino-2-chloropyridine (96%) were heated for 1.5 hr at 180° C. under nitrogen atmosphere. The mixture was cooled to room temperature and methylene chloride added. After stirring for 30 min., solids were separated by filtration and triturated in hot 190 proof ethanol. The remaining insoluble material was collected by filtration and recrystallized from benzeneisooctane to give 2.7 g product, m.p. 203°-204.5° C. Drying conditions prior to analyses were: overnight at 97°-98° C./0.1 mm Hg.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>CN(C=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1
Reactant: O=Cc1c[nH]cn1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2ncccn2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Sodium hydride (60% in oil, 1.44 g, 36.00 mmol) was added to a 0° C. solution of 1H-imidazole-4-carboxaldehyde (4.40 g, 36.03 mmol) in DMF (16 mL). After stirring for 20 min at 0° C., the mixture was allowed to warm to RT and a solution of 2-chloropyrimidine (4.12 g, 35.97 mmol) in DMF (8 mL) was added. The resulting mixture was heated to 100° C. for 18 h. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated to provide 6.20 g (86%) of the title compound. MS 175 (M+H)+.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[C:24]([CH3:26])[CH:25]=1.C1C(=O)N([Br:38])C(=O)C1>ClCCl>[Br:38][CH2:26][C:24]1[CH:23]=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:21]=[C:20]([F:19])[CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc(CC(=O)O)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(O)Cc1cc(F)cc(CBr)c1
Temperature: 25 °C

Procedure:
Benzoyl peroxide (0.5 g) was added to a stirred mixture of 2-(3-fluoro-5-methylphenyl)acetic acid (5.19 g) and NBS (6.04 g) in dichloromethane (100 mL). The resultant mixture was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and then washed twice with water, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% acetic acid and 17% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 4.3 g.