Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([P:13]([O:24][CH2:25][CH3:26])([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[CH:9][C:8]=1[C:27]([CH3:40])([CH3:39])[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(OCC)(=O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([P:13]([O:24][CH2:25][CH3:26])([CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[CH:9][C:8]=1[C:27]([CH3:40])([CH3:39])[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(OC(=O)CC)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Reaction time: 3 h
Yield: 66.2 %

Procedure:
Proprionyl chloride (190 μL, 2.17 mmol) was added drop-wise to a stirring solution of crude phenol 122 (880 mg, 1.67 mmol) and DMAP (2 mg, 0.016 mmol) in pyridine (5 mL). The reaction was continued for 3 hr at room temperature followed by the addition of ethyl acetate (100 mL). The organic layer was washed with cold aqueous HCl (0.5 N), H2O and saturated aqueous NaCl then dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (0 to 20% methanol in ethyl acetate) using a Biotage Horizons™ system, resulting in 123 as a pale yellow liquid (644 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J=7.0, 3H), 1.26 (t, J=7.5, 3H), 1.30 (t, J=7.0, 3H), 1.46 (s, 3H), 1.48 (s, 3H), 2.50-2.63 (m, 4H), 2.82 (AB q, J=14.4, 2H), 3.93-4.16 (m, 6H), 4.93 (s, 2H), 7.12-7.18 (m, 3H), 7.26-7.32 (m, 3H), 7.70 (ddd, J=1.8, 8.4, 11.6, 1H), 7.86 (dd, J=1.8, 13.4, 1H): 31P (162 MHz, CDCl3) δ 20.21 (d, J=9.7, 1 P), 34.03 (d, J=9.7, 1 P).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1COCC1>[CH:9]1([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cc(OC2CCCC2)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(OC2CCCC2)ccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a round bottomed flask 2-bromo-4-cyclopentyloxy-pyridine (339 mg, 1.40 mmol) was dissolved in THF (6 mL). The solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.1 mL, 1.47 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 min then at room temperature for 2 h. An additional portion of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 0.27 mL, 0.35 mmol) was added and stirring was continued at room temperature for 30 min. Tributyltin chloride (0.42 mL, 1.54 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to give 4-cyclopentyloxy-2-tributylstannanyl-pyridine as a light brown oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)cc2-c2ccncc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 8 h

Procedure:
A solution of 10.0 mg of the product of Example 4 was dissolved in 0.5 ml of pyridine and treated with 2.6 μL of acetic anhydride. The solution was stirred overnight and diluted with 5 ml water and was extracted with ethyl acetate (2×5 ml). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:30]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:25]=[CH:20][C:21]=1[OH:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(O)c(I)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(S(C)(=O)=O)ccc1O

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-4-(methylsulfonyl)phenol (Intermediate 78), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](OC)[CH:12]=2)[NH:7][CH:6]=1.O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[CH:17][CH:18]=4)[NH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:6]1
Reactant: Oc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: COc1ccc2[nH]cc(CCCCl)c2c1
Product: c1ccc2c(CCCN3CCC(c4c[nH]c5ccccc45)CC3)c[nH]c2c1

Procedure:
of 3-(3-chloropropyl)-5-methoxyindole with 4-(5-hydroxyindol-3-yl)piperidine:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(CO)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OC
Yield: 109 %

Procedure:
A 100 mL, round bottom flask equipped with a magnetic stirrer and a nitrogen inlet is added N-benzyloxycarbonyl-L-valine (3.6 g), dichloromethane (25 mL), and 2,2-dimethoxyethanol (1.85 g) and the mixture is cooled using an ice bath (0-5° C.). DMAP (0.089 g) is added to the reaction mixture followed by the addition of DCC (3.6 g) over a period of 2 minutes. The suspended solid is filtered, the filter cake is washed with 3×10 mL of heptanes, and the filtrate is concentrated. The crude product is purified by silica gel chromatography (4:1, heptanes/ethyl acetate eluent) to provide 5.3 g of 2,2-dimethoxyethyl N-benzyloxycarbonyl-L-valinate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][C:15]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[O:16]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCl)Nc1cccc2ncccc12
Reaction time: 8 h
Yield: 30 %

Procedure:
In 60 ml of methylene chloride was dissolved 4.5 g of 5-aminoquinoline, and 10.5 g of 3-chloropropionyl chloride and 9 g of triethylamine were then added thereto. After the liquid was allowed to stand at room temperature overnight, a 1N aqueous sodium hydroxide solution was added to the liquid, and the latter was then extracted with methylene chloride. The extract was washed twice with an aqueous sodium bicarbonate solution, was then dried, and was concentrated to obtain crystals. The latter were washed with methylene chloride, and filtered to obtain 2.2 g of 5-(3-chloropropionamido)quinoline in a crystalline state.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O.CCOCC>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCOc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution of 7.94 g (48.9425 mmol) of 4,4-dimethylchroman in 70 ml of nitromethane was added under argon 4.0 g (50.96 mmol) of acetyl chloride followed by 6.8 g (51 mmol) of aluminum chloride. This was stirred at room temperature for 5.5 hours and then cooled in an ice bath and treated slowly with 70 ml 6N hydrogen chloride. The resultant mixture was stirred at room temperature for 10 minutes, then treated with 100 ml ether and the organic layer separated. The organic layer was washed with water, saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexanes). This was followed by kugelrohr distillation (95°-100° C.; 0.15 mm) to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[Cl:19]N1C(=O)CCC1=O>C(#N)C>[Cl:19][C:11]1[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:10]=1[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(-c2ccc(O)c(C#N)c2)s1
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(-c2ccc(O)c(C#N)c2)s1

Procedure:
Methyl 5-(3-cyano-4-hydroxyphenyl)thiophene-2-carboxylate and N-chlorosuccinimide were stirred at room temperature in acetonitrile to obtain methyl 4-chloro-5-(3-cyano-4-hydroxyphenyl)thiophene-2-carboxylate. ESN: 292.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].C1(C)C([C:16]([O-:18])=[O:17])=CC=CC=1O.[K+].C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: Cc1c(O)cccc1C(=O)[O-]
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 79.6 %

Procedure:
A pressure vessel was charged with 6.65 grams of potassium phenolate and 7.40 grams of potassium ortho-cresolate both in dry powder form. With stirring, reaction was carried out at a carbon dioxide pressure of 7 kg/cm2 (G) and 220° to 240° C. for ten minutes. The equimolar mixture of potassium phenolate and potassium ortho-cresolate has a eutectic point of 209° C. in peak value as measured by differential thermal analysis (same throughout the examples). An analysis of the product at the end of reaction showed a para-hydroxybenzoic acid yield of 79.6% on the basis of the potassium phenolate.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[C:1]1([NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:31]3[CH2:32][CH2:33][N:28]([C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)[CH2:29][CH2:30]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(Nc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(Nc1ccccc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(phenyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: Br[CH:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C1CCN2C(=NCCC2)CC1>CC(C)=O>[F:16][C:12]1[N:11]=[C:10]([O:9][CH:2]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:15]=[CH:14][CH:13]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)C(Br)Oc1cccc(F)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C(Oc1cccc(F)n1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a stirred solution of 14.5 g (0.05 mole) of 1-bromo-1-(6-fluoro-2-pyridinyloxy)-3,3-dimethyl-2-butanone in 75 ml acetone cooled to -10° C. was added 3.4 g (0.05 mole) imidazole. Then, 7.61 g (0.05 mole) of 1,5-diaza(5.4.0)undec-5-ene was added dropwise. After the addition was complete, the mixture was stirred for 30 minutes at 0° C. and the solvent evaporated. Water was added to the residue and the mixture extracted with diethyl ether. The ether extract was dried using magnesium sulfate and the solvent evaporated. Chromatography on silica gel (8:2 hexane:acetone) gave 6.3 g (55% yield) of 1-(6-fluoro-2-pyridinyloxy)-3,3-dimethyl-1-(imidazol-1-yl)-2-butanone. Recrystallization from hexane gave product melting at 90°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:10]([O-])([OH:12])=[O:11]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)cc(F)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1c(F)cc(O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-difluorophenol (10 g, 76.9 mmol) in CH2Cl2 at 0° Celsius was added 4.9 mL of 70% nitric acid dropwise. After addition was complete, the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was poured into a separatory funnel and washed once with 750 mL water. The organic layer was dried with Na2SO4, filtered and concentrated to dryness. The resulting residue was purified via FCC to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 6.81-6.67 (m, 2H), 3.40 (bs, 1H).
Reaction SMILES: [Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5]([Cl:7])=[O:6].S(Cl)([Cl:12])=O.ClN1C(=O)CCC1=O>>[Cl:12][CH:4]([CH2:3][C:2]([Br:9])([Br:8])[Br:1])[C:5]([Cl:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(Cl)CCC(Br)(Br)Br
Agent: O=C1CCC(=O)N1Cl
Product: O=C(Cl)C(Cl)CC(Br)(Br)Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of 343,2 g (1 mole) 4,4,4-tribromobutyric acid chloride in 600 g of thionylchloride 266,0 g (2 mole) of N-chlorosuccinimide is added portion wise at 60° C. while the reaction mixture is irradiated with a mercury high-pressure lamp. After addition of the N-chlorosuccinimide the reaction mixture is stirred for 5 hours at 60° C. while irradiation is continued. Then the thionyl chloride is evaporated and the residue is distilled in vacuo. 309.7 (82% of theory) of 2-chloro-4,4,4-tribromobutyric acid chloride, b.p. 59°-63° C./0,05 torr is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][N:14]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C1COCC1.CCOCC>[Br:24][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]=1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(-c3ccc(F)cc3)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(Br)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
Step 3 A solution of tert-butyl 6-(4-fluorophenyl)-1H-indole-1-carboxylate (187.8 mg, 0.603 mmol) in THF (4 mL) was treated with N-bromosuccinimide (118 mg, 0.663 mmol) and stirred at rt. After 18 h, the solution was diluted with ether, washed with 2×10 mL aqueous sodium bisulfite (ca. 1.5 M), then with NaHCO3 (aq), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 90:10 hexane-EtOAc) provide tert-butyl 3-bromo-6-(4-fluorophenyl)-1H-indole-1-carboxylate as a white glassy foam (134 mg, 57%). 1H NMR (400 MHz, chloroform-d) δ 8.39 (1H, br. s.), 7.59-7.68 (3H, m), 7.54-7.59 (1H, m), 7.48-7.53 (1H, m), 7.14 (2H, t, J=8.7 Hz), 1.67 (9H, s).
Reaction SMILES: [S:1]=[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[NH:3]1.CI.[OH-].[Na+].[C:13](O)(=O)C>O>[CH3:13][S:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[N:3]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]ncc(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1cn[nH]c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound 9a (30 g, 232 mmol) and CH3I (15.9 ml, 255 mmol) are placed in 300 ml of water. 18.6 g of NaOH (465 mmol) are added and the mixture is stirred for 1 h at room temperature. The reaction mixture, cooled on a bed of ice, is neutralized using 27 ml of acetic acid and then extracted with dichloromethane. The organic phases are dried (MgSO4) and then concentrated to dryness. After recrystallizing from ether, 29.9 g of compound 9b are isolated.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[O:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>C(Cl)Cl>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:9]1[CH:10]=[CH:11][C:6]([O:5][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:8]=1)=[O:25])[CH3:24]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To 301 g (2.26 mol) of AlCl3 in CH2Cl2 (750 ml) a mixture of 383 g (2.25 mol) of 4-phenoxybenzene and 205 g (1.50 mol) of ethyl chloroglyoxylate in CH2Cl2 (750 ml) is added dropwise at ice-bath temperature during one hour. Thereafter, the mixture is gradually warmed up to room temperature and stirred overnight. Then, the reaction mixture is poured onto ice. The aq. solution is acidified to pH 3 with aqueous HCl solution, followed by an extraction with CH2Cl2. The extract is dried over anhydrous MgSO4. The desired product is purified by silica gel column chromatography using CH2Cl2-hexane mixture as eluent. 338 g of colorless oily 4-phenoxyphenyl glyoxylic acid ethyl ester is obtained (83%).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[OH:6][CH:7]([CH2:14][OH:15])[CH2:8][S:9]([CH2:11][CH2:12][NH2:13])=[O:10]>O>[OH:6][CH:7]([CH2:14][OH:15])[CH2:8][S:9]([CH2:11][CH2:12][NH:13][C:2]([NH2:3])=[O:1])=[O:10]
Reactant: NCCS(=O)CC(O)CO
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCCS(=O)CC(O)CO
Temperature: -5 °C
Reaction time: 1 h

Procedure:
There is slowly added to an aqueous solution of potassium cyanate (5 × 10-3 mole) a solution of 5 × 10-3 mole of 2-(2,3-dihydroxy propylsulfinyl) ethylamine hydrochloride in water. This mixture is agitated for 1 hour at a temperature lower than -5° C. The mixture is then concentrated under reduced pressure and the resulting residue is taken up in methanol and filtered. The filtrate is evaporated and the residue is crystallized in a mixture of isopropanol and acetonitrile, yielding white crystals having a melting point of 102° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])=[CH:17][C:16]=1[NH:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])=[CH:17][C:16]=1[N:28]([C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:2]=1[F:1])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C=NC(=O)c1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C2CC2)ccc1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)NC(=O)c1ccc(I)cc1F)c1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 18.5 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-fluoro-4-iodobenzoyl isocyanate (Intermediate-47, 0.500 g, 1.71 mmol), tert-butyl 2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazine carboxylate (0.582 g, 1.71 mmol) and DCM (20 mL) to afford 0.200 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.42 (s, 9H), 1.56 (m, 1H), 4.17 (d, J=5.7 Hz, 2H), 6.58-6.63 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 7.30 (m, 3H), 7.63-7.79 (m, 2H), 8.53 (m, 1H), 8.90 (s, 1H); MS (m/z): 630.85 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A mixture of 3-hydroxybenzoic acid (5 g), dimethyl formamide (50 ml), 3,4-dichloronitrobenzene (7 g) and anhydrous potassium carbonate (10 g) was stirred and heated at 100° C. for 14 hours. The solvent was removed under reduced pressure and the residue poured into water and acidified with 2 molar hydrochloric acid. The yellow solid which separated was recrystallised from toluene to give the required benzoic acid derivative (8.0 g) with a melting point of 172°-173° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[N:6][CH:7]=1.C([Li])CCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>CCOCC>[CH3:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([B:14]([OH:19])[OH:15])[CH:3]=1
Reactant: Cc1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cncc(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-3-picoline (0.25 g, 1.45 mmol) in Et2O (5 mL) at −78° C., was added n-butyl lithium (1.6 M in hexanes, 0.92 mL, 1.48 mmol) dropwise. The mixture was stirred at −78° C. for 1 hour and then triisopropyl borate was added quickly. The mixture was stirred at −78° C. for 1 hour and then quenched with water (2 mL). The mixture was warmed up to room temperature overnight. Solvent was removed under reduced pressure to yield a yellow solid (0.25 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:17][C:18]([CH2:21][OH:22])=[N:19][N:20]=1.Cl>N1C=CC=CC=1>[OH:22][CH2:21][C:18]1[S:17][C:16]([NH:15][S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[N:20][N:19]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nnc(CO)s1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82 %

Procedure:
To a solution of p-acetamidobenzenesulfonyl chloride (510 mg, 2.18 mmol) in pyridine (6 mL) was added 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (260 mg, 1.98 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (4×50 mL). The organic extracts were washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1 to give the product as a solid, mp 101-102° C., in 82% yield (533 mg, 1.62 mmol); 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 4.56 (d, 2H, J=5.1 Hz), 6.09 (t, 1H, J=4.8 Hz), 7.73 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 24.8, 59.1, 119.3, 127.7, 136.2, 143.5, 161.7, 168.1, 169.6; MS (LCQ, ESI+) Calcd for C11H13N4O4S2 329.0. found 329.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C11H13N4O4S2 329.0378. found 329.0376 (M+H)+.