Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:22][C:23](=[O:25])[NH2:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23](=[O:25])[NH:24][C:15]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)C1c2ccccc2Sc2ccccc21
Reactant: CCCCOC(N)=O
Product: CCCCOC(=O)NC(=O)C1c2ccccc2Sc2ccccc21

Procedure:
The title compound, white solid, m.p.=151-154° C., MS: m/e=342.2 (M+H+) was prepared in accordance with the general method of example 6 from 9H-thioxanthene-9-carbonyl chloride and carbamic acid butyl ester.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([N+:17]([O-])=O)=[C:9]([Cl:16])[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:20])[CH3:2].[H][H]>[Pt]=O.CO>[CH2:1]([N:3]1[C:7]2[C:8]([NH2:17])=[C:9]([Cl:16])[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:20])[CH3:2]
Reactant: CCn1c(C)nc2cc(S(C)(=O)=O)c(Cl)c([N+](=O)[O-])c21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CCn1c(C)nc2cc(S(C)(=O)=O)c(Cl)c(N)c21
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
1-Ethyl-2-methyl-5-methylsulfonyl-6-chloro-7-nitrobenzimidazole (2.50 g.) was combined with 75 ml. of methanol and 0.2 g. of 87% platinum oxide catalyst in a hydrogenation bottle. The bottle was charged with 37 psi of hydrogen and shaken at room temperature for 22.5 hours. The resultant reaction mixture was filtered to remove the catalyst and the filtrate evaporated to dryness under reduced pressure to give 2.27 g. (100%) of the desired 7-amino derivative, melting at 179°-186° C.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]([NH2:15])=[C:8]([O:16][CH3:17])[C:7]=1[O:18][CH3:19].[O-:20][C:21]#[N:22].[K+].[OH-].[Na+]>O>[Cl:5][C:6]1[CH:14]=[C:10]2[C:9](=[C:8]([O:16][CH3:17])[C:7]=1[O:18][CH3:19])[NH:15][C:21](=[O:20])[NH:22][C:11]2=[O:13]
Reactant: COc1c(Cl)cc(C(=O)O)c(N)c1OC
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Cl)cc2c(=O)[nH]c(=O)[nH]c2c1OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Acetic acid (10.5 g., 0.175 mole) was added to a vigorously stirred suspension of 5-chloro-3,4-dimethoxyanthranilic acid (28.9 g., 0.125 mole) in 600 ml. water. Then 506 ml. 5% potassium cyanate (0.312 mole) solution was gradually added and stirred 1 hour at 40° C. After cooling the reaction mixture to 20° C., 175 g. (4.37 moles) of sodium hydroxide pellets were added while maintaining the temperature below 40° C. The reaction mixture was heated to 90° C. for 45 minutes. Upon cooling in an ice bath, the sodium salt of the product precipitated, was filtered, resuspended in 125 ml. water, acidified with concentrated hydrochloric acid, cooled and filtered to yield 25.8 g. (80%) of colorless, pure product, M.P. 272°-3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[CH2:18][CH2:19][CH3:20].[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(C1C2C(=CC(C(OC)=O)=CC=2)N(CC2C=CC=CC=2OC)C=1CCC)(=O)C(C)C>>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([C:32](=[O:33])[CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:6]1[CH2:18][CH2:19][CH3:20]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCc1cc2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Agent: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)OC)cc2n1Cc1ccccc1OC
Product: CCCc1c(C(=O)Cc2ccccc2)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Yield: 45 %

Procedure:
Methyl 1-(2-chlorobenzyl)-3-phenylacetyl-2-propylindole-6-carboxylate (230 mg) was prepared from methyl 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (380 mg) and phenylacetyl chloride (189 mg) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:25]([NH2:26])=[CH:24][NH:23][N:22]=2)=[O:20])=[CH:14][CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[C:25]([NH:26][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:24][NH:23][N:22]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: O=C(Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
2-Fluorobenzoic acid (36 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMSO (1 ml). The reaction mixture was stirred at room temperature for 24 hours and purified by preparative LC/MS. Evaporation of product-containing fractions yielded the product as a white solid (15 mg, 19%). (LC/MS: Rt 3.91, [M+H]+ 342.66).
Reaction SMILES: Cl.[NH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:9][C:10]=1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:12])=[O:4]>CO.O1CCOCC1>[NH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:9][C:10]=1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)=[O:12])=[O:4]
Reactant: COc1ccc(-c2cc(C(=O)N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c(NC(N)=O)s2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C(=O)N[C@H]3CCCNC3)c(NC(N)=O)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
hydrochloride. To a stirred solution of tert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate (0.70 g, 1.47 mmol) in anhydrous MeOH (5.0 mL) was added 4.0N HCl in 1,4-dioxane (10 mL). A small amount of precipitate forms shortly and the reaction is stirred for an additional 4 h at room temperature. The solvent was removed under vacuum. The residue was redissolved in methanol and concentrated under vacuum (2×) to yield 0.51 g (85%) of a light yellow solid. 1H NMR (d6-DMSO δ 10.9, s, 1H; δ 9.39, br s, 1H; δ 9.20, br s, 1H; δ 8.37, d, 1H; δ 7.88, s, 1H; δ 7.49, d, 2H; δ 6.96, d, 2H; δ 6.97, br s, 2H; δ 4.24, m, 1H; δ 3.77, s, 3H; δ 3.29, m, 1H; δ 3.11, m, 1H; δ 2.93, m, 2H; δ 1.91, m, 2H; δ 1.68, m, 2H), LC/MS (APCI, ES, M+H=6875).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]O)[CH2:2][CH3:3].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Cl:15])[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCOc1ccccc1CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCOc1ccccc1CCl
Yield: 104.6 %

Procedure:
A 2 liter flask was charged with 316 grams (1.9 moles, 1.0 eg.) of 2-propoxybenzyl alcohol and 15 grams of pyridine (0.0126 moles) in 750 ml of toluene. 237 grams (1.99 moles, 1.01 ec.) of thionyl chloride was slowly added dropwise, allowing the reaction mixture to reflux during the addition. The reaction was stirred 4 hours at room temperature after which the toluene and thionyl chloride were removed under reduced pressure. To the remaining oil was added water and ether and washed with saturated NaHCO3 Drying and removal of the solvent gave 367 grams (100% yield) of a red oil.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.O.[OH-].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Yield: 136.1 %

Procedure:
(R)-4-methyl-4-(6-(4-pentylcyclohexyloxy)naphthalen-2-yl)oxazolidin-2-one (0.3672 g, 0.0009284 mol) was dissolved in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL EPA vial equipped with a stir bar. 4.2 M Lithium hydroxide, monohydrate in water (2.00 mL) was added and the mixture was heated at 80° C. overnight. TLC analysis showed that the reaction was complete. The mixture was concentrated to dryness under vacuum. The product was dissolved in methylene chloride (5 mL) and washed with water (2×5 mL). The layers were separated (phase separator cartridge) and the organic layer was concentrated to dryness and purified by HPLC to give 0.467 g of the title compound (14% yield). MS: m/z=353.36 [M−NH2]+. 1H NMR (400 MHz, MeOD) δ 0.90-0.98 (m, 3H), 1.10-1.24 (m, 1H), 1.26-1.54 (m, 8H), 1.58-1.74 (m, 2H), 1.80 (s, 3H), 1.86-1.95 (m, 2H), 2.03-2.13 (m, 2H), 2.20-2.29 (m, 2H), 3.80-3.87 (m, 1H), 3.91-3.97 (m, 1H), 4.36-4.79 (m, 1H, 1:1 ratio), 7.17-7.26 (m, 1H, 1:1 ratio), 7.28 (d, J=2.51 Hz, 1H), 7.53 (dd, J=8.78, 2.01 Hz, 1H), 7.80-7.90 (m, 3H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:13]>C(OCC)(=O)C>[Br:13][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br
Reactant: OCCCCCc1ccccc1
Solvent: CCOC(C)=O
Product: BrCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
50 g (0.304 mol) of 5-phenylpentan-1-ol are added to a solution of 416.7 ml (1.83 mol) of 48% strength hydrobromic acid at 0° C., and the mixture is stirred at 0° C. for 30 min. The reaction solution is subsequently stirred at 10° C. for 12 hours. After reaction is complete, the mixture is cooled to room temperature and mixed with 200 ml of ethyl acetate. After extraction, the organic phase is separated off, washed with saturated sodium bicarbonate solution and dried over sodium sulphate. After filtration, the filtrate is evaporated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane). 59.4 g (0.26 mol, 86% yield) of a colourless liquid are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[O:26]=[S:27]1(=[O:33])[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28]1>>[O:26]=[S:27]1(=[O:33])[CH2:31][CH2:30][CH:29]([NH:32][C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:24])[CH2:28]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)NC3CCS(=O)(=O)C3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and (1,1-dioxotetrahydrothiophen-3-yl)amine
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:4]1.CCN(CC)CC.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([NH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH2:4]1)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
A mixture of 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 3.8 mmol), Et3N (5.7 mmol), N-tert-butoxycarbonylglycine (704 mg), EDCI (594 mg), HOBt (673 mg), and dichloromethane (20 mL) was stirred at room temperature for 15 h. Dichloromethane (50 mL) was added and the solution was washed with 2 N NaOH solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-[{N-(tert-butoxycarbonyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (1.31 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH3:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH3:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:37])[F:38]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1N(C)S(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN(c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)S(C)(=O)=O

Procedure:
A mixture 4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg crude) in 4 M HCl in dioxane (12 mL) and water (4 mL) were heated at 100° C. for 18 h. The reaction mixture was concentrated to dryness under reduced pressure and subsequently neutralized aqueous NaHCO3 to pH to 5-6. The aqueous layer was extracted with EtOAc, the combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (20→80% gradient of MeCN-water) to provide 4-chloro-N{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide as a solid. MS m/z: 582.0 (M+H).
Reaction SMILES: [Na].[SH:2][C:3]1[S:7][S:6][C:5](=[S:8])[C:4]=1[C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:24]([S:2][C:3]1[S:7][S:6][C:5](=[S:8])[C:4]=1[C:9]1[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCBr
Reactant: CC(C)(C)c1cc(-c2c(S)ssc2=S)cc(C(C)(C)C)c1O
Agent: [Na]
Solvent: CCO
Product: CCCCCCSc1ssc(=S)c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 50 °C

Procedure:
0.92 parts of sodium was dissolved in 80 parts of ethanol and to this was added 14.8 parts of 5-mercapto-4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione, as prepared in example 11 dissolved in 200 parts ethanol. The mixture was then warmed to 50°C and a solution of 6.6 parts n-hexyl bromide in 50 parts ethanol was added dropwise. The mixture was refluxed for 5 hours, the ethanol evaporated, and the residue extracted with diethyl ether. Evaporation of the ether solution gave a crystalline residue which was crystallised from ether to give 12 parts of 5-n-hexylthio 4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione, m.p. 110°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylsulfamoyl chloride (81 μL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 77%). 1H NMR (400 MHZ, CDCL3) δ7.19 (D, 2H), 6.93-6.91 (D, 2H), 4.05 (T, 2H), 3.78-3.76 (M, 2H), 3.59-3.54 (M, 2H), 3.17-3.15 (D, 2H), 2.76-2.70 (M, 12H), 2.15-2.06 (M, 4H), 1.90-1.87 (M, 6H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[N:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[N:5][CH:4]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cncc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
2-[6-(Methylthio)-2-pyrazinyl]-4H-1,3-benzothiazine-4-one (0.14 g, 0.50 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.11 g, 0.50 mmol) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.12 g, 79%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[OH:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][OH:38]>>[OH:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][OH:38])[C:20]1[S:21][C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=2[C:28]([F:31])([F:30])[F:29])[N:8]=[CH:9]3)[C:18](=[O:25])[N:19]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCCNCCO
Product: O=C1N=C(N(CCO)CCO)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
2-[Bis-(2-hydroxy-ethyl)-amino]-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and 2-(2-Hydroxy-ethylamino)-ethanol following General Procedure C.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([O:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=5[F:41])=[CH:26][CH:27]=[N:28]4)=[CH:23][C:22]=3[O:42][CH3:43])[CH2:18][CH:13]2[CH2:12]1)=O)C1C=CC=CC=1.Br>C(O)(=O)C.CCOC(C)=O>[F:41][C:33]1[CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=[CH:37][C:32]=1[O:31][C:25]1[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH:17]3[CH2:18][CH:13]4[CH2:12][NH:11][CH2:15][CH:14]4[CH2:16]3)=[C:22]([O:42][CH3:43])[CH:23]=2)[N:28]=[CH:27][CH:26]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydrocyclopenta-[c]pyrrole-2-carboxylic acid benzyl ester (2.5 g, 4.1 mmol, 1.0 eq), 33% HBr in acetic acid (5 ml) and acetic acid (5 ml). The mixture was stirred at room temperature for 1 hour and diluted with EtOAc to give a pale orange solid. The solid was filtered, washed with EtOAc and dried, giving 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 95% yield). 1H NMR (400 MHz, CDCl3): 8.83 (d, 1H), 8.32 (m, 2H), 8.02 (s, 1H), 7.76 (t, 1H), 7.65 (s, 1H), 6.89 (d, 1H), 5.3 (d, 2H), 4.11 (m, 3H), 3.26 (m, 4H), 2.95 (m, 2H), 2.68 (m, 3H), 2.36 (m, 2H), 1.68 (m, 2H); MS (EI) for C24H24FN3O5: 454 (M+H+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([NH:8][C:16](=[O:17])[C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][C:12]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Br)ccc1C(=O)Cl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)ccc1C(=O)NCc1ccccc1
Reaction time: 3 h
Yield: 86 %

Procedure:
Benzylamine (0.69 mL, 6.31 mmol) was added slowly to a mixture of 4-Bromo-2-methoxy-1-benzenecarbonyl chloride (1.5 g, 6.01 mmol) and triethylamine (1.3 mL, 9.02 mmol) in dichloromethane (60 mL). After 3 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was re-crystallized from ethyl acetate/heptane to give N1-benzyl-4-bromo-2-methoxybenzamide (1.654 g, 86%). 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 4.67 (d, J=5.67 Hz, 32H), 7.31 (m, 7H), 8.03 (bs, 1H), 8.13 (d, J=8.41, 1H).
Reaction SMILES: [N:1]1[C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10](Cl)=[O:11].[Cl-].[Cl-].[Cl-].[Al+3].O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:10]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7](=[O:8])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:1]=1)(=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)n1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)n1
Reaction time: 4 h

Procedure:
20.0 g (98 mmol) pyridine-2,6-dicarboxylic acid chloride in 250 ml of dry benzene were mixed with 32.4 g (243 mmol) of anhydrous aluminum trichloride under an argon atmosphere in a 500 ml round-bottom flask fitted with a reflux condenser. The batch was stirred for 4 hours under reflux, was then cooled and stirred overnight at room temperature (“RT”), and was then stirred for a further 6 hours under reflux. After cooling, the batch was carefully poured into 500 ml of iced water. The organic phase was separated and the aqueous phase was washed twice with 100 ml diethyl ether each time. The combined organic phases were washed twice with 100 ml water each time and were then dried over sodium sulphate. The solvents were removed in a rotary evaporator and the product was recrystallized from diethyl ether. Yield: 16.80 g.