Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH:11]=[C:10]([F:12])[C:8](=[O:9])[NH:7][C:5]1=[O:6])(=[O:3])[CH3:2].[H-].[Na+].Br[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1.O>CN(C=O)C>[C:1]([N:4]1[CH:11]=[C:10]([F:12])[C:8](=[O:9])[N:7]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18](=[O:19])[O:17]2)[C:5]1=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc(F)c(=O)[nH]c1=O
Reactant: O=C1OC(Br)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)n1cc(F)c(=O)n(C2OC(=O)c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
In 8 ml of DMF was dissolved 3.44 g of 1-acetyl-5-fluorouracil and 0.80 g of sodium hydride (60% content) was added to the stirred solution mentioned above under ice cooling. Then, a solution of 4.69 g of 3-bromophthalide in 7 ml of DMF was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for 3.5 hours at room temperature. Then, 100 ml of water was added to the mixture and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate and then, the solvent was distilled off. The residue was washed twice with 25 ml each of n-hexane to obtain crude N1 -acetyl-N3 -phthalidyl-5-fluorouracil. To this product were added 50 ml of 0.05N hydrochloric acid and 50 ml of ethanol and the mixture was refluxed for 15 minutes. After the solvent was distilled off, water was added to the residue and the colorless crystal produced was collected by filtration. After washing with water and drying, the product was heated with 15 ml of chloroform under reflux for 3 minutes. After filtration while hot, there was obtained 2.65 g (50%) of colorless crystal. This was recrystallized from methanol to obtain colorless needles having a melting point of 234°-237°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:9][CH:8]=1)=[O:6].[N:18]1(C(N)=O)[CH2:22]CC[CH2:19]1>>[CH3:19][N:18]([CH3:22])[C:14](=[O:15])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:8][CH:9]=1)[CH3:17]
Reactant: NC(=O)N1CCCC1
Reactant: CC(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Product: CC(C(=O)N(C)C)c1ccc(C(=O)CCCCl)cc1

Procedure:
2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, pyrroldineamide;
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:21]3[CH:22]=[C:23]([NH:28][CH:29]4[CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[C:24](=[O:27])[NH:25][N:26]=3)[CH:17]=[CH:18][C:19]=2[F:20])=[O:12])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[C:1]([C:5]1[N:6]=[CH:7][C:8]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:21]3[CH:22]=[C:23]([NH:28][CH:29]4[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]4)[C:24](=[O:27])[NH:25][N:26]=3)[CH:17]=[CH:18][C:19]=2[F:20])=[O:12])=[N:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(-c3ccc(F)c(NC(=O)c4cnc(C(C)(C)C)cn4)c3)n[nH]c2=O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)c1cnc(C(=O)Nc2cc(-c3cc(NC4CCCNC4)c(=O)[nH]n3)ccc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
In a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer 10d (300 mg, 0.530 mmol) was dissolved in methanol (3.0 mL). To this solution 4M hydrogen chloride in dioxane (3 mL) was added, and this mixture was stirred at room temperature for 2 h under nitrogen. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The mixture was neutralized with saturated potassium carbonate to pH 6.5 (pH meter). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL), The combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting residue was purified on a silica gel column eluting the desired product with 16% methanol in methylene chloride to afford a 65% yield (161 mg) of 10e as a off-white solid: mp 140-141° C.; 1H NMR (500 MHz, DMSO d6) δ 12.79 (s, 1H), 10.37 (s, 1H), 9.23 (s, 1H), 8.92 (s, 1H), 8.48 (d, 1H, J=7.5 Hz), 7.75 (m, 1H), 7.40 (m, 1H), 6.91 (s, 1H), 4.19 (d, 1H, J=9.5 Hz), 4.03 (d, 1H, J=13.0 Hz), 2.99-2.82 (m, 4H), 1.93 (m, 1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.42 (s, 9H), 1.29 (m, 1H); MS (APCI−) m/z 464.6 (M−H).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:14][O:15][C:16](=O)[O:17]C>>[CH3:14][O:15][C:16](=[O:17])[CH2:12][C:11](=[O:13])[C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
The procedure is as described in Example 1, except that 54 g of sodium methylate in 600 ml dimethylcarbonate are used and 154.5 g of p-chloro-acetophenone are added dropwise over a period of 2.5 hours at 60°C. Working up in accordance with Example 1 gives at 60°C 187 g (87% of the theoretical amount) of p-chloro-benzoylacetic acid methyl ester with a boiling point of 113°C/0.3 torr.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][CH:21]([CH3:30])[CH2:22][N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH:21]([CH3:30])[CH3:20])[CH2:24][CH2:25]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)CN1CCC(=O)CC1
Product: CC(C)CN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 48 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with 1-(2-methylpropyl)-4-piperidone using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-isobutyl-piperidin-4-yl)-methyl-amine as a solid (48% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethylether and methanol to give 346 as a solid (60% yield). NMR (CDCl3, 400 MHz), 0.91 (6H, d, J=6.6), 1.587-1.70 (2H, m), 1.71-1.79 (3H, m), 1.89 (2H, t, J=11.7), 2.07 (2H, d, J=7.3), 2.37 (3H, s), 2.48-2.54 (1H, m), 2.96 (2H, d, J 11.6), 3.88-3.90 (4H, m), 3.93 (2H, s), 4.03-4.06 (4H, m), 5.22 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=497
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:12]2[C:7]([CH2:8][O:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=32)=[N:6]1.[I-].[K+].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:12]4[C:7]([CH2:8][O:9][C:10]5[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=54)=[N:6]3)[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1n(CCCCl)nc2n1-c1ccccc1OC2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCN2CCN(c3ccccc3)CC2)nc2n1-c1ccccc1OC2
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 1.32 g. (0.005 mole) of 2-(3-chloropropyl)2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-one in 25 ml. of dry DMF was treated with 0.83 g. (0.005 mole) of potassium iodide and 1.78 g. (0.011 mole) of N-phenylpiperazine. The resulting mixture was kept at 50° C. for 18 hours, at 85° C. for 2 hours and at 105° C. for 2.5 hours. The mixture was then cooled, poured into ice water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with dilute brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on 125 g. of silica gel and eluted therefrom with a 1.5% v/v methanol in chloroform mixture. The eluted product was crystallized in the manner described in example 1, hereinabove, from an ethyl acetate/Skellysolve®B hexane mixture to give in two crops 0.74 g., m.p. 95°-96.5° C., and 0.37 g., m.p. 94°-96° C. of the titled compound. The analytical sample has a melting point of 96°-96.5° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: CNC
Reactant: O=C1NCCc2cc(F)ccc21
Solvent: CCO
Product: CN(C)c1ccc2c(c1)CCNC2=O
Temperature: 150 °C

Procedure:
6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (1.56 g, 9.45 mmol) was deposited in a sealed vessel with 25 mL 33% dimethylamine in ethanol. This was heated at 150° C. for 7 hours. The resulting solution was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (elution with ethyl acetate) to yield 6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (787 mg, 4.14 mmol). MS (ESI) 191.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([C:24]([NH2:26])=O)[CH2:12]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([CH2:24][NH2:26])[CH2:12]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(OC)cc(N2CCN(Cc3ccccc3)C(CN)C2)c1

Procedure:
In a manner similar to Preparation 2, react 4-(3,5-dimethoxyphenyl)-1-(phenylmethyl)-2-piperazinecarboxamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([NH2:12])[CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.CO[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#N)[CH:25]=1)=[NH:23].C(Cl)(Cl)Cl>CO>[C:22]([C:24]1[CH:25]=[C:26]([C:30]2[NH:11][CH:9]([CH3:10])[C:8]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:12]=2)[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: COC(=N)c1cccc(C#N)c1
Reactant: CC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1NC(c2cccc(C#N)c2)=NC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
1,1-bis(4-fluorophenyl)-1,2-propanediamine(50 mg) was dissolved in methanol(1 mL), and to the solution was added 3-cyanobenzeneimidic acid methyl ester (75 mg). The mixture was stirred at room temperature for 24 hrs. After chloroform (5 ml) was added to the reaction mixture, insolubles were removed by filtration. After concentrating the filtrate in vacuo, the obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=3:1→1:1) to give the objective compound (10 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])[CH:23]=[CH:24][C:25]=1[F:26]>>[F:26][C:25]1[CH:24]=[CH:23][C:22]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[CH:21][C:20]=1[C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: O=C(O)C=Cc1ccc(F)c(Br)c1
Product: Cc1cc2c(cc1-c1cc(C=CC(=O)O)ccc1F)C(C)(C)CCC2(C)C
Yield: 63.3 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 2.0 g (8.12 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid (prepared in Example 5(a) of the patent WO-97/33881) and 1.54 g (6.25 mmol) of 3-(3-bromo-4-fluorophenyl)acrylic acid, 1.45 g (63%) of the expected compound was obtained in the form of a beige powder having a melting point of 181°-183° C.
Reaction SMILES: Br.C(O)(=O)C.[CH2:6]([S:10]([NH:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]3[CH2:24][CH2:25][C:26](=[O:29])[NH:27][N:28]=3)[CH:20]=2)[CH2:15]1)(=[O:12])=[O:11])[CH2:7][CH2:8][CH3:9]>CS(C)=O>[CH2:6]([S:10]([NH:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26](=[O:29])[NH:27][N:28]=3)[CH:20]=2)[CH2:15]1)(=[O:11])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCS(=O)(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
In 100 ml of a 25% hydrogen bromide-acetic acid solution was suspended 17.44 g of 2-n-butylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane, and 3.6 ml of dimethylsulfoxide was added thereto. The mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was poured into ice water, and crystals precipitated were collected by filtration and recrystallized from methanol to obtain 14.60 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH3:10]O>>[OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:10])=[O:4]
Reactant: CO
Reactant: CC(C)C[C@H](O)C(=O)O
Product: COC(=O)[C@@H](O)CC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of (S)-2-hydroxy-4-methylpentanoic acid (3.0 g, 22.7 mmol) in methanol was added TMS.CH2N2 (2M in hexanes, 34 mL, 17 mmol) dropwise, at 0° C., over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The solution was concentrated using a bath temperature of 20° C. and vacuum greater than 50 mm Hg. Purification via silica gel chromatography using 2-100% EtOAc in hexanes gave the ester as a yellow oil (2.14 g, 14.5 mmol, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ 5.13 (s, 1H), 4.1-4.0 (m, 1H), 3.81 (s, 3H), 1.6-1.5 (m, 1H), 2.35-2.20 (m, 2H), 1.05-0.84 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: OCCc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OCCc1cccc(Nc2nc(Nc3cccc(O)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
A solution of 2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethanol (0.10 g, 0.35 mmol) and 3-aminophenol (58 mg, 0.53 mmol) in 1,4-dioxane (3.5 mL) was treated with p-toluenesulfonic acid monohydrate (54 mg, 0.28 mmol) and heated at 100° C. for 1 h. The reaction mixture was treated with additional 3-aminophenol (19 mg, 0.18 mmol) and heated at 100° C. for 1 h. The reaction mixture was poured into 10% potassium carbonate (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude brown oil. This material was purified by flash column chromatography to give the desired product (0.12 g, 96%) as a light brown solid. LCMS for C18H18ClN4O2 (M+H)+: m/z=357.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:11]=2[N:10]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47]>CN(C=O)C.O>[CH3:43][C:44]1[CH:45]=[C:46]([NH:47][C:19]([C:17]2[CH:16]=[CH:15][C:12]3[N:13]([CH3:14])[C:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10][C:11]=3[CH:18]=2)=[O:20])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: Cn1c(-c2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)nc(-c2c(Cl)cccc2Cl)n3C)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), EDCI (59 mg) and HOBt (42 mg) in DMF (2 mL) was added 3,4-dimethylaniline (38 mg) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography using EtOAc/CH2Cl2 (1:5) as eluent to give 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a glasslike solid; MS (m/z) 424 (M+1); 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.24 (s, 1H), 8.00 d, J=8.59 Hz, 1H), 7.52-7.39 (m, 6H), 7.10 (d, J=8.08 Hz, 1H), 3.65 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[H][H]>O1CCCC1.C(O)C.[Ni]>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[NH2:20])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1

Procedure:
A solution of 59 g of 1-carbethoxy-4-(2-nitro-4-chloroanilino)-piperidine in 270 ml of tetrahydrofuran and 96 ml of absolute ethanol was hydrogenated under normal pressure and at room temperature, using 15 g of Raney nickel as a catalyst. When the uptake of hydrogen had ended, the mixture was filtered and the filtrate was evaporated. Melting point: 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.BrC1C=C([F:31])C=CC=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:31])[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: Fc1cccc(Br)c1
Product: O=C(O)Cc1c(C(=O)c2cccc(F)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 3-bromofluorobenzene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]=[C:21]=[S:22]>C(O)C>[CH3:19][NH:20][C:21]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[S:22]
Reactant: NCCSCc1ncccc1N
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CNC(=S)NCCSCc1ncccc1N

Procedure:
3-Amino-2-[(2-aminoethyl)thiomethyl]pyridine (3.0 g,) prepared from an aqueous slurry of the dihydrobromide and potassium carbonate, by extraction with ethanol-ether (2:1) was dissolved in ethanol (25 ml.), methyl isothiocyanate (1.16 g.) added, and the solution then heated under reflux for 30 minutes. The residue was triturated with ether affording a solid (3.4 g.) m.p. 98°-100°. Recrystallisation from isopropyl acetate gave N-methyl-N'-[2-((3-amino-2-pyridyl)methylthio)ethyl]thiourea in 3 crops, m.p. 99.5°-100.5 (1.33 g.), m.p. 100°-101° (1.04 g.) and m.p. 99°-100° (1.0 g.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([N:12]1[C:16](=[O:17])[C:15]([NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:13]1(=[O:39])=[O:38])([CH3:11])([CH3:10])[CH3:9].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]([N:12]1[C:16](=[O:17])[C:15]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:14]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:13]1(=[O:39])=[O:38])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 97.2 %

Procedure:
TFA (1 ml) was added to a solution of tert-butyl 4-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]piperidine-1-carboxylate (Example 86) (2.138 g, 4.612 mmol) in DCM (20 ml) and the mixture was stirred at rt for 80 mins. TFA (1 mil) was added and the reaction mixture was stirred for 18 h. The reaction mixture was basified by addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, and evaporated to give the title compound (1.630 g, 97%) as a solid. 1H NMR (500 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.50-7.40 (m, 3H), 5.20 (d, 1H), 3.08-2.92 (m, 3H), 2.19 (dt, 2H), 1.74 (s, 9H), 1.72-1.46 (m, 2H), 1.36-1.24 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.9, 134.0, 131.8, 130.1, 128.9, 125.3, 107.1, 61.8, 50.2, 44.7, 33.1, 27.9; Mass Spectrum: M+H+ 364.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:1][C:2]1[C:3]([CH3:13])=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c(N)cccc1NS(C)(=O)=O
Product: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O

Procedure:
The product from Example 1B and benzaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:10]([S:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:9]=2)[N:7]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[OH-].[K+]>N1C=CC=CC=1.CO>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[S:19][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:3]([NH:2][S:29]([CH3:28])(=[O:31])=[O:30])[S:4][CH:5]=2)[CH:18]=[CH:17][C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Nc1ccc(-c2csc(N)n2)cc1Sc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)c(Sc3ccc(F)cc3F)c2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
A mixture of 4'-(2-amino-4-thiazolyl)-2'-(2,4-difluorophenylthio)methanesulfonanilide hydrobromide (1.2 g) and methanesulfonyl chloride (0.556 g) in pyridine (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, dried and evaporated. The residue obtained was dissolved in methanol and treated with potassium hydroxide (0.4 g). The solution was concentrated and the residue was dissolved in water. The aqueous solution was acidified with dilute hydrochloric acid and extracted with chloroform. The extract was evaporated to dryness. The residue (1 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of toluene and ethyl acetate (1:1) followed by recrystallization from ethanol to give crystals of 2'-(2,4-difluorophenylthio)-4'-[2-(methanesulfonamido)-4-thiazolyl]methanesulfonanilide (0.26 g).