Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][CH3:11])[C:7](Cl)=[O:8].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:7](=[O:8])[CH:6]([CH3:5])[CH2:10][CH3:11])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: CCC(C)C(=O)Cl
Reactant: COc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(C)C(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 0.15 mole (15.0 g) of (S)-(+)-2-methylbutyric acid and 0.3 mole (35.5 g) of thionyl chloride in 100 ml of chloroform was refluxed for three hours. After chloroform and the excessive thionyl chloride had been distilled out at reduced pressure, the reaction solution was concentrated at reduced pressure to obtain 12.8 g of 2-methylbutyryl chloride. A suspension of 0.1 mole (13.3 g) of aluminum chloride in 100 ml of dry methylene chloride was cooled to 0° C., then 12.8 g of 2-methylbutyryl chloride was added dropwise thereto, and stirred for 30 min.. Maintaining the mixed solution at 0° C., a solution of 0.08 mole (14.7 g) of 4-methoxybiphenyl in 80 ml of dry methylene chloride was added dropwise, and stirred for 10 hours at room temperature. The reaction mixture was decomposed by adding into ice and dil. hydrochloric acid, and the organic layer was washed with dil.hydrochloric acid and an aquious sodium hydrogen carbonate solution, and then dried with magnesium sulfate. The concentrated product was purified by column chromatography to obtain 10.3 g of 4'-methoxy-4-(2-methylbutyryl)biphenyl. (yield: 48%)
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:11][C:12]1[C:5]2[C:3](=[C:2]([I:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccccc1I
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(I)cccc2c1O
Temperature: 25 °C

Procedure:
A solution of 2-iodoaniline (8.22 g) and diethyl ethoxymethylenemalonate (8.00 mL) is heated at 130° C. for 1 h. The reaction is cooled to room temperature. Diphenyl ether (100 mL) is added and the reaction is heated at 250° C. for 1.25 h. The reaction is cooled to room temperature and the resulting solid is filtered, washed thoroughly with hexanes, and dried to give ethyl 4-hydroxy-8-iodo-3-quinolinecarboxylate (6.84 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[Cl:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[O:21][C:20]([CH2:22][NH:15][CH2:14][CH2:13][CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])=[CH:19][CH:18]=1
Reactant: NCCCc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)o1
Product: Clc1ccc(CNCCCc2ccc3ccccc3c2Cl)o1
Yield: 85 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and 5-chlorofuran-2-carbaldehyde in 85% yield as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:14]#[C:13][C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:7][C:8]=23)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (77 mg, 0.25 mmol) (Example B.2) according to general procedure II. Obtained as a yellow solid (93 mg, 67%). MS (ISP) 556.3 [(M+H)+]; mp 190-191° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=1O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([CH3:37])[C:31]=3[CH3:30])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(O)c1C
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1cccc(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1C

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}methanol and 2,3-dimethylphenol according to the procedure of Example 69. MS (ESI) m/z 498.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]=[C:13]1[CH2:19][N:18]([C:20]2[N:21]([CH3:28])[N:22]=[CH:23][C:24]=2[N+:25]([O-:27])=[O:26])[CH2:17][CH2:16][C@H:15]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:14]1>C(Cl)Cl>[CH3:28][N:21]1[C:20]([N:18]2[CH2:19][C:13]3([CH2:12][O:9]3)[CH2:14][C@@H:15]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:16][CH2:17]2)=[C:24]([N+:25]([O-:27])=[O:26])[CH:23]=[N:22]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1C[C@@H](NC(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)C1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1N1CC[C@H](NC(=O)OC(C)(C)C)CC2(CO2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
MCPBA (335 mg, 1.49 mmol, 77 mass %) was added to a stirred solution of tert-butyl N-[(4R)-6-methylene-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]carbamate (350 mg, 1.00 mmol) in DCM (12 mL). The mixture was stirred at room temperature overnight. The reaction was quenched with sat NaHCO3 and extracted with DCM 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give tert-butyl N-[(5S)-8-(2-methyl-4-nitro-pyrazol-3-yl)-2-oxa-8-azaspiro[2.6]nonan-5-yl]carbamate (316 mg, 86%).
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12](=[S:31])[NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:27](=[O:30])[CH2:28][CH3:29])[N:20]=2)[N:18]=1)(=O)C1C=CC=CC=1>O.CO>[C:27]([NH:26][CH2:25][C:21]1[N:20]=[C:19]([C:17]2[N:18]=[C:14]([NH:13][C:12]([NH2:11])=[S:31])[S:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:30])[CH2:28][CH3:29]
Reactant: CCC(=O)NCc1cccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(=O)NCc1cccc(-c2csc(NC(N)=S)n2)n1
Temperature: 60 °C
Yield: 117.7 %

Procedure:
A solution of sodium hydroxide (3.7 g) in water (30 ml) was added to a suspension of 2-(3-benzoylthioureido)-4-(6-propionylaminomethylpyridin-2-yl)thiazole (16.5 g) in methanol (300 ml) at room temperature. The mixture was heated at 60° C. for 4.5 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (200 ml). The mixture was neutralized with 6N hydrochloric acid. The resulting precipitate was collected by filtration to afford 4-(6-propionylaminomethylpyridin-2-yl)-2-thioureidothiazole (14.67 g).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([CH:26]3[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:32]=4)[CH2:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[F:47])=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:37]([O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH:26]([C:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:9]([OH:10])=[O:8])=[C:12]([F:47])[CH:13]=3)=[CH:22][CH:21]=1)=[O:25])[CH2:35][CH2:34]2)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1ccc2c(c1)CCC(C(=O)Oc1ccc(-c3ccc(C(=O)OCc4ccccc4)c(F)c3)cc1)C2
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2c(c1)CCC(C(=O)Oc1ccc(-c3ccc(C(=O)O)c(F)c3)cc1)C2
Reaction time: 72 h
Yield: 96.7 %

Procedure:
Into a mixture of 4.19 g (6.59 mmol) of the 4'-(6-decyloxy-1,2,3,4-tetrahydro-2-naphthalenecarbonyloxy)-3-fluoro-4-biphenylcarboxylic acid benzyl ester obtained in the fourth stage and 50 ml of a THF solution containing 0.838 g of 5% palladium/carbon was blown hydrogen gas with stirring for 3 days. The reaction mixture was filtered, and the filtrate thus obtained was concentrated to obtain 3.48 g (6.37 mmol) of 4'-(6-decyloxy-1,2,3,4-tetrahydro-2-naphthalenecarbonyloxy)-3-fluoro-4-biphenyl carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(COc2cccnc2N)c1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F

Procedure:
A mixture of 2-amino-3-(2-fluoro-3-methylbenzyloxy)pyridine (2.00 g, 0.0086 mol), 4chlorophenyl isothiocyanate (1.75 g, 0.0103 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 3.21g (93%), m.p. 184°-187 ° C.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:4]([OH:12])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.CO[C:23]([CH3:25])=[CH2:24]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:4]([C:5]2[CH:6]=[CH:7][C:8]([I:11])=[CH:9][CH:10]=2)[O:12][C:23]([CH3:25])([CH3:24])[N:13]1[C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CF)[C@H](O)c1ccc(I)cc1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A 1 L round bottom flask containing tert-butyl ((1R,2S)-3-fluoro-1-hydroxy-1-(4-iodophenyl)propan-2-yl)carbamate (24.4 g, 61.8 mmol) is charged with CH2Cl2 (250 mL) followed by 2-methoxypropene (9.0 mL, 92.8 mmol). The solution is cooled via ice bath and para toluene sulfonic acid (59 mg, 0.31 mmol) added. The reaction is stirred for 2 hours at room temperature then quenched with saturated sodium bicarbonate solution (200 mL). The organics were separated, dried over MgSO4 and concentrated to give the title compound (26.5 g): 1H NMR (400 MHz, CDCl3) 7.73 (d, 2H), 7.20 (d, 2H), 5.08 (d, 1H), 5.03-4.69 (m, 1H), 4.54-4.31 (m, 1H), 3.91-3.68 (m, 1H), 1.70 (s, 3H), 1.58 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:22].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:23])=[C:7]([CH3:22])[CH:8]=2)=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Reactant: CCc1cc(Br)cc(Oc2ccc(CCC(=O)OC)c(C)c2)c1
Product: CCc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(Cl)cc2Oc2ccccc2)c1
Yield: 36 %

Procedure:
The compound of 3-[4-(3-bromo-5-ethyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester is reacted with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.237 g (36%) of the title compound after saponification. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H28O5Cl 503.1625, found 503.1625.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH2:11]([C:15]1[CH:20]=[C:19](Cl)[N:18]2[N:22]=[CH:23][CH:24]=[C:17]2[N:16]=1)[CH2:12][CH:13]=[CH2:14].O>CN(C=O)C>[CH2:11]([C:15]1[CH:20]=[C:19]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[N:18]2[N:22]=[CH:23][CH:24]=[C:17]2[N:16]=1)[CH2:12][CH:13]=[CH2:14]
Reactant: OCc1ccncc1
Reactant: C=CCCc1cc(Cl)n2nccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCc1cc(OCc2ccncc2)n2nccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
60% sodium hydride, 0.55 g, was added to a 10 ml-solution of 1.6 g of 4-(hydroxymethyl)pyridine in DMF while being ice-cooled. After the mixture was stirred at 0° C. for 30 minutes, a DMF solution (2.5 ml) containing 2.6 g of 5-(3-butenyl)-7-chloropyrazolo[1,5-a]pyrimidine was added dropwise while being ice-cooled. The mixture was stirred at the same temperature for another 1 hour. After completion of the reaction, water was added to the reaction mixture. The crystals precipitated were collected by filtration and washed with water and then with diethyl ether. The crude crystals obtained were recrystallized from ethyl acetate-n-hexane to provide 1.5 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12](=[O:15])[CH2:13]Br)[CH3:8].[SH:21][C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>CN(C=O)C.C(OCC)(=O)C>[NH2:25][C:24]1[C:23]2[C:22](=[N:29][CH:28]=[CH:27][CH:26]=2)[S:21][C:13]=1[C:12](=[O:15])[C:11]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:10]=1[O:9][CH2:7][CH3:8]
Reactant: CCOc1ccc(F)cc1C(=O)CBr
Reactant: N#Cc1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)cc1C(=O)c1sc2ncccc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (0.189 g, 1.37 mmol), 2-ethoxy-5-fluorophenacyl bromide and 2-mercaptonicotine nitrile in dry DMF (8 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 130° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:41]>ClCCl>[C:43]1([O:42][C:40]([N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][N:8]3[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]4[C:26]5[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=5[CH:21]=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)=[O:41])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(C(=O)Oc5ccccc5)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of 2-isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (0.22 g, 0.55 mmol) and N,N-diisopropylethylamine (0.19 mL) in dichloromethane (5.0 mL) was added phenyl chloroformate (70 μL). The mixture was stirred at room temperature for 10 min, then concentrated in vacuo and purified via preparative reverse phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (98.4 mg, 0.13 mmol, 24%). (m/z): [M+H]+ calcd for C30H39N5O3 518.32; found 518.6. 1H NMR (300 MHz, MeOD-d3): δ (ppm) 1.14-1.28 (m, 2H), 1.39-1.53 (m, 6H), 1.52-1.62 (m, 2H), 1.70-1.78 (m, 2H), 1.92-2.06 (m, 4H), 2.82-2.97 (m, 6H), 3.32-3.38 (m, 2H), 3.43-3.50 (m, 1H), 3.52-3.69 (m, 2H), 4.04-4.12 (m, 1H), 4.18-4.26 (m, 1H), 6.91-6.98 (m, 1H), 7.08-7.13 (m, 1H), 7.21-7.28 (m, 1H), 7.45-7.50 (m, 1H), 7.73-7.77 (m, 1H), 7.81-7.87 (m, 1H), 9.02-9.32 (brs, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[Cl:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>C1COCC1>[Cl:16][C:17]1[S:21][C:20]([S:22]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:6]2=[O:14])(=[O:24])=[O:23])=[CH:19][CH:18]=1
Reactant: CN(C)CCn1c(=O)[nH]c2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCn1c(=O)n(S(=O)(=O)c2ccc(Cl)s2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-[2-(dimethylamino)ethyl]-1,3-dihydrobenzimidazol-2-one (20 mg, 0.1 mmol) in THF at room temperature is treated with (5-chlorothien-2-yl)sulfonyl chloride (26 mg, 0.12 mmol) followed by diisopropylethylamine (25 uL, 0.2 mmol) and dimethylaminopyridine (5 mg), stirred at room temperature for 16 hours and concentrated in vacuo. The resultant residue is dissolved in a mixture of dimethylsulfoxide, methanol and water and purified by Gilson1 preparative HPLC to give the title product, 16 mg, [M+H] 386, retention time (RT) 2.83 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:23]#[N:24])(C)C>>[C:2]1([CH:1]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)[C:23]#[N:24])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccccc2)cc1
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccccc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-benzylidene-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 96%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:10]
Reactant: C1COCCN1
Reactant: O=C(O)c1cnccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1cnccc1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
Combine 4-chloronicotinic acid (0.10 g, 6.0 mmol) and 1,1′-carbonyldiimidazole (0.97 g, 6.0 mmol) in dry THF (15 mL). Stir at room temperature under nitrogen for 90 min. Add morpholine (1.58 mL, 18.0 mmol) and stir at room temperature under nitrogen for 15 hours. Dilute with dichloromethane, wash with saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride. Separate the layers and dry the organic layer over magnesium sulfate. Concentrate in vacuo. Purify the crude residue by column chromatography [5% to 25% (10% 2 M ammonia/methanol solution in dichloromethane)/dichloromethane] to give the title compound (1.17 g, 86%). MS (ES) m/z 227 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:4]=1.[F:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[F:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([O:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:6][CH:7]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(CCCF)cc1
Reactant: COc1nc(OCCN2CCCC2)ccc1N
Solvent: c1ccncc1
Product: COc1nc(OCCN2CCCC2)ccc1NS(=O)(=O)c1ccc(CCCF)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.4 %

Procedure:
After a solution of 2-Methoxy-6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-ylamine (200 mg, 0.84 mmol) in pyridine (3 ml) was stirred at room temperature for 30 minutes 4-(3-fluoro-propyl)-benzenesulfonyl chloride (200 mg, 0.84 mmol) was added. The mixture was stirred at room temperature for 16 h, thereafter the solvent was evaporated under reduced pressure. The residue was taken up in toluene and the solvent was evaporated. This procedure was repeated once. The residue was purified by silica gel chromatography with dichloromethane/methanol (100:0; 95:5; 0:100) as eluent to give 20 mg (5.4%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:37](OC=O)=[O:38]>C(O)=O>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([CH:37]=[O:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reactant: O=COC=O
Solvent: O=CO
Product: CCOP(=O)(CCN(C=O)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (74 mg, 0.14 mmol) in formic acid (1 mL) was added formic anhydride (1 mL) and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the crude product carried onto the next step. The NMR data of this compound shows two rotamers with the ratio of 70:30. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.18-1.28 (m, 2H), 1.28 and 1.30 (t, 6H, J=7 Hz), 1.74 (s, 3H), 1.84-2.08 (m, 2H), 2.19 (s, 3H), 3.34-3.45 (m, 2H), 3.47 (d, 2H, J=7 Hz), 3.72 and 3.87 (s, 2H), 3.78 and 3.79 (s, 3H), 4.06 and 4.07 (pent, 4H, J=7 Hz), 4.26-4.37 (m, 2H), 5.13 (s, 2H), 5.30-5.46 (m, 1H), 8.03 and 8.19 (s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 27.5 and 28.1 ppm; MS (m/z) 570.1 [M+H]+, 592.2 [M+Na]+.