Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[OH-:3].[Na+].[OH:5][C@:6]1([CH3:29])[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:27])[CH2:20][C@@:19]2(C)[C@H:12]3[CH2:13][CH2:14][C@@H:15]2C(=O)C)[CH2:7]1.Cl.O1[CH2:36][CH2:35][O:34][CH2:33]C1>O>[OH:5][C@:6]1([CH3:29])[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:27])[CH2:20][C@@:19]2([CH3:15])[C@H:12]3[CH2:13][CH2:14][C@@H:36]2[C:35]([O:34][CH3:33])=[O:3])[CH2:7]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: C1COCCO1
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 1 h
Yield: 45 %

Procedure:
Bromine (0.54 ml.) was added to a solution of sodium hydroxide (1.5 g.) in water (13 ml.) at -5° over a period of 5min. Cold dioxan (9 ml.) was then added and the resulting solution was added to a solution of 3α-hydroxy-3β-methyl-5α-pregnane-11,20-dione (1.0 g.) in dioxan (40 ml.) at 0°. The resulting mixture was kept at 5° for 1 hr., neutralised with concentrated hydrochloric acid and poured into water. Excess 2N-hydrochloric acid was then added and the precipitated solid was collected by filtration, dried in vacuo and dissolved in tetrahydrofutan (100 ml.). The resulting solution was treated with excess ethereal diazomethane at room temperature for 15 min. A few drops of acetic acid were then added and the mixture was partitioned between water and ether. The organic layer was washed with water, dried (MgSO4) and evaporated. Recrystallisation of the residue gave the title compound (0.49 g., 45%) as white needles, m.p. 150°; [α]D + 77° (c 1.0). (Found: C, 72.4; H, 9.2. C23H34O4Inquires C, 72.7; H, 9.4%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1>>[NH2:31][C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[CH:33][CH:32]=1)=[O:30]
Reactant: NCc1ccc(C(N)=O)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(C(N)=O)cc4)cc3)c2)o1

Procedure:
N-[4-(Aminocarbonyl)benzyl]-2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-aminomethylbenzamide using method H. NMR; δH [2H6]—DMSO 9.20,(1H, t), 8.01,(2H, d), 7.93,(1H, b), 7.89,(1H, dd), 7.83,(2H, d), 7.77,(1H, d), 7.54,(3H, m), 7.39,(2H, d), 7.32,(1H, b), 4.54,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 2.82 min, MH+ 427.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])[N:3]=[CH:2]1.[OH-].[Na+].O>CO>[S:1]1[CH:5]=[C:4]([CH:6]([CH3:12])[C:7]([OH:9])=[O:8])[N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)c1cscn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1cscn1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 5.0 g (27 mmol) of ethyl 2-(1,3-thiazol-4-yl)proparioate from step A in 25 mL of methanol was added dropwise to a mixture of 6.6 mL (33 mmol) of a 5 N aq. NaOH solution, water (16ml) and methanol (30 ml). After addition was complete the mixture was stirred for 2 h. The methanol was removed by evaporation and the pH of the remaining aqueous was adjusted to ˜2.5 with a concentrated hydrogen chloride solution. The mixture was saturated with solid sodium chloride and extracted with EtOAc (3×100 mL)). The combined organic layers were washed with brine, dried over sodium sulfate and treated with activated charcoal overnight. The mixture was filtered and evaporated to afford the title compound as an off-white solid 4.0 g (95%). 1H NMR (500 MHz, CDCl3) δ: 1.63 (d, J=7.3, 3H), 4.11 (q, J=7.3), 7.25 (d, J=1.8, 1H), 8.88 (d, J=1.8, 1H), 10.25 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-])=O)=[CH:19][S:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.[SH-].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:29])=[CH:19][S:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cn3c(-c4ccccc4[N+](=O)[O-])csc3n2)CC1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn3c(-c4ccccc4N)csc3n2)CC1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
4-[3-(2-Nitro-phenyl)-imidazo[2,1-b]thiazol-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (320 mg, 0.73. mmol) was mixed with 20 mL of MeOH and 5 mL of water containing sodium hydrosulfide hydrate (244 mg, 6 eq). The reaction mixture was stirred under reflux for 4 hours. It was then cooled to room temperature and concentrated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford 280 mg of 4-[3-(2-amino-phenyl)-imidazo[2,1-b]thiazol-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (92% yield).
Reaction SMILES: C[O-].[Na+].C([S:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])(=O)C.[CH:21]1[C:26]([C:27]([CH2:29]Br)=[O:28])=[CH:25][CH:24]=[C:23]([F:31])[CH:22]=1>C(O)C>[F:31][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH2:29][S:7][CH2:8][CH2:9][N:10]2[C:11](=[O:20])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]2=[O:19])=[O:28])=[CH:21][CH:22]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(=O)SCCN1C(=O)c2ccccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CSCCN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
0.803 kg (14.8M) sodium methoxide in 16 1 of ethanol is added to a stirred solution of 3.7 kg (14.8M) 2-(acetylthioethyl)-1,3-isoindoledione in 29.2 1 ethanol at 0° . The temperature is maintained between 0°-5° and the reaction mixture is stirred for one hour. 3.23 kg (14.8M) a-bromo-4-fluoroacetophenone in 14.6 1 of ethanol is added at such a rate to maintain the temperature between 0° and 10° . The reaction mixture is stirred overnight at room temperature. The product is collected by filtration, washed with ethanol and ether and dried. M.P. 123.5°-125.5°.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2O[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:34]>C(O)(=O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[NH:34][C:9](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1cc(/C=C/c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(Cc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of 2-(4-fluorobenzyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (65 mg) and ammonium acetate (256 mg) in acetic acid (1 mL) was stirred at 150° C. for four hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=5:1). The resulting solid was suspended in diethyl ether and collected by filtration to obtain 40 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[S:34]([Cl:37])(=[O:36])=[O:35])[CH:27]=[CH:26][CH:25]=1>>[ClH:37].[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:34]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:33]=3[N:24]=[CH:25][CH:26]=[CH:27]4)(=[O:35])=[O:36])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: Cl
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4cccc5cccnc45)c2)c1=O)CCCC3
Yield: 13 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 8-quinolinesulfonyl chloride (33 mg, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a pale yellow amorphous, 7 mg, yield 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, pyrrolidine (1.99 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature over the weekend. The precipitate which had formed was filtered and the filtrate was evaporated to dryness. The solid residue was triturated with water and dried under high vacuum at 50° C. overnight. The solid was recrystallized from isopropyl alcohol with refrigeration. The precipitate was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at room temperature overnight to give 2.84 g (60%) of title compound, mp 224°-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=O)[CH3:11])=[N:6][CH:7]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:11])=[N:9][CH:8]=2)[CH:7]=1
Reactant: CC(=O)NCc1ccc(Br)cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ncc2ccc(Br)cn12
Yield: 70 %

Procedure:
To a solution of N-((5-bromopyridin-2-yl)methyl)acetamide (450 mg, 1.96 mmol) in toluene (15 mL) was added POCl3 (600 mg, 3.92 mmol) and the mixture stirred at refluxing temperature for 6 h. After cooling, the reaction mixture was quenched by adding water (1 mL) and concentrated to remove toluene. The residue was diluted with water (5 mL) and extracted with EtOAc (3×10 mL) with the organic layer concentrated to give a crude product which was used in next step without further purification (290 mg, Yield 70%). LCMS (m/z): 211.0 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([CH:14]=O)[CH2:13][C:7]=3[C:6]=2[CH:16]=1.[CH3:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]3[O:31][CH2:30][C@H:29]([CH2:32][NH2:33])[O:28][C:24]3=2)[N:19]=1.[BH3-]C#N.[Na+].CC(O)=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([CH2:14][NH:33][CH2:32][C@@H:29]4[O:28][C:24]5=[C:25]6[C:20](=[CH:21][CH:22]=[C:23]5[O:31][CH2:30]4)[N:19]=[C:18]([CH3:17])[CH:27]=[CH:26]6)[CH2:13][C:7]=3[C:6]=2[CH:16]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN)O3
Reactant: O=CC1CCc2oc3ccc(F)cc3c2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCC1CCc2oc4ccc(F)cc4c2C1)O3
Reaction time: 3 h

Procedure:
8-fluoro-1,2,3,4-tetrahydrodibenzo[b,d]furan-2-carbaldehyde (0.040 g, 0.18 mmol), [(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methylamine (0.042 g, 0.18 mmol), and NaBH3CN (0.023 g, 0.38 mmol) were stirred together in MeOH (1.2 mL) under a N2 atmosphere. To this mixture was added AcOH (0.023 mL) and reaction was allowed to stir for 3 h. The reaction mixture was concentrated and the resulting oil was purified by flash chromatography on silica gel to afford title compound as a mixture of two diastereomers (0.068 g, 88%). The diastereomers were separated by HPLC on a Chiracel AD column (2×25 cm), eluting with 100% ethanol; MS (ES) m/z=433.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.O.[NH2:10][NH2:11]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][NH2:11])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(Br)cn1
Reaction time: 16 h
Yield: 95.5 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (10 g, 56.8 mmol) in EtOH (120 ml) was added hydrazine hydrate (14.22 g, 284 mmol), the mixture was heated to reflux and stirred overnight (16 hr). The solvent of the reaction mixture was evaporated about half under reduced pressure, then cooling in an ice bath there precipitation was occurred, filtered and washed the product with a minimum of EtOH and water, dried in vacuum to obtain pure desired product as white powder (10.2 g, yield 91%). LCMS (method A): [M+H]+=188.1, 190.1, tR=0.62 min.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:22])[C:3]1=[O:32].[C:33](N1C=CN=C1)([N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1)=[O:34].C(OCC)(=O)C>O>[CH:25]12[CH2:31][CH2:30][CH:28]([CH2:27][CH2:26]1)[CH2:29][N:23]([C:21]([CH2:20][N:4]1[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:33]([N:35]3[CH:39]=[CH:38][N:37]=[CH:36]3)=[O:34])[C:3]1=[O:32])=[O:22])[CH2:24]2
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)C(NC(=O)n2ccnc2)N=C(c2ccccc2F)c2ccccc21)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl]carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.2 g) and carbonyldiimidazole (895 mg) was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture, and organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The amorphous powder was washed with isopropyl ether to afford (3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-3-(imidazol-1-yl) carbonylamino-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.43 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH2:14][CH3:15])[CH2:12][CH3:13].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:12]([C:5]1([CH2:14][CH3:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=2)[S:8][CH2:7][CH2:6]1)[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CCC1(CC)CCSc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCC1(CC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 0 °C

Procedure:
A mixture of 1.96 g (6.90 mmol) of 6-bromo-4,4-diethylthiochroman (Compound 25), 0.11 g (0.59 mmol) of copper (I) iodide and 4.36 g (4.31 mmol) of triethylamine was degassed with argon for 15 minutes at -78° C. To the suspension was added 6.95 g (71 mmol) of (trimethylsilyl)acetylene then 0.41 g (58 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0° C. The tube was sealed and the mixture heated to 55° C. for 15 hours.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH3:13][N:14]([CH3:17])C=O.[C:18](Cl)(=[O:22])C(Cl)=O>C1(C)C=CC=CC=1>[CH2:17]([N:14]([CH2:13][CH2:18][OH:22])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[C:3]=1[F:12])[C:2]1[CH:3]=[CH:4][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)c(Br)c1F
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)c(Br)c1F)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a mixture of 3-bromo-2,4-difluorobenzoic acid (1.00 g, 4.22 mmol), N,N-dimethylformamide (0.2 ml) and toluene (20 ml) was added under ice-cooling oxalyl dichloride (0.434 ml). The mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. To a solution of the residue in tetrahydrofuran (30 ml) were added N-benzylethanolamine (702 mg) and 1N aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (1.41 g, 90.3%) as a solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1ccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.145 g, 0.767 mmol) and 6-methyl-3-(piperidin-4-yl)-1H-indole (0.150 g, 0.697 mmol) using ethanol as reaction solvent. Yield 0.140 g (49%) as a tan foam. FDMS m/e=403 (M+ of free base). α[D]589 =+3.8 (c=0.98, dimethylsulfoxide).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=[NH:16])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27].O>ClCCl>[Cl:24][C:25]([Cl:30])([Cl:29])[C:26]([N:16]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]1[CH2:9][C:6]1[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=1)=[O:27]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: N=c1ccccn1Cc1ccc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
70 mg (0.27 mmol) of the 1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-imine hydrochloride obtained by the method described in another method of Synthetic Example P1 was dissolved in 4 ml of anhydrous dichloromethane, 94 μl (0.68 mmol, 68 mg) of triethylamine and 33 g (0.27 mmol, 49 mg) of trichloroacetyl chloride were added thereto in sequence, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added thereto to stop the reaction and liquid separation was performed with dichloromethane and water. The organic layer was washed once with water and twice with 1% hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether was added thereto to precipitate a solid, and thus the solid was collected and dried to obtain the subject material. Amount obtained 61 mg (yield 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([CH3:31])[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:39]([C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)(=[O:41])=[O:40])[N:15]=[C:14]([CH3:31])[N:13]=2)(=[O:9])=[O:10])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
According to the procedure described in Example 4a) 94 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 82 mg 5-methyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.86 min, [M+1]+=600.59, [M−1]−=598.55.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>CO>[F:19][C:2]([F:1])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[C:12](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Solvent: CO
Solvent: C1CCNC1
Product: O=C1C(=Cc2ccccc2)COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of the product of Step C (27 g, 91.2 mmole) in 183 mL of methanol was added benzaldehyde (11.1 mL, 109 mmole) followed by pyrrolidine (9.1 mL, 109 mmole). The mixture was stirred at room temperature overnight, cooled to 0° C. and filtered. The solid was washed once with 50 mL of ice-cold methanol and then dried in vacuo; 35.2 g, (75% yield) of the title product was recovered.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[N:4]([CH2:10][CH2:11][C:12](O)=[O:13])[C:3]1=[O:15].C(Cl)(=O)C([Cl:19])=O.C(Cl)Cl>CN(C)C=O>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[N:4]([CH2:10][CH2:11][C:12]([Cl:19])=[O:13])[C:3]1=[O:15]
Reactant: CN1C(=O)N(CCC(=O)O)C(C)(C)C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C(=O)N(CCC(=O)Cl)C(C)(C)C1=O
Temperature: 24 °C
Reaction time: 0.92 h
Yield: 97.7 %

Procedure:
A mixture of 10.71 g (50 mmol) 3-(3,5,5-trimethyl-2,4-dioxo-imidazolidin-1yl)-propionic acid (synthetized according to example 15), 31.73 g oxalyl chloride, 25 ml methylenechloride and 0.5 ml dimethylformamide is stirred for 1 h and 55 minutes at 24° C., thereafter evaporated in a rotary evaporator at 70° C. in vacuo, stripped 3 times with about 50 ml of toluene, evaporated completely do dryness and dried at 70° C./10.1 mbar. 11.36 g (97.6% of theory) of crystalline 3-(3,5,5-trimethyl-2,4-dioxo-imidazolidin-1yl)-propionylchloride are obtained.