Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=[O:17].BrCC1C=CC=CC=1[Cl:26]>>[ClH:26].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:1])[C:4]1=[O:17]
Reactant: Clc1ccccc1CBr
Reactant: N[C@H]1CCCCN(Cc2ccccc2)C1=O
Agent: Cl
Product: N[C@H]1CCCCN(Cc2ccccc2Cl)C1=O

Procedure:
(S)-3-Amino-1-(2-chlorobenzyl)azepan-2-one hydrochloride (270 mg, 0.934 mmol) was synthesized as described for the preparation of Intermediate 42 using 1-(bromomethyl)-2-chlorobenzene in step A. Anal. Calcd. for C18H25ClN2O3 m/z 352.8. found: 353.2 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([S:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(SCc2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(SCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of 4-benzylsulfanyl-benzaldehyde (840 mg 3.68 mmol) described in Manufacturing Example 205-1-2, nitromethane (997 μL, 18.4 mmol), ammonium acetate (567 mg, 7.36 mmol), and acetic acid (10 mL) was stirred for 2 hours at 100° C. This mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (950 mg). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=3)[C:18]([O:20]CC)=[O:19])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[NH:3]1.[OH-].[Na+].Cl>C1COCC1.O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=3)[C:18]([OH:20])=[O:19])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[NH:3]1
Reactant: CCOC(=O)c1cccc(N2CCC(N3CCc4ccccc4NC3=O)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(N2CCC(N3CCc4ccccc4NC3=O)CC2)c1
Temperature: 25 °C

Procedure:
650 mg (1.65 mmol) ethyl 3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-benzoate, 10 mL THF, 2 mL water and 2 mL (8.00 mmol) of an aqueous 4M sodium hydroxide solution were stirred at RT until the reaction was complete. Then the THF was eliminated i. vac. The aqueous residue was acidified with a 4M hydrochloric acid solution. After several hours' stirring at RT the precipitate was suction filtered and dried.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13](OC)=[O:14])[C@@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C.[BH4-].[Na+].Cl>O1CCCC1.O.C(Cl)(Cl)Cl>[CH2:20]([N:10]1[C@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A solution of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =-27.7° at c=1 in DMF, 368 mg) in tetrahydrofuran (3 ml) and isopropanol (0.50 g) was added dropwise to a mixture of sodium borohydride (100 mg) and tetrahydrofuran (3 ml) at 5°-10° C. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 5 hours. Then, 1N hydrochloric acid (10 ml) was added dropwise to the reaction mixture. The mixture was stirred at 55°-60° C. for 30 minutes. Chloroform (30 ml) and water (30 ml) were added to the mixture. Aqueous layer was separated from organic layer and extracted once with chloroform. The organic layers were combined, washed successively with water, 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (314 mg). M.P., 116°-117° C. [α]D25 =+61.1° (c=1, CHCl3).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:18])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: NCCCn1cncn1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1cncn1)c1ccco1

Procedure:
A mixture of about 3.78 g of 1H-1,2,4-triazole-1-propanamine, about 33 ml of 1N sodium hydroxide and about 100 ml of methylene chloride was stirred, then about 3.3 ml of 2-furoyl chloride was added. The mixture was stirred overnight, then about 15 ml of 1N sodium hydroxide and about 100 ml of methylene chloride were added. The mixture was shaken, the organic layer separated, washed with two approximately 50 ml portions of water, dried, filtered and evaporated to an oil. Ether was added to the oil which was then triturated and the crystals collected. These were recrystallized from ether giving about 2.0 g of the desired product as beige crystals, mp 63°-66° C. The fumarate salt melts at 65° C.-70° C.
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=C(C)C=1.COC1C=CC(CN2C(=O)C(C)NC2=O)=CC=1.[CH3:42][C:43]1[C:44]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH3:69])[C:67](=[O:70])[N:66](CC5C=CC(OC)=CC=5)[C:65]4=[O:80])=[CH:60][C:59]=3[CH3:81])=[O:57])[CH2:52][CH2:51]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1>>[CH3:42][C:43]1[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH3:69])[C:67](=[O:70])[NH:66][C:65]4=[O:80])=[CH:60][C:59]=3[CH3:81])=[O:57])[CH2:54][CH2:55]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1
Reactant: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(C)c3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3C)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (311 mg) described in Preparation Example 118 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 508, the title compound (91 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:29])[CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Cl-].C[Zn+].[C:33](=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>[OH:29][C@H:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:33])=[CH:3][CH:4]=1)[CH2:9][NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3ccc(Cl)nc3)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn+]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Product: COC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3ccc(C)nc3)cc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Under nitrogen to a solution of methyl 4′-[2-[[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate (110 mg) in tetrahydrofran (10 ml) was added 1M methylzinc chloride in tetrahydrofran (0.8 ml) and tetrakis(triphenylphosphine)palladium (15.5 mg) at room temperature. The mixture was stirred at 80° C. for 24 hours, and then poured into an aqueous solution (60 ml) of ethylenediaminetetraacetic acid (1 g). The resulting mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give methyl 4′-[2-[[(2R)-2-hydroxy-2-(6-methyl-3-pyridyl)ethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate (41 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1>>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)[OH:8])[CH3:23]
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Reactant: CCOC(CC(C(=O)c1ccccc1)c1ccccc1)OCC
Product: CCOC(CC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCN2CCOCC2)cc1)OCC

Procedure:
The compound is prepared from the evaporation residue obtained in Example 26 and 42.9 g of 1-bromo-4-(2-morpholinoethoxy)benzene according to the procedure described in Example 1(c).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:24])=[CH:21][C:20]=1[Cl:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[Cl:35][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])[C:23]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)=[O:24]
Reactant: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: CO
Solvent: O
Product: CC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3Cl)nc21
Temperature: 140 °C
Yield: 30.6 %

Procedure:
10-chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 76, 100 mg, 0.39 mmol) and 4-amino-3-chloro-N-(1-methyl-4-piperidyl)benzamide (Intermediate 79; 127 mg, 0.47 mmol) were suspended in 4-methyl-2-pentanol (3 mL) and p-toluenesulphonic acid monohydrate (74 mg, 0.97 mmol) added. The mixture was heated at 140° C. for 4 hours The mixture was cooled causing a white solid to formed. The whole mixture was diluted with MeOH to give a solution which was absorbed on to an SCX-3 column, washed with methanol and eluted with ammonia/methanol. Concentration and column chromatography (1-2-3-5% NH3 in MeOH/DCM) of the product containing fractions gave the title compound as a white solid (58 mg, 31%).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([CH2:19][CH2:20][CH2:21][C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:23]=3)=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:33]N1C(=O)CCC1=O>C1COCC1>[Br:33][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([CH2:19][CH2:20][CH2:21][C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=4)=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCc3nc(-c4ccccc4)no3)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCCc3nc(-c4ccccc4)no3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
To the solution of 9-pentyl-3-[3-(3-phenyl-1,2,4-oxadiazol-5-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.50 g, 1.16 mmole) in THF (125 ml) at room temperature was added N-bromosuccinimide (0.309 g, 1.73 mmole). The mixture was stirred at 70° C. for 1 h. The mixture was concentrated and purified by preparative LCMS to yield the desired product (122 mg, 21% yield). LCMS calculated for C22H24BrN8O2 (M+H): 511.1; found: 511.0.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:7].CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH3:2])=[CH:23][CH:24]=3)=[C:16]([F:25])[CH:15]=2)=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCc1ccc(-c2ccc(-c3ccc(C)[se]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.5 ml (32.3 mmol) of TMP are initially introduced at −15° C. in 20 ml of diethyl ether, and 20.0 ml (31.8 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min, a solution of 10.0 g (30.4 mmol) of 2-(4′-ethyl-3-fluorobiphenyl-4-yl)selenophene in 80 ml of diethyl ether is added. When the addition is complete, the batch is warmed to RT and stirred for 90 min. The solution is cooled to −70° C., and 10.0 ml (0.16 mol) of methyl iodide are added. The reaction mixture is warmed to RT and stirred for 20 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:toluene=95:5). The further purification is carried out by recrystallisation from n-heptane. 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 121° C.
Reaction SMILES: FC(F)(F)C([O-])=O.N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O.C(Cl)Cl.[NH:61]([C:108]([O:110][CH2:111][C:112]1[CH:117]=[CH:116][CH:115]=[CH:114][CH:113]=1)=[O:109])[C@H:62]([C:64]([NH:66][C@H:67]([C:78]([NH:80][C@H:81]([C:83]([NH:85][C@H:86]([C:97]([NH:99][C@H:100]([C:105]([NH2:107])=[O:106])[CH2:101][CH:102]([CH3:104])[CH3:103])=[O:98])[CH2:87][CH2:88][CH2:89][NH:90][C:91](=[NH:96])[NH:92][N+]([O-])=O)=[O:84])[CH3:82])=[O:79])[CH2:68][CH2:69][CH2:70][NH:71][C:72](=[NH:77])[NH:73][N+:74]([O-:76])=[O:75])=[O:65])[CH3:63]>CN(C=O)C>[NH:61]([C:108]([O:110][CH2:111][C:112]1[CH:117]=[CH:116][CH:115]=[CH:114][CH:113]=1)=[O:109])[C@H:62]([C:64]([NH:66][C@H:67]([C:78]([NH:80][C@H:81]([C:83]([NH:85][C@H:86]([C:97]([NH:99][C@H:100]([C:105]([NH2:107])=[O:106])[CH2:101][CH:102]([CH3:104])[CH3:103])=[O:98])[CH2:87][CH2:88][CH2:89][NH:90][C:91](=[NH:92])[NH2:96])=[O:84])[CH3:82])=[O:79])[CH2:68][CH2:69][CH2:70][NH:71][C:72](=[NH:77])[NH:73][N+:74]([O-:76])=[O:75])=[O:65])[CH3:63]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(N)=O

Procedure:
From 715 g of trifluoroacetate of E-Arg(NO2)Ala-Arg(NO2)-Leu-NH2 in solution in 4 l of DMF and 233 g of Z-Ala-OH and 500 g of BOP employing the same technique as the one described in I-2 (and without treatment in that case by TFA-CH2Cl2), 612 g of Z-Ala-Arg(NO2)-Ala-Arg(NO2)Leu-NH2 (76%) are obtained, after recrystallization in the DMF-ether mixture, in the form of a white pulverulent solid, monitored by TLC and NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:23]([C:37]1[CH:38]=[C:39]([CH:46]=[CH:47][CH:48]=1)[O:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:44][CH2:43][CH:42]([OH:45])[CH2:41][O:40][C:39]2[CH:46]=[CH:47][CH:48]=[C:37]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:38]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCc1cccc(OCC(O)CO)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1cccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)c1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A solution of 25.94 g of 4-methoxytrityl chloride in 15 ml of dry tetrahydrofuran was added to a stirred solution of 21.84 g of 3-(3-tetradecylphenoxy)-1,2-propanediol in 40 ml of pyridine under argon. This mixture was stirred overnight, the solvents removed under reduced pressure and the residue dissolved in chloroform. This solution was washed with saturated aqueous sodium bicarbonate, then water, dried and evaporated, giving 34.3 g of the desired compound.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:43][CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:41][CH2:42][CH2:43]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC4CCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(CC4CCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([C:22]([OH:24])=[O:23])[O:19][C:18]3=[O:25])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:28]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:21][CH:20]([C:22]([OH:24])=[O:23])[O:19][C:18]3=[O:25])=[CH:15][CH:16]=2)=[O:8])=[CH:26][CH:27]=1)(=[S:28])[NH2:2]
Reactant: N#Cc1ccc(C(=O)NCc2ccc(N3CC(C(=O)O)OC3=O)cc2)cc1
Reactant: S
Product: NC(=S)c1ccc(C(=O)NCc2ccc(N3CC(C(=O)O)OC3=O)cc2)cc1

Procedure:
In analogy to Example 10, reaction of 3-[4-(4-cyanobenzamidomethyl)phenyl]-2-oxo-5-oxazolidinylcarboxylic acid with hydrogen sulfide gives 3-[4-(4-thiocarbamoylbenzamidomethyl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid, m.p. 105°-110°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19](OC)=[O:20])[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[O:20])[N:14]([CH3:18])[S:15](=[O:16])(=[O:17])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2c(c3cc(Cl)ccc3n2C)S(=O)(=O)N1C
Reactant: Nc1ccccn1
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2c(c3cc(Cl)ccc3n2C)S1(=O)=O
Yield: 72 %

Procedure:
8-Chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(2-pyridyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 18 from methyl 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 2-amino-pyridine with a yield of 72% of theory; M.p.: 245° C. (decomposition).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCC3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (110 mg, 0.32 mmol, 1.00 equiv) in methanol (20 mL). Then a solution of sodium hydroxide (63.4 mg, 1.58 mmol, 5.00 equiv) in water (2.5 mL) was added dropwise with stirring. The resulting solution was stirred for 8 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 10 ml of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration and washed with hexane. This resulted in 40 mg (38%) of 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])(C)(C)C.CCCCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:16][Sn:17]([CH3:19])([CH3:18])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1ccsc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: C[Sn](C)(C)c1cccs1
Temperature: -38 °C
Reaction time: 1 h

Procedure:
To a solution of thiophene (2.1 g, 25.0 mmol) in anhydrous THF (50 mL) was added dropwise over 30 minutes at −38° C. t-butyllithium in pentane (1.6 M, 16.0 mL, 25.6 mmol). The solution was stirred for 1 h at −38° C. and then cooled to −78° C. Trimethyltin chloride in THF (1 M, 25.3 mL, 25.3 mmol) was added dropwise over 30 min. The reaction was then stirred for 2 h at −78° C. and then for 15 h at r.t. The solvent was evaporated and the resulting yellow solid was taken up in other, washed with water and dried Na2SO4 and then evaporated to give a light brown liquid which solidified on standing.