Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Br[CH2:6][C:7]([NH:9][C:10]1[S:11][C:12]([C:20]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:8]>C(O)C>[CH2:2]([O:1][CH2:6][C:7]([NH:9][C:10]1[S:11][C:12]([C:20]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:8])[CH3:3]
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
Sodium ethoxide (62.0 mg, 0.900 mmol) was dissolved in ethanol (2 mL), and Compound 531 (120 mg, 0.300 mmol) was added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=99:1) and crystallized from 2-propanol to afford the entitled Compound 532 (53.4 mg, 49%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=1)[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39]([S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:41][C:35]=2[O:34][CH2:33]1.O>ClCCl>[CH2:1]([N:8]([S:42]([C:39]1[CH:40]=[CH:41][C:35]2[O:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=2[CH:38]=1)(=[O:44])=[O:43])[C:9]1[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=1)[C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COc2ccc(S(=O)(=O)Cl)cc2N1
Reactant: CC(C)NC(=O)c1cc(NCc2ccccc2)ccc1F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cc(N(Cc2ccccc2)S(=O)(=O)c2ccc3c(c2)NC(=O)CO3)ccc1F

Procedure:
A solution of 5-benzylamino-2-fluoro-N-isopropyl-benzamide (30 mg, 0.1 mmol), diisopropylethylamine (37 μL, 0.2 mmol), and 3-oxo-3,4-dihydro-2H-1,4-benzooxazine-6-sulfonyl chloride (52 mg, 0.2 mmol) was refluxed in dry dichloromethane (3 ml) for 18 hrs. On cooling, water (10 ml) was added with stirring. The organic layer was separated, dried (PTFE frit), then concentrated in vacuo. The crude residue was purified by preparative TLC (10% v/v ethyl acetate/dichloromethane) to afford the title compound as an off white solid (23 mg). HPLC retention time 7.72 min. Mass spectrum (ES+) m/z 499 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.[Pd]>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])[CH:12]=1
Reactant: O=[N+]([O-])c1cccc(Sc2cccnc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(Sc2cccnc2)c1
Yield: 71.6 %

Procedure:
3-(3-nitrophenylthio)pyridine (3.2 g, 13.8 mmol) was dissolved in 200 ml of THF, 2 g of palladium on carbon was added, reacted with hydrogen gas at normal pressure and 50° C. for 8 h. Suction filtration was carried out, and the reaction solution was concentrated to obtain an object product 2 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:21][CH2:22]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2cnc(N3CCNCC3)cn2)c1=O
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Br)cc(Nc2cnc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
A mixture of 189f (740 mg, 2.0 mmol), oxetan-3-one (288 mg, 4.0 mmol), NaBH3CN (315 mg, 5.0 mmol), and zinc chloride (680 mg, 5.0 mmol) in methanol (60 mL) was stirred at 50° C. for 5 hours. It was then quenched with water and concentrated under reduced pressure. The residue was extracted with dichloromethane three times. The combined extract was concentrated under reduced pressure to afford crude 189g as a yellow solid (660 mg, 78%), which was used in the next step without further purification. MS: [M+H]+ 423.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:25][C:23]1[N:24]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([F:38])([F:37])[F:26])=[CH:29][CH:30]=3)[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=3)[N:5]2[CH:22]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Product: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(-c3ccc(C(F)(F)F)cc3)cc2n1

Procedure:
In analogy to the procedure described for Example 7, 30.2 mg (48% of theory) of the product are obtained starting from 50 mg (0.13 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 31A) by coupling with 30.2 mg (0.15 mmol) of [4-(trifluoromethyl)phenyl]boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=2)=[CH:18][CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=3)=[CH:32][CH:33]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
A solution of 494 mg (2.23 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 10 ml THF was added within 15 min. to a solution of 580 mg (2.23 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 10 ml THF and stirring continued overnight. The reaction mixture was evaporated and purified by HPLC/MS (Reprosil 100 C18, 10 μm, methanol/water 80:20) to give 500 mg oil that solidified by treatment with a small amount of ether. The precipitate was filtered and dried to yield 400 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:7]([OH:11])=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:7](=[CH:8][C:9]=1[CH3:10])[O:11][CH:21]([C:20]([F:19])([F:29])[F:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2
Reactant: Cc1cc(O)c(C=O)c(C)c1Cl
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2c(cc(C)c(Cl)c2C)OC1C(F)(F)F
Temperature: 65 °C
Yield: 110.2 %

Procedure:
To a solution of 3-chloro-6-hydroxy-2,4-dimethylbenzaldehyde (6.9 g, 37.4 mmol) in 80 mL of DMF was added dried finely powdered K2CO3 (11.36 g, 82.2 mmol). With mechanical stirring, the reaction was heated to 65° C. To the suspension was added dropwise ethyl trifluorocrotonate (7.54 g, 44.9 mmol). The stirring reaction was heated at 90° C. for 1.5 h. K2CO3 was filtered from the cooled reaction. From the reaction under vacuum, DMF was removed. The resulting residue was dissolved in 400 mL EtOAc. The organic solution was washed with 100 mL 1 M KHSO4, 70 mL of satd. KHCO3, 100 mL brine, followed by drying over MgSO4, and concentrating under vacuum. The crude desired product (13.8 g) of was isolated. After employing flash chromatography conditions, pure compound (9.8 g, 78%) of was isolated and its structure confirmed by NMR and LC-MS.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[C:11](=[CH2:12])[C:10]([CH3:14])([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[C:11]3([O:25][CH2:12]3)[C:10]([CH3:13])([CH3:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: C=C1C(Cc2ccc(F)cc2)CCC1(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(Cc2ccc(F)cc2)C12CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 170 ml of chloroform, 17 g of 5-(4-fluorobenzyl)-2,2-dimethyl-1-methylenecyclopentane (the compound No. 124 shown in Table 3) were dissolved, and then, 27.1 g of m-chloroperbenzoic acid were added to the mixture within 10 min, and the thus obtained mixture was stirred for 2 hours at room temperature. In the next place, 25.4 g of calcium hydroxide were added to the mixture within 10 min, and the mixture was stirred for 30 min at room temperature.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[C:15]2=[O:30])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[CH3:29][S:26]([C:23]1[N:22]=[CH:21][C:20]([O:19][C@H:16]2[CH2:17][CH2:18][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:30])=[CH:25][CH:24]=1)(=[O:27])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(S(C)(=O)=O)nc3)C2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)cn1
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of (S)-tert-butyl-4-(3-(6-(methylsulfonyl)pyridine-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (259 mg, 0.59 mmol) in DCM (10 mL) was added excess 4N HCl in dioxane (3 mL). The reaction was stirred for 4 hours, then concentrated in vacuo to yield (S)-3-(6-(methylsulfonyl)pyridin-3-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride salt (210 mg, 94%) as an off white solid, which was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:38]2[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:24]#[CH:25].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:38]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=4[C:32]4[C:27]3=[CH:28][CH:29]=[CH:30][CH:31]=4)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCn1c2c(c3ccccc31)CCCC2
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#CCn3c4c(c5ccccc53)CCCC4)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 1,2,3,4-tetrahydro-9(2-propynyl)-9H-carbazole under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 8 % (v/v) of ethanol in methylene chloride for elution. The residue obtained after evaporation of the combined clean fractions containing product was crystallized from ethanol to give colorless crystals of 4-(2-chlorophenyl)-2-[3-(1,2,3,4-tetrahydro 9H-carbazol-9-yl)-1-propynyl]-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with m.p. 164°-166°. These crystals contained 0.66 molar amounts of ethanol according to analytical and spectral data.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]=[O:12].[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].NC1C=CC=CC=1>>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:10][C:11]([NH:16][C:15]1[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=1[CH3:13])=[O:12]
Reactant: Cc1cc(C)c(N=C=O)c(C)c1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: Nc1ccccc1
Product: Cc1cc(C)c(NC(=O)Nc2c(C)cc(C)cc2C)c(C)c1

Procedure:
2,4,6-Trimethylphenyl isocyanate (Lancaster Co., 20.5 g, 0.127 mol) and 2,4,6-trimethylaniline (17.2 g, 0.127 mol) were reacted in a procedure analogous to that described in Example 1, giving a brown solution. A thick, white flaky precipitate was observed to form about 2 hours after aniline addition. This material was collected by filtration, rinsed with hexanes, and dried in vacuo (crop 1). The CHCl3 reaction filtrate (also containing rinse hexanes) was set aside and was observed to produce additional white precipitate overnight. It was concentrated somewhat using a rotary evaporator and insolubles were similarly collected by filtration, rinsed with hexanes until a pinkish impurity was removed, and dried (crop 2). Three additional crops of material were collected in this fashion. Crop 3 was collected by removal of volatiles from the filtrate of crop 2, crushing the resultant solid, slurrying it in hexanes overnight, and collecting insolubles by filtration and rinsing them with hexanes. Crop 4 was collected by removal of volatiles from the filtrate of crop 3, slurrying with petroleum ether, and collecting insolubles by filtration and rinsing them with petroleum ether. Crop 5 was collected identically by treatment of the filtrate from Crop 4, using smaller slurry and rinse volumes of petroleum ether. The weights of crops 1 to 5 were 11.1 g, 8.32 g, 5.96 g, 2.30 g, and 4.19 g, respectively (total 31.9 g, 84.6%). 1H NMR (solid state CRAMPS, 500 MHz): δ 7.5 (br, aryl), 6.1 and 5.1 (NH), 1.4, 0.9 (sh), and 0.5 (sh) (overlapping, CH3). 13C{1H} NMR (solid state CPMAS, 50 MHz): δ 157.9 and 154.9 (br, C═O, 1 C), 135.0, 129.6, 128.7, and 127.6 (aryl, 12 C), 22.8, 20.0, 19.4, and 17.9 (CH3, 6 C). IR (KBr pellet): 3286 (vs), 3003 (w), 2972 (m), 2918 (s), 2855 (w), 1640 (vs), 1609 (s), 1553 (vs), 1485 (m), 1470 (sh), 1446 (sh), 1377 (w), 1308 (w), 1285 (w), 1252 (sh), 1223 (s), 1065 (w), 1032 (w), 1013 (w), 882 (w), 849 (m), 760 (w), 748 (w), 721 (sh), 696 (m), 580 (w) cm−1. FD-MS m/z (%): 296.7 (MH+, 100). Exact mass calculated for C19H24N2O: 296.19. Melting point (DSC): onset (extrapolated) 236° C., max. 240° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:12]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:12]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1ccn(-c2ccc(-n3ccccc3=O)cc2)c1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 18.1 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide (118 mg, 0.27 mmol), 2-hydroxypyridine (50 mg, 0.53 mmol), 8-hydroxyquinoline (14 mg, 0.097 mmol) and K2CO3 (120 mg, 0.87 mmol) in DMSO (2 mL) was degassed with Argon before being charged with CuI (19 mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C. for 4 h. It was then purified by HPLC to give the titled compound (20 mg). MS 410.0 and 412.0 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:34]=[CH:33][C:20]4[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:34]=[CH:33][C:20]4[CH2:21][NH:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCNC4)no2)cc1Cl
Reaction time: 3 h
Yield: 156.1 %

Procedure:
1,1-Dimethylethyl 8-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 34) (0.171 g, 0.352 mmol) was dissolved in 1,4-dioxane (1 ml) and 4M HCl (4 ml, 16.00 mmol) in dioxane was added. The reaction mixture was left at room temperature for 3 hours. The resulting precipitated solid was filtered off and washed with dioxane and ether to give the title compound (116 mgs) as a white solid hydrochloride salt. δH (400 MHz, MeOD) 1.42 (6H, d), 3.64 (2H, m), 4.34 (2H, m), 4.48 (2H, s), 4.86 (1H, m), 7.31 (1H, d), 7.59 (1H, d), 7.87 (1H, d), 7.94 (1H, dd), 8.11 (1H, dd), 8.21 (1H, dd); MS (ES) C20H2035ClN3O3 requires 385; found 486 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[F:24]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[F:24])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: COc1cc(C=O)c(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(Cl)cc1OCc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-4-hydroxy-5-methoxy-benzaldehyde (136, 0.548 g, 2.94 mmol, prepared as described in Example 46, Scheme 45, step 1) was dissolved in N,N-dimethylformamide (40 mL) and sodium hydride (60% dispersion in mineral oil, 0.200 g, 5.00 mmol) was added. After 20 minutes, 1-bromomethyl-4-chloro-2-fluoro-benzene (139, 685 μL, 5.00 mmol) was added to the reaction mixture. The reaction was stirred at room temperature under an atmosphere of nitrogen for 5.5 hours. The reaction was concentrated to dryness in vacuo. The reaction was resuspended in water/saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography, eluting with 5-35% ethyl acetate in hexane give a white solid (140, 0.942 g, 97%), consistent with the desired compound by 1H-NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=O.[CH3:13][N:14]=[C:15]=[S:16].C([O-])(O)=O.[Na+].Cl>CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:14]([CH3:13])[C:15](=[S:16])[NH:8][N:7]=2)[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: NNC(=O)c1cc(F)cc(F)c1
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cn1c(-c2cc(F)cc(F)c2)n[nH]c1=S
Temperature: 70 °C

Procedure:
3,5-difluorobenzohydrazide (5 g, 29 mol) and methyl isothiocyanate (2.1 g, 29 mmol) were mixed in 2-propanol (100 ml) and heated to 70° C. o.n. The reaction was cooled to r.t. and the formed precipitate was filtered off. H2O (100 mL) and NaHCO3 (4 g, 48 mmol) were added to the solid and the mixture was heated to 70° C. for 2 h. The reaction mixture was cooled to r.t., acidified with concentrated HCl and the title compound, 6.4 g (97%), was collected by filtration. LC-MS (M++1): 228
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1C
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1C
Temperature: -5 °C
Yield: 52.2 %

Procedure:
A stirred mixture of 100.0 g (0.73 mole) of 4-methyl-3-methoxyaniline in 800 mL of concentrated hydrochloric acid was cooled to -5° C. A solution of 501.5 g (0.73 mole) of sodium nitrite in 250 mL of water was added slowly while maintaining the temperature of the reaction mixture below 0° C. The resultant mixture was stirred at -5° C. for 30 minutes. A cold solution of 330.0 g (1.46 mole) of tin (II) chloride dihydrate in 360 mL of concentrated hydrochloric acid was added over one hour. After complete addition the resultant mixture was allowed to warm to room temperature. A solid precipitate formed and was collected by filtration and stirred in 200 mL of water. This mixture was neutralized with 50% aqueous sodium hydroxide, and extracted with toluene. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 58.0 g of 4-methyl-3-methoxyphenylhydrazine as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].C(=O)=O.Cl>N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Product: CSc1ccc(C=CC(=O)O)cc1
Temperature: 0 °C

Procedure:
A mixture of 50.70 g (0.33 mol) 4-methylsulfanyl-benzaldehyde, 39.65 g (0.38 mol) malonic acid 3.25 g (0.04 mmol) piperidine and 150 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (5 h). The reaction mixture was poured into a solution of 750 ml ice water and 190 ml 6N HCl. The precipitate was isolated, washed with water, then with n-heptane and dried at 50° C. Yield: 60.0 g (93%) 3-(4-methylsulfanyl-phenyl)-acrylic acid as a light brown solid melting at 163-165° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:15]1[C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[NH:17][C:16]1=[O:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[CH3:27][C:28]1[C:36]2[C:35]([CH2:37]O)=[CH:34][S:33][C:32]=2[CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:15]1[C:19]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=2[N:17]([CH2:37][C:35]2[C:36]3[C:28]([CH3:27])=[CH:29][CH:30]=[CH:31][C:32]=3[S:33][CH:34]=2)[C:16]1=[O:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: Cc1cccc2scc(CO)c12
Reactant: CCOC(=O)C[C@H](CCc1ccccc1)n1c(=O)[nH]c2ccc(C)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](CCc1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a solution of (S)-3-(6-Methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-5-phenyl-pentanoic acid ethyl ester (0.2 g, 0.57 mmol), (4-Methyl-benzo[b]thiophen-3-yl)-methanol (0.10 g, 0.57 mmol), and triphenylphosphine (0.18 g, 0.68 mmol) was added dropwise DIAD (0.14 g, 0.68 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting oily residue was purified by prep TLC using 4:1 Hexane:EtOAc as an eluent to afford 0.12 g of the desired product as a brown oil.
Reaction SMILES: [NH:1]([C:13]([CH3:15])=[O:14])[C@@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]2)=[CH:21][CH:20]=1>>[NH:1]([C:13]([CH3:15])=[O:14])[C@@H:2]([C:10]([NH:16][C@H:17]([C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]2)=[CH:21][CH:20]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Product: COC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)[C@@H](Cc1ccccc1)NC(C)=O

Procedure:
N-Ac-D-Phe-2-Nal-OMe was prepared according a similar manner as described in example 2 using N-Ac-D-Phe-OH and H-2-Nal-OMe.