Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl.O=C(C1C=CC=CC=1)C[O:43][C:44](=[O:72])[C@H:45](O)[CH2:46][N:47]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)[NH:48][C:49]([C:51]1[O:55][N:54]=[C:53]([OH:56])[CH:52]=1)=[O:50].CCN(C(C)C)C(C)C.CC(O)=O>[Zn]>[C:44]([C@H:45]([O:8][C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])[CH2:46][N:47]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)[NH:48][C:49]([C:51]1[O:55][N:54]=[C:53]([OH:56])[CH:52]=1)=[O:50])([OH:72])=[O:43]
Reactant: O=C(COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)O[C@H](CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
(S)-2-Methoxycarbonylamino-3-methylbutyric acid (9.6 mg, 54.5 μmol) and HATU (23.5 mg, 62 μmol) were stirred in DCM (1.0 mL, 16 mmol) for 10 minutes. (R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (20.0 mg, 36.4 μmol) and DIPEA (31.7 μL, 182 μmol) were added, and the resulting mixture was stirred at room temperature overnight. The mixture was then concentrated and purified by flash chromatography (EtOAc/hexanes=0-100%). Zinc (119 mg, 1.8 mmol) and AcOH (0.5 mL, 9 mmol) were added. The mixture was stirred for 2 hours and filtered. The solids were washed with AcOH (1 mL) and filtered. The combined filtrates were purified by reverse phase preparative HPLC to yield the title compound (0.8 mg). MS m/z [M+H]+ calc'd for C27H29ClN4O9, 589.16. found 589.3.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:50]([O:57][C:58]([NH:60][C@H:61]([C:73](=[O:79])[NH:74][CH2:75][CH2:76][CH:77]=O)[CH2:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[CH2:66]([O:65][C:63](=[O:64])[CH2:62][C@@H:61]([C:73](=[O:79])[NH:74][CH2:75][CH2:76][CH2:77][NH:1][C@@H:2]([C@H:10]([CH:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:60][C:58](=[O:59])[O:57][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: O=CCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 70.1 %

Procedure:
By using an analogous procedure to that described in Example 1, a solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (100 mg, 0.139 mmol, obtained from Reference Example 6), benzyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-oxo-4-[(3-oxopropyl)amino]butanoate (71 mg, 0.173 mmol, obtained from Reference example 24), acetic acid (1 drop), and sodium triacetoxyborohydride (59 mg, 0.277 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred under nitrogen at room temperature for 5 hours. The product was purified by chromatography (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-5-[2-(benzyloxy)-2-oxoethyl]-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (109 mg, 70%) as a white amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)\[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:36].[OH-].[Na+]>CO>[CH3:36][C:7]1[CH:8]=[C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)\[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:37])=[O:2]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC/C=C(/c2ccccc2)c2ccc(C#Cc3ccccn3)cc2)ccc1OCC(=O)O
Temperature: 25 °C

Procedure:
To a solution of the above ester (239 mg, 0.488 mmol) in methanol (40 ml) was added 1N NaOH (0.975 ml, 0.975 mmol) and the mixture were refluxed for 2 hr. After cooling to room temperature the mixture were evaporated in vacuo. The residue was dissolved in dichloromethane (50 mL) and extracted with water (10 ml). The aqueous phase was acidified with 1N HCl (1 ml) pH 3 and extracted with dichloromethane (20 ml). The dichloromethane phase were dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo yielding the title acid as light green foam.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:13]([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:18][CH2:2][CH2:3][N:4]1[CH:13]([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15]
Reactant: CC1c2ccccc2NC(=O)N1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1c2ccccc2NC(=O)N1CCCl

Procedure:
A mixture of 8 parts of 3,4-dihydro-3-(2-hydroxyethyl)-4-methyl-2(1H)-quinazolinone, 8 parts of thionyl chloride and 90 parts of trichloromethane is stirred and refluxed for 1.50 hours. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 6.6 parts of 3-(2-chloroethyl)-3,4-dihydro-4-methyl-2(1H)-quinazolinone; mp. 126.4° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][OH:34])[CH:14]([N:16]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C:17]3=[O:32])[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:36]>[Ag]=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][O:34][CH3:36])[CH:14]([N:16]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C:17]3=[O:32])[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC(N3CCC(NC(=O)OCc4ccccc4)C3=O)C(CO)C2C1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COCC1C2CN(C(=O)OC(C)(C)C)CC2CC1N1CCC(NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
A solution of 5-(3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-4-hydroxymethyloctahydrocyclopenta[c]-pyrrole-2-carboxylic acid tert-butyl ester in a small amount of DMF and a large excess of iodomethane is treated with silver oxide and stirred at room temperature until the reaction is complete. Upon completion of the reaction, the reaction mixture is filtered through celite and concentrated under vacuum yielding a residue. The residue is purified by flash column chromatography providing the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[NH2:16][CH:17]1[CH2:26][CH:25]2[N:20]([CH2:21][CH2:22][C:23]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:24]=32)[CH2:19][CH2:18]1>N1C=CC=CC=1>[ClH:8].[CH3:32][O:31][C:29]1[C:28]([O:33][CH3:34])=[CH:27][C:24]2[CH:25]3[N:20]([CH2:21][CH2:22][C:23]=2[CH:30]=1)[CH2:19][CH2:18][CH:17]([NH:16][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)[CH2:26]3
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)c3cc(OC)c(OC)c(OC)c3)CCN1CC2
Product: Cl
Temperature: 0 °C
Yield: 14.7 %

Procedure:
A solution of 3,4,5-trimethoxy benzoyl chloride (13 g) in pyridine was added dropwise to 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (13 g) in 200 ml of pyridine, and the solution was warmed at 60°-70° for 30 minutes and poured into ice water. The mixture was extracted with chloroform and the extracts dried over MgSO4, concentrated in vacuo and the concentrated material chromatographed over silica gel using ethyl acetate-methanol-chloroform (4:1:0.5) as eluant. The major fraction (9.9 g) was converted to the HCl salt with hydrogen chloride in a mixture of 2-propanol, methanol and ethyl acetate, isolated as a solid and recrystallized from methanol-ethyl acetate and again from methanol to yield 3.6 g of the desired product, m.p. (decomposed at 259°-61°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR20##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:12]1(/[CH:18]=[CH:19]/[C:20](=O)[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:23]([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:23][C@H:20]([CH:19]=[CH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:21][NH:11][C@@H:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10]
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: [BH3-]C#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Product: COc1cccc([C@@H](C)NC[C@H](C)C=Cc2ccccc2)c1

Procedure:
In a similar fashion, an equal molar amount of (R)-1-(3-methoxyphenyl)ethylamine, trans-4-phenyl-3-butene-2-one and 1.25 molar equivalents titanium(IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up and chromatography afforded (R,R)-N-(2-methyl-4-phenybut-3-enyl)-1-(3-methoxyphenyl)ethylamine, 25H, as an oil; m/z (rel. int.) 283 (M+, 4), 268 (13), 178 (40), 135 (100), 105 (15), 91 (47), 77 (13) and (S,R)-N-(2-methyl-4-phenybut-3-enyl)-1-(3-methoxyphenyl)ethylamine, 25I, as an oil; m/z (rel. int.) 283 (M+, 4), 268 (13), 178 (40), 135 (100), 105 (15), 91 (47), 77 (13).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1>C(O)C>[NH3:1].[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nc2ccccc2o1
Reactant: C1CNCCN1
Solvent: CCO
Product: N
Product: c1ccc2oc(N3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of piperazine (8 g, 93 mmole) in ethanol (30 ml) was added 2-chlorobenzoxazole (3 g, 19.5 mmole) dropwise. The resulting reaction was exothermic. The mixture was then stirred for 18 hours at room temperature, quenched by the addition of methylene chloride (50 ml) and the resulting precipitate removed by filtration. The filtrate was concentrated under reduced pressure then purified by flash column chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia solution (90:10:1) to yield the title compound, m.p. 70°-72° (1.8 g, 46%), which was used directly.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[NH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=4)=[O:14])[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][N:37]=1>>[Cl:35][C:36]1[N:37]=[CH:38][C:39]([N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]4)=[O:25])=[CH:19][CH:18]=3)[CH:23]=[C:15]2[C:13]([N:10]2[CH2:9][CH2:8][N:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:5])=[O:6])[CH2:12][CH2:11]2)=[O:14])=[CH:40][CH:41]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C4CC4)CC2)n3-c2ccc(Cl)nc2)CC1
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 5, from (4-cyclopropanesulfonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 33) and 2-chloropyridine-5-boronic acid to afford the desired product as light brown foam (44%). MS (ISP): 599.4 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[C:25]([C:27]1[N:28]=[C:29]([C:40](O)=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26].[K]>>[C:9]([O:8][CH2:7][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:40]([C:29]2[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=2)=[O:41])=[C:14]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:13]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: [K]
Product: CC(=O)OCC(COC(C)=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1

Procedure:
Acetic acid 3-acetoxy-2-(4-amino-3-cyclohex-1-enyl-phenyl)-propyl ester (as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d)) as described in Example 1, step (f) to obtain the title compound: Mass spectrum (ESI, m/z): Calcd. for C30H40N4O6Si, 581.2 (M+H). found 581.0.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[Br-:11].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:11][C:2]1[NH:1][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=1
Reactant: [Br-]
Reactant: O=C1CCCc2[nH]ccc21
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C1CCCc2[nH]c(Br)cc21

Procedure:
was prepared using a literature procedure (Remers et al., J. Org. Chem., 36:1241-1247 (1971) (“Remers”), which is hereby incorporated by reference). To a 100 mL round bottom flask charged with a magnetic stir bar was added 1,5,6,7-tetrahydro-4H-indol-4-one (1.2 g, 8.8 mmole) and dry THF (20 mL). Stirring was commenced, and a solution of phenyltrimethylammonium tribromide (3.33 g, 8.8 mmole) in 15 mL of dry THF was added dropwise over 10 minutes at ambient temperature. After the addition was complete, the reaction mixture was stirred for an additional 2 hours and then filtered to remove the precipitate. The filtrate was concentrated in vacuo and the residue treated with dichloromethane (30 mL) and 5% aqueous Na2CO3 solution (30 mL). The layers were separated and the dichloromethane layer was then washed with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the crude product as a white solid which was directly used without further purification. 1H NMR data matched the literature values exactly (“Remers”, which is hereby incorporated by reference).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]([NH2:15])=[O:14])[C:9](OC)=[O:10].C[O-].[Na+].C([O-])(=O)CC(N)=O>CN(C)C=O>[OH:10][C:9]1[S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]=1[C:13]([NH2:15])=[O:14]
Reactant: COC(=O)C(C(N)=O)c1ccccc1S
Agent: C[O-]
Agent: NC(=O)CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(O)sc2ccccc12

Procedure:
Methyl o-mercaptophenylmalonamate (4.5 g, 0.02 m) and dried dimethylformamide (50 ml) at 10° C. is treated with sodium methoxide (3.2 g, 0.06 m) under a nitrogen atmosphere, and the resultant mixture allowed to stir at ambient temperature until no starting malonamate remains (thin-layer analysis). The reaction mixture is added to a stirred excess dilute hydrochloric acid-ice mixture, aged and filtered to yield 2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CO[C:14]2([CH:19]=[CH:18][C@H:17]3[C@H:20]4[C@H:30]([C@@H:31]([OH:33])[CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([OH:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)[O:13]1>O.CC(C)=O>[OH:34][C@H:25]1[CH2:26][CH2:27][C@@:28]2([CH3:29])[C:23](=[CH:22][CH2:21][C@@H:20]3[C@@H:30]2[C@@H:31]([OH:33])[CH2:32][C@@:15]2([CH3:16])[C@H:17]3[CH:18]=[CH:19][C:14]2=[O:13])[CH2:24]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)C=C[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4 ml of a solution of 100 mg of p-toluenesulphonic acid in 10 ml of water are added to a solution of 800 mg of 17,17-ethylenedioxyandrosta-5,15-diene-3β,11β-diol in 40 ml of acetone and the whole is stirred for 6 hours at room temperature. After dilution with 40 ml of water, the acetone is distilled off under a water-jet vacuum and the oily residue is taken up in chloroform and washed with ice-cold saturated sodium bicarbonate solution. Evaporation of the organic solvent yields amorphous 3β,11β-dihydroxyandrosta-5,15-dien-17-one which can be used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F>ClCCl.CO>[Cl:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1[NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CCN(CC)CCN
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1Cl

Procedure:
Prepared analogously to Example 4.25.a. from N1,N1-diethylethane-1,2-diamine and 3-chloro-4-fluoronitrobenzene. Yield: 9.2 g (99.1% of theory); C12H18ClN3O2 (M=271.74); calc.: molecular ion peak (M+H)+: 272/274; found: molecular ion peak (M+H)+: 272/274; Rf value: 0.72 (Alox, dichloromethane/methanol (49:1)).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8]2[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8]2[S:12][C:11]([CH2:13][OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(C=O)s2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cc2ccc(CO)s2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
To a solution of 5-(5-methyl-thiophen-2-ylmethyl)-thiophene-2-carbaldehyde described in Preparation Example 66 (790 mg, 3.56 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (41 mg, 1.06 mmol), and the mixture was stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction mixture, which was then partitioned, the organic layer was filtered with a glass filter lined with silica gel, the filtrate was evaporated in vacuo, and the title compound (640 mg, 2.86 mmol, 80.3%) was obtained as a light brown oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:47][NH:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:49]1([N:48]([CH3:47])[C:12](=[O:14])[C:11]2[CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:17]=[C:9]([CH3:8])[CH:10]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)O)c1
Reactant: CNC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(C)C2CCCCC2)c1
Reaction time: 64 h

Procedure:
A stirred solution of 3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate salt (0.031 g) in DMF (1 ml) was treated with HOBt (0.011 g), DIPEA (0.028 ml), N-methylcyclohexylamine (0.010 ml), and TBTU (0.026 g). The resulting solution was retained in a sealed flask for 64 h. The reaction mixture was concentrated under reduced pressure and the resulting gum subjected to preparative hplc. The required fraction was concentrated and then dried by addition of methanol and concentration under reduced pressure, addition of toluene and again concentration under reduced pressure giving the title compound as a colourless gum (0.034 g).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:7]2[N:8]=[N:9][S:10][C:11]=2[C:12]([O:14]C)=O)[CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:7]2[N:8]=[N:9][S:10][C:11]=2[C:12]([NH:2][NH2:3])=[O:14])[CH2:6][CH2:5]1
Reactant: COC(=O)c1snnc1C1CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1snnc1C1CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.1 %

Procedure:
Hydrazine monohydrate (1.75 g; 35 mmols) was dissolved in ethanol (15 ml), and methyl 4-cyclopropyl-1,2,3-thiadiazole-5-carboxylate (1.29 g; 7 mmols) was added thereto, followed by stirring at room temperature for 10 hours. Ethanol was evaporated under reduced pressure and, after adding thereto water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was washed with a mixed solvent of hexane-ethyl acetate to obtain 1.2 g of 4-cyclopropyl-1,2,3-thiadiazole-5-carbohydrazide.
Reaction SMILES: [F:1][CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6]1.O.NN.Cl>C1COCC1.C(O)C>[F:1][CH:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][O:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([NH2:11])[CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC(F)c2ccccc2)CC1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](OCC(F)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 0.7 g of racemic trans-2-[4-(2-fluoro-2-phenyl-ethoxy)-cyclohexyl]-isoindole-1,3-dione in 15 mL of THF and 15 mL of ethanol was added 0.3 mL of hydrazine hydrate and the mixture heated to reflux for 4 h, then 5 mL of 6N HCl was added and the reflux was continued for 1 h. The cooled mixture was concentrated under reduced pressure to remove ethanol and filtered. The filter pad was washed with 2×10 mL of dilute HCl and the combined filtrates basified to pH 10 with 20% sodium hydroxide and extracted with 3×25 mL portions of chloroform. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Further drying under vacuum gave 0.4 g of product as an oil. MS (m+1)=238.3.