Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:8]=1[CH:9]=O)C>C(O)(=O)C>[CH3:18][O:17][C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:7]2[O:6][C:5]([CH:4]=[O:3])=[CH:9][C:8]=2[CH:11]=1
Reactant: CCOC(COc1c(C=O)cc(OC)cc1OC)OCC
Solvent: CC(=O)O
Product: COc1cc(OC)c2oc(C=O)cc2c1
Yield: 27.9 %

Procedure:
A stirred solution of 3 (1.2 g, 4.0 mmol) in acetic acid (35 mL) was refluxed for 16 h. After cooling, the solution was evaporated to dryness. The crude product was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (2:1) to give 4 (230 mg, 28%) as a white solid. 1H NMR (500 MHz, CDCl3): δ: 9.89 (1H, s, CHO), 7.50 (1H, s, H-3), 6.69 (1H, d, J4,6=2.2 Hz, H-6), 6.64 (1H, d, J4,6=2.2 Hz, H-4), 4.01 (3H, s, OMe), 3.87 (3H, s, OMe). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ: 179.91 (CHO), 153.37 (C-2), 116.10 (C-3), 101.80 (C-6), 94.90 (C-4), 56.20 (OMe), 55.88 (OMe).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]([NH:24][NH2:25])(=O)[CH2:21][CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:20]([CH2:21][CH3:22])=[N:24][N:25]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: CCC(=O)NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCO
Product: CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione was heated in ethanol with propionic acid hydrazide and the resulting product heated to 250° C. to give 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine of melting point 231.5°-232.5° C. The ultraviolet spectrum (ethanol) had end absorption λ max. 224 (ε = 39,250) and inflections 248 (ε = 15,000), 266 (ε = 6,900) and 290 mμ(ε = 3,250).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:11][CH3:12])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][Cl:14])=[CH:19][CH:20]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc2occc2c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2occc2c1
Yield: 79.8 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(benzofuran-5-yl)propan-1-one (250 mg, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (794 mg, 2.0 eq) to give 480 mg desired product (80%, Z/E=1/1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:35]N)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc2ccccc12
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=433.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]=O>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([CH3:26])[CH:28]=4)[NH:32][CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1ccc2[nH]cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 571.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.070 g, 0.020 mmol) in methanol (2.0 mL) was added with 5-methyl-1H-indole-3-carboxaldehyde (0.034 g, 0.021 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (93:7)) to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(5-methyl-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.056 g, 55%).
Reaction SMILES: Br[C:2]1([C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[P:20]([O:25]C)([O:23][CH3:24])[O:21][CH3:22]>>[P:20]([O:23][CH3:24])([O:21][CH3:22])([O:8][C:7](=[C:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[O:25]
Reactant: COP(OC)OC
Reactant: COc1ccc2c(C(=O)C3(Br)CCCC3)n[nH]c2c1
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C3CCCC3)n[nH]c2c1

Procedure:
The title compound was prepared from (1-bromocyclopentyl)(6-methoxy-1H-indazol-3-yl)methanone and trimethyl phosphite using the procedure described in Method I Step B of Example 1 followed by RP-HPLC purification using 20-100% MeCN gradient. It was isolated as a white solid following lyophilization. 1H NMR (CDCl3, 500 MHz) δ 7.79 (d, 8.9 Hz, 1H), 6.85 (dd, 2.1 & 9.0 Hz, 1H), 6.81 (d, 1.8 Hz, 1H), 3.88 (s, 3H), 3.67 (d, 11.3 Hz, 6H), 2.72˜2.79 (m, 2H), 2.53˜2.59 (m, 2H), 1.70˜1.81 (m, 4H). LC-MS: 3.00 min. (n/Z=227.2, 353.2, 375.2).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[CH:16][N:11]3[CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[S:17]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)([O:20][CH3:21])(=[O:19])=[O:18]>CC#N>[S:17]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)([O-:20])(=[O:19])=[O:18].[CH3:21][SH:13]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:10]=[N+:11]2[CH:16]=[CH:15][N:14]=[C:12]12
Reactant: O=Cc1ccc(-c2cn3ccnc3s2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Product: C[SH]1C2=NC=C[N+]2=CC1c1ccc(C=O)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A mixture of 1.0 g of 2-(4'-formylphenyl)imidazo-[2,1-b]thiazole and 1.0 g of methyl tosylate in 10 ml of dry CH3CN was refluxed for 20 hours. The solution was then evaporated to dryness. The residue was dissolved in hot water and extracted with chloroform to remove excess methyl tosylate. The aqueous layer was evaporated and the residue was recrystallized from acetone. Yield 1.4 gm (77%); mp 195° C.
Reaction SMILES: NC1C=CC=CC=1C1N=C(CCCC(O)=O)OC=1.C([O:21][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[O:29][CH:30]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH2:39])[N:32]=1)C>>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]1[N:32]=[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22]([OH:40])=[O:21])[O:29][CH:30]=1
Reactant: CCOC(=O)CCCCCc1nc(-c2ccccc2N)co1
Agent: Nc1ccccc1-c1coc(CCCC(=O)O)n1
Product: Nc1ccccc1-c1coc(CCCCCC(=O)O)n1
Yield: 83.1 %

Procedure:
Using a method similar to the procedure described for the preparation of 4-[4-(2-amino-phenyl)-oxazol-2-yl]-butyric acid; hydrolysis of 6-[4-(2-amino-phenyl)-oxazol-2-yl]-hexanoic acid ethyl ester (2.7 g, 8.9 mmol) gives 6-[4-(2-amino-phenyl)-oxazol-2-yl]-hexanoic acid (2.03 g, 83%). MS (ES): (M+1)+ 274.9 m/z.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[O:25]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]23[CH2:24][CH:19]4[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]4)[CH2:22]2)[CH2:16]3)=[CH:9][CH:10]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOC23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOC23CC4CC(CC(C4)C2)C3)cc1
Yield: 79.6 %

Procedure:
A mixture of alpha-oxo-4-[[2-[tricyclo(3.3.1.1-3,7)dec-1-yloxy]ethyl]oxy]benzeneacetic acid methyl ester (0.685 g) in methanol (10 mL) heated on the steam bath and added sufficient actone to dissolve the solids. Then 0.5N sodium hydroxide (8 mL) was added and the mixture was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from diethyl ether-hexane to give 0.524 g of colorless alpha-oxo-4-[[2-[tricyclo(3.3.1.1-3,7)dec-1-yloxy]ethyl]oxy]benzeneacetic acid, mp 155°-156° C.
Reaction SMILES: CC(N(C)C)=O.[CH3:7][C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[C:10]([OH:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2.F[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:7][C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[C:10]([O:20][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2
Reactant: COc1cccc(-c2c(C)cc3cc(OC)ccc3c2O)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
A dimethylacetamide solution (2 mL) of 3-methyl-6-(methyloxy)-2-[3-(methyloxy)phenyl]-1-naphthalenol (247) (0.072 g, 0.25 mmol, 1 equiv) was treated with 4-fluorobenzaldehyde (0.030 mL, 0.27 mmol, 1.1 equiv) followed by cesium carbonate (0.096 g, 0.29 mmol, 1.2 equiv). After 10 min at gentle reflux, the mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5 mL). The pooled organic portions were dried (Na2SO4) and concentrated. Radial chromatography (SiO2, 1 mm plate, 80:20; hexanes/EtOAc) afforded the title compound (248) as a pale yellow oil (0.060 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 9.80 (s, 1H), 7.68-7.59 (m, 4H), 7.19-7.14 (m, 2H), 7.05 (dd, J=9.2, 2.4 Hz, 1H), 6.78-6.65 (m, 5H), 3.93 (s, 3H), 3.64 (s, 3H), 2.26 (s, 3H). TLC (75:25; hexanes/EtOAc): Rf=0.55.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH:22]=O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]>>[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH:22]2[NH:10][CH2:9][CH2:8][N:3]3[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]23)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: Cc1cn(CCN)c(C)n1
Reactant: COc1ccc(CCC=O)cc1F
Product: COc1ccc(CCC2NCCn3c(C)nc(C)c32)cc1F

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(3-fluoro-4-methoxy-phenyl)-propionaldehyde. LC-MS: tR=0.57 min.; [M+H]+=304 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc2ccc(O)cc2nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(OCc3cccc(Cl)c3)cc2nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of ethyl 7-hydroxy-2-methylquinoline-3-carboxylate (100 mg, 0.43 mmol) in DMF (3.0 mL) was added Cs2CO3 (212 mg, 0.65 mmol) and 3-chlorobenzyl chloride (0.052 mL, 0.43 mmol). The reaction was stirred overnight at ambient temperature. The reaction mixture was loaded directly onto a column and purification (FCC, SiO2, 0-40%, EtOAc/hexanes) afforded the title compound as a white solid (86 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J=2.3 Hz, 1H), 7.37-7.30 (m, 3H), 7.29-7.26 (m, 1H), 5.19 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 2.97 (s, 3H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=356.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:38]([C@H:34]4[CH2:35][CH2:36][CH2:37][N:33]4[C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])=[O:39])[CH2:24][CH2:25]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCNCC3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a stirred solution of (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(piperazin-1-yl)-1H-indazole (0.051 g, 0.14 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.061 g, 0.28 mmol) in dichloromethane (1 mL) was added HATU (0.11 g, 0.28 mmol) and iPr2NEt (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by the addition of dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% methanol in dichloromethane) to afford the (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.052 g, 0.088 mmol, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1)([O-])=O.[C:13]1(=O)[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12.Cl.[OH-].[NH4+]>C1(C)C=CC=CC=1.O>[C:13]1(=[O:18])[N:10]([CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(CCN2C(=O)[C@H]3CC=CC[C@H]3C2=O)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
16.6 g of p-nitrophenethylamine and 15.1 g of cis-1,2,3,6-tetrahydrophthalic anhydride are heated under reflux in 300 ml of toluene, with stirring and a water trap, for 16 hours. This mixture is cooled and take to dryness by warming under reduced pressure. The residue is transferred to a flask containing 500 ml of water, 270 g ferrous sulfate heptahydrate and 1.3 ml concentrated hydrochloric acid. Steam is delivered to the mixture. When the temperature reaches 90° C., 75 ml of concentrated ammonium hydroxide is added in one portion, and at two-minute intervals three 25 ml portions of ammonium hydroxide are added. Continue stirring and heating during the additions. The total reaction time is 8-10 minutes. Immediately pour the mixture onto 1 kg of cracked ice. The solid is collected by filtration and washed with water. Recrystallize from water ethanol to obtain -4-(cis-1,2,3,6-tetrahydrophthalimidoethyl) aniline (1f).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[S:13])[NH2:12])=[CH:5][CH:4]=1.[C:14](O)(=O)C.C(=N)N.C(O)CCC.O(C(C)C)C(C)C>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]=[N:12][C:11]([SH:13])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: COc1ccc(NNC(N)=S)cc1
Agent: N=CN
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCCCO
Product: COc1ccc(-n2cnc(S)n2)cc1
Yield: 73 %

Procedure:
A mixture of 10 parts of 2-(4-methoxyphenyl)hydrazinecarbothioamide, 10.6 parts of methanimidamide acetate and 80 parts of 1-butanol is stirred and refluxed for 1 hour. After cooling, water and 2,2'-oxybispropane are added, whereupon the product is precipitated. It is filtered off and dried, yielding 7.6 parts (73%) of 1-(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][CH3:22])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([CH2:21][CH3:22])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CCC(CSC(C)=O)C(=O)N1CC(OC)(OC)C[C@H]1C(=O)O
Agent: N
Product: CCC(CS)C(=O)N1CC(OC)(OC)C[C@H]1C(=O)O

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to give (S)-1-(3-mercapto-2-ethyl-1-oxopropyl)-4,4-dimethoxy-L-proline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:3]=12.O.[OH-].[Li+].CO.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:3]=12
Reactant: COC(=O)c1cc2c(F)cncc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(F)cncc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of methyl 4-fluorothieno[2,3-c]pyridine-2-carboxylate (0.942 g, 4.46 mmol) in THF (23 mL) was added a solution of lithium hydroxide monohydrate (0.384 g, 9.14 mmol) in water (23 mL). Methanol (2.8 mL) was then added until the solution was transparent. The reaction mixture stirred 2 h at room temperature. The reaction was then adjusted to pH ˜4 by addition of 2 N aqueous HCl, causing formation of a white precipitate. THF and methanol were removed by rotary evaporation, and then the residual solid was collected by vacuum filtration, washing with water (2×25 mL). The collected white solid was dried in an oven at 50° C. to afford 765 mg (87%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 14.15 (br. s., 1 H), 9.23 (s, 1 H), 8.54 (s, 1 H), 8.14 (s, 1 H); MS (ESI): 198.05 [M+H]+; HPLC tR=2.40 min (ZQ3, polar—4 min).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH:24]=[N:25][C:26]([C:27](O)=[O:28])=[C:22]3[C@@H:21]3[CH2:30][CH2:31][CH2:32][N:20]3[C:19](=[O:33])[C:18]=2[C:34]=1[F:35].N>CN(C)C=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH:24]=[N:25][C:26]([C:27]([NH2:3])=[O:28])=[C:22]3[C@@H:21]3[CH2:30][CH2:31][CH2:32][N:20]3[C:19](=[O:33])[C:18]=2[C:34]=1[F:35]
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
6.1 g (37.9 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 11 g (34.5 mmol) of (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid in 80 ml of dimethylformamide. The resulting pale brown solution was heated to 50° for 45 minutes. The solution was subsequently cooled to room temperature and 12 ml of aqueous ammonia solution were added dropwise. After stirring for a further 30 minutes the reaction mixture was poured into 150 ml of ice-water and extracted seven times with methylene chloride. Drying of the organic phases with sodium sulfate, filtration and evaporation yielded a colourless residue which was triturated with methylene chloride. After drying in a high vacuum there were obtained 9.8 g of (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide m.p. 221°-224°.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH:16]1([CH2:20][S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH2:18][CH2:17]1.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[CH:16]1([CH2:20][S:21]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:32]([C:31]4[CH:33]=[CH:34][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:23])=[O:22])[CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(Cl)CC1CCC1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC1CCC1)CC2

Procedure:
Light brown solid. MS (ESI): 447.15 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), cyclobutyl-methanesulfonyl chloride, 4-(trifluoromethoxy)-aniline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:29])[C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].CO.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:30])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:29])[C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(C(O)C(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1cccc(C(O)C(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]propionate (5.878 g, 13.59 mmol), sodium hydroxide (1.09 g, 27.2 mmol), methanol (20 ml), water (30 ml) and tetrahydrofuran (20 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]propionic acid as a liquid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10](=[CH:15][CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:12][CH2:13][NH2:14])[CH3:9].[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[C:19]([NH:14][CH2:13][CH:12]=[CH:11][C:10]([CH2:8][CH3:9])=[CH:15][CH:16]([CH3:17])[CH3:18])(=[O:21])[CH3:20]
Reactant: CCC(C=CCN)=CC(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C=CCNC(C)=O)=CC(C)C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of triethylamine (2.22 g) and 4-ethyl-6-methyl-2,4-heptadiene-1-ylamine (3.07 g) in dichloromethane (50 ml) at 0° C. was added dropwise acetic anhydride (4.08 g). After one hour, the reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10% methanol-chloroform) to give 1-acetylamino-4-ethyl-6-methyl-2,4-heptadiene (3.86 g) as an oil.