Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>CCOC(C)=O>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(N)cc1C(F)(F)F

Procedure:
Methyl 4-nitro-2-(trifluoromethyl)benzoate (5.20 g, 20.9 mmol) was dissolved in EtOAc (100 mL) and tin chloride dihydrate (9.41 g, 41.7 mmol) was added to the reaction mixture. The reaction was heated at reflux for 2 h. The crude reaction mixture was purified by column chromatography (SiO2, EtOAc/hexanes) to give the title compound. LCMS: (FA) ES− 218.4 (M−1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.[C:21](=O)([O-])[O-].[K+].[K+].Cl.[CH3:28][N:29]([CH3:34])[CH:30](C)[CH2:31]Cl>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:21][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CC(CCl)N(C)C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 23.9 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl) -1,2,4-oxadiazole (31 mg, 0.12 mmol), potassium carbonate (381mg, 2.8 mmol) and 2-dimethylaminopropyl chloride hydrochloride (51 mg, 0.32 mmol) in N,N-dimethylformamide (1 mL) were heated in a sealed vial at 150° C. for 5 minutes. Standard work up and chromatography afforded 10 mg (24%) of 3-(2-pyridyl)-5-(3-cyano-5-(dimethylaminopropoxy)phenyl) -1,2,4-oxadiazole: 1H NMR (CDCl3): δ-8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.41 (s, 1H), 4.17 (t, 2H), 2.49 (t, 2H), 2.28 (s, 6H), 2.02 (q, 2H).
Reaction SMILES: [CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:11](OC=C)(=[O:13])[CH3:12]>C(OC)(C)(C)C>[C:11]([O:10][C@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)(=[O:13])[CH3:12].[C@@H:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC1C=Cc2ccccc21
Reactant: C=COC(C)=O
Solvent: COC(C)(C)C
Product: CC(=O)O[C@@H]1C=Cc2ccccc21
Product: O[C@H]1C=Cc2ccccc21
Temperature: 37 °C
Reaction time: 168 h
Yield: 38 %
Yield: 10 %

Procedure:
100 mg (0.76 mmol) of racemic inden-1-ol, 0.13 mg (1.15 mmol) of vinyl acetate and 75.6 mg (100 mg of racemate/mmol) of lipase PS were suspended in 10 ml of t-butylmethyl ether and stirred at 37° C. for 7 days. After the end of the reaction, the suspension was filtered off to remove lipase. The filtrate was concentrated and the residue was subjected to silica gel column chromatography (eluate: ethyl acetate-hexane, 1:10 V/V), to separate into 50 mg (yield 38.0%, optical purity 22% ee) of (R)-1-acetoxyindene and 10 mg (yield 10.0%, optical yield 22% ee) of (S)-inden-1-ol respectively. The optical purities were determined by an analysis according to high speed liquid chromatography (column: chiral cell OD, eluate: isopropanol-hexane, 1% V/V).
Reaction SMILES: N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC([C:28](OC)=[O:29])=CC=2)=CC3)CC1.CN(C)CCC([NH:47][C@:48]12[CH2:82][CH2:81][C@@H:80]([C:83]([CH3:85])=[CH2:84])[C@@H:49]1[C@@H:50]1[C@@:63]([CH3:66])([CH2:64][CH2:65]2)[C@@:62]2([CH3:67])[C@@H:53]([C@:54]3([CH3:79])[C@@H:59]([CH2:60][CH2:61]2)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]2[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=2)=[CH:56][CH2:55]3)[CH2:52][CH2:51]1)=O.[Cl:87][C:88]1[CH:102]=[CH:101][C:91]2OC[C:94](=[O:100])[N:95]([CH2:96][C:97]([OH:99])=O)[C:90]=2[CH:89]=1>>[Cl:87][C:88]1[CH:102]=[CH:101][C:91]2[CH2:28][O:29][C:94](=[O:100])[N:95]([CH2:96][C:97]([NH:47][C@:48]34[CH2:82][CH2:81][C@@H:80]([C:83]([CH3:85])=[CH2:84])[C@@H:49]3[C@@H:50]3[C@@:63]([CH3:66])([CH2:64][CH2:65]4)[C@@:62]4([CH3:67])[C@@H:53]([C@:54]5([CH3:79])[C@@H:59]([CH2:60][CH2:61]4)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]4[CH:71]=[CH:72][C:73]([C:74]([OH:76])=[O:75])=[CH:77][CH:78]=4)=[CH:56][CH2:55]5)[CH2:52][CH2:51]3)=[O:99])[C:90]=2[CH:89]=1
Reactant: O=C(O)CN1C(=O)COc2ccc(Cl)cc21
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3C(=O)OCc4ccc(Cl)cc43)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(6-chloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 653.5 (M+H)+, 2.29 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.05-7.01 (m, 1H), 7.01-6.97 (m, 2H), 6.83 (s, 1H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.73 (d, J=1.8 Hz, 1H), 4.70 (d, J=1.2 Hz, 2H), 4.66 (br. s., 1H), 4.63 (s, 1H), 4.57-4.50 (m, 1H), 2.65-2.57 (m, 1H), 2.51-2.34 (m, 2H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.96-1.85 (m, 1H), 1.83-1.72 (m, 3H), 1.70 (s, 3H), 1.69-1.64 (m, 1H), 1.63-1.55 (m, 2H), 1.54-1.45 (m, 4H), 1.45-1.30 (m, 5H), 1.30-1.23 (m, 1H), 1.18-1.12 (m, 2H), 1.10 (s, 3H), 1.02 (s, 6H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH3:31])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:13]=[CH:12][C:11]([N:8]4[CH:7]=[N:6][N:5]([CH:3]([CH3:4])[CH:2]([O:1][S:38]([C:35]5[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=5)(=[O:40])=[O:39])[CH3:31])[C:9]4=[O:10])=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)O)c4=O)cc3)CC2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)OS(=O)(=O)c5ccc(C)cc5)c4=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of [S-(R*,S*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.01 mol), p-toluene-sulfonyl chloride (0.012 mol), triethylamine (2 g) and dimethylaminopyridine (0.5 g) in CH2Cl2 (100 ml) was stirred at room temperature for 4 days. The mixture was taken up in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2 100%). The pure fractions were collected and the solvent was evaporated. The residue was triturated in methylisobutyl keton, filtered off and dried, yielding 4.6 g (79%) [S-(R*,S*)]-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-[1-methyl-2-[[(4-methylphenyl)sulfonyl]oxy]propyl]-3H-1,2,4-triazol-3-one (interm. 134).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[N+:24]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[N:37]([CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)[CH3:38])[C:30]([O:32][CH3:33])=[O:31])([O-:26])=[O:25]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOCC.C1C=CC2N(O)N=NC=2C=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:41]2[CH2:42][CH2:43][CH2:44][CH:40]2[CH2:39][N:37]([C:36]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=2[N+:24]([O-:26])=[O:25])[CH3:38])=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reactant: COC(=O)c1ccc(N(C)CC2CCCN2)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 105.5 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (630.0 mg, 1.979 mmol), methyl 3-nitro-4-[N-(2-pyrrolidinyl)methyl-N-methylamino]benzoate (553.0 mg, 1.885 mmol), EDC(Hydrochloride) (542.0 mg, 2.827 mmol), HOBt (25.5 mg, 0.189 mmol), and DMAP (23.1 mg, 0.189 mmol) in DMF (5.0 mL) was stirred at room temp. for 2 hr. The mixture was diluted with Et2O, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the residue was chromatographed on silica-gel with CHCl3-MeOH (30:1, v/v) as eluent to afford 1.18 g (100%) methyl 4-[N-[1-[3-methoxy4-[N′-(2-fluorophenyl)ureido]phenylacetyl]-2-pyrrolidinyl methyl]-N-methylamino]-3-nitrobenzoate as a yellow foam, which is used to the subsequent reaction without further purification.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:31][O:32][C:33]([C:35]1[O:36][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:38][CH:39]=1)=[O:34]>ClCCl>[CH3:31][O:32][C:33]([C:35]1[O:36][C:37]([S:40]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:42])=[O:41])=[CH:38][CH:39]=1)=[O:34]
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)o1
Reaction time: 0.05 h
Yield: 74.2 %

Procedure:
To 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 280 mg, 0.78 mmol) in 5 mL of dichloromethane was added triethylamine (240 mg, 2.37 mmol). The mixture was stirred for 3 min followed by the addition of 5-chlorosulfonyl-furan-2-carboxylic acid methyl ester (210 mg, 0.94 mmol). The stirring was continued for 2 h at room temperature and then the reaction was quenched with 20 mL of saturated NaH2PO4. The mixture was extracted with Ethyl acetate (40 mL) and the organic phase was dried over Na2SO4 and concentrated under reduced pressure. Chromatography (3-50% Ethyl acetate/hexanes) gave 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-furan-2-carboxylic acid methyl ester as a clear oil (295 mg, 74%). ESI/CI-MS m/z 508 ([M−H]−).
Reaction SMILES: CC1C(C(C2C=CC(C#N)=CC=2)C=C)=CC2C(C)(C)CCC(C)(C)C=2C=1.[CH3:27][C:28]1([CH3:52])[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]2[CH:33]=[C:32]([CH:40]([C:43]3[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=3)[CH:41]=[CH2:42])[CH:31]=[CH:30][C:29]1=2.O.[NH2:54][C:55]1[NH:59][N:58]=[N:57][N:56]=1>C1COCC1>[CH3:27][C:28]1([CH3:52])[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]2[CH:33]=[C:32]([CH:40]([C:43]3[CH:51]=[CH:50][C:46]([C:47]([NH:54][C:55]4[NH:59][N:58]=[N:57][N:56]=4)=[O:48])=[CH:45][CH:44]=3)[CH:41]=[CH2:42])[CH:31]=[CH:30][C:29]1=2
Reactant: Nc1nnn[nH]1
Reactant: C=CC(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: C=CC(c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Solvent: O
Solvent: C1CCOC1
Product: C=CC(c1ccc(C(=O)Nc2nnn[nH]2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
1 equivalent of N,N′-carbonyldi-imidazole (Aldrich, 0.46 g, 0.29 mmol) is added, at ambient temperature to a solution of acid (E) 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]benzoic acid (0.10 g, 0.29 mmol) in 5 ml of anhydrous THF. Half an hour later, 1 equivalent of 5-aminotetrazole monohydrate (Aldrich, 0.30 g, 0.29 mmol) is added. The magnetic stirring is continued for 15 hours 30 minutes. A white precipitate forms in the reaction medium. The mixture is evaporated to dryness and 10 ml of HCl is added. The solution is filtered and the filtrate washed with water and with methanol. After drying one night in a desiccator (with P2O5), 15 mg of a white solid is obtained the compound (E) 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]-N-(tetrazol-5-yl)-benzamide (compound CB73364) (yield=12%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[OH2:19].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[C:31]3[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]3=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[C:31]3[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]3=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Cl)c(Cl)c2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc(Cl)c(Cl)c2)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 3.9 g of ethyl 2-[3-(3,4-dichlorophenyl)ureido]thiazol-4-ylglyoxylate, 1.9 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 60 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: CC(C)([O-])C.[K+].Br.[CH3:8][N:9]1[CH2:14][CH2:13][C:12](=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]([Br:26])[CH:18](Br)[C:17]3[CH:28]=[CH:29][CH:30]=[CH:31][C:16]2=3)[CH2:11][CH2:10]1>C(O)(C)(C)C>[CH3:8][N:9]1[CH2:14][CH2:13][C:12](=[C:15]2[C:16]3[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=3[CH:18]=[C:19]([Br:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)[CH2:11][CH2:10]1
Reactant: CN1CCC(=C2c3ccccc3C(Br)C(Br)c3ccccc32)CC1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN1CCC(=C2c3ccccc3C=C(Br)c3ccccc32)CC1

Procedure:
To 600 ml. of a 0.40 M (0.24 mole) solution of potassium t-butoxide in t-butanol is added 42.1 g. (0.079 mole) of 1-methyl-4-(10,11-dibromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrobromide and the mixture stirred vigorously under anhydrous conditions for 6 hours at room temperature. The reaction mixture is poured into 2 L. of water and extracted 3 times with 100 ml. each of benzene. The combined benzene extracts are dried over anhydrous MgSO4, filtered, the MgSO4 washed with benzene, and the benzene solution evaporated to dryness on a rotary evaporator. There remains 27.9 g. of crystalline product. This product is recrystallized by dissolving in 750 ml. of boiling hexane, filtered hot, the volume reduced to 200 ml. by boiling off hexane, seeding and allowing to crystallize. The crystals are collected and dried in a vacuum oven at 60° overnight to give 1-methyl-4-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 127°-129°C. Three more recrystallizations from hexane gives an analytical sample with m.p. 130°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[C:33]([F:34])=[C:32]([CH2:35][CH3:36])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[C:33]([F:34])=[C:32]([CH2:35][CH3:36])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: CCc1ccnc(C(=O)CBr)c1F
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-ethyl-3-fluoropyridine*.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:31][Si](C)(C)C>C(Cl)Cl.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH2:31])=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A mixture of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.62 mmol) in methylene chloride (2 mL) cooled to 0° C. was treated with N,N-dimethylformamide (2 drops). The reaction mixture was then slowly treated with oxalyl chloride (60 μL, 0.69 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1.5 h. The resulting reaction mixture was then treated dropwise with 1,1,1,3,3,3-hexamethyldisilazane (395 μL, 1.87 mmol) and subsequently stirred at 25° C. for 15 h. The reaction mixture was then partitioned between methylene chloride (20 mL), methanol (15 mL), and a 5% aqueous sulfuric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (141 mg, 70%) as a white foam: mp 67-70° C. (foam to gel); EI-HRMS m/e calcd for C16H20N2O3S (M+) 320.1195, found 320.1195.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30]N>C(O)C>[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cn1
Yield: 63 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone and 2-(5-methyl-4-imidazolylmethylthio)ethylamine was heated under reflux in ethanol for 18 hours. The solid which crystallised out on cooling was recrystallised from ethanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, m.p. 197°-8.5°, in 63% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][CH:9]=1.[F:19][C@H:20]1[CH2:22][C@H:21]1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:19][C@H:20]1[CH2:22][C@H:21]1[C:23]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH:17]=2)=[O:24]
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Reactant: Cc1ccncc1-c1ccc2cc(N)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 70 °C
Yield: 3.1 %

Procedure:
A mixture of 7-(4-methylpyridin-3-yl)-isoquinolin-3-amine (350 mg, 1.5 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (232 mg, 2.2 mmol), HATU (1.13 g, 3.0 mmol), and N,N-diisopropylethylamine (0.52 mL, 3.0 mmol) in N,N-dimethylformamide (3 mL) was heated at 70° C. for 3 hours. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (15 mg, 23%). 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.20 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.09 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.76 (dd, J=8.5, 1.4 Hz, 1H), 7.40 (d, J=5.0 Hz, 1H), 4.95 (m, 1H), 2.33 (s, 3H), 2.28 (m, 1H), 1.70 (dtd, J=23.2, 6.8, 3.8 Hz, 1H), 1.25-1.14 (m, 1H). LCMS (Method E): RT=3.063 min, M+H+=322.1.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].[O-]CC.[Na+:16].C(OCC)C>CC(OC)(C)C>[Cl:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][O-:9].[Na+:16]
Reactant: CCOC(=O)CCl
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C[O-]
Reaction time: 16 h

Procedure:
89.31 g (728 mmol) of ethyl chloroacetate and 63.7 g (859.9 mmol) of ethyl formate were dissolved in 500 ml of MTBE. 259.77 g (801 mmol) of an ethanolic solution of sodium ethoxide were added dropwise while stirring. After 16 hours, the supernatant was decanted off from the precipitate formed, the residue was stirred with approx. 500 ml of diethyl ether and filtered with suction, and the solid was washed with a further 500 ml of diethyl ether and dried.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C@H:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>P([O-])([O-])([O-])=O>[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[C:1]([O-:9])(=[O:8])[CH:2]([CH3:4])[OH:3]
Reactant: O=C([O-])C[C@H](O)C(=O)[O-]
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P([O-])([O-])[O-]
Product: CC(O)C(=O)[O-]
Product: O=C([O-])CC(O)C(=O)[O-]

Procedure:
0.35 g of the preparation from Example 18 were added to 10 ml 33 mM L-malate in 0.1 M phosphate pH 4.0 together with 17 μmol NAD+ and 7 μmol MnCl2. Total conversion of malate to lactate was obtained in six hours, and the procedure could be repeated with fresh malate, NAD+ and MnCl2 at least five times without any increase in reaction times.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)[CH3:2].[C:32](Cl)(=[O:34])[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:32](=[O:34])[CH3:33])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:7]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN(Cc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(benzylamino-methyl)-4-bromo-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and acetyl chloride.