Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:32][C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:29]3)[CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:51].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:51][C:16]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:29][C@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:32]3)[CH2:27]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2cnccn2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3cnccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-(pyrazin-2-yl)hexane-1,4-dione (284 mg) in acetic acid (2.2 mL) was added ammonium acetate (530 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (94.3 mg, yield 34%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:14][CH:15]=1
Reactant: ClCC1CO1
Reactant: CNC(=O)CCC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CNC(=O)CCC(=O)c1ccc(OCC2CO2)cc1
Yield: 81.1 %

Procedure:
A mixture of finely ground 3-(4-hydroxybenzoyl)-N-methylpropionamide (20.7 g, 0.1 mole), epichlorohydrin (77 g, 0.83 mole), and piperidine (0.5 ml) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane (500 ml) and shaken with dilute sodium hydroxide (100 ml). The organic phase was washed with water, dried and evaporated to a slurry. Addition of ether gave the required 3-[4-(2,3-epoxypropoxy)benzoyl]-N-methylpropionamide (21.36g.,81%) which was recrystallised from chloroform/ether, m.p. 133°-140° C.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][NH2:16]>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][NH:16][CH:5]1[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]1
Reactant: CN1CCC(=O)CC1
Reactant: NCCc1cccs1
Product: c1csc(CCNC2CCNCC2)c1

Procedure:
Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), thiophene-2-ethylamine (0.563 g, 1.0 eq.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([N+:16]([O-:18])=[O:17])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31](B(O)O)=[CH:30][C:29]=2[CH:36]=1)[CH3:21]>>[C:1]([O:5][C:6](=[O:19])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:31]2[O:32][C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][O:22][CH2:20][CH3:21])=[CH:36][C:29]=3[CH:30]=2)=[C:11]([N+:16]([O-:18])=[O:17])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Reactant: CCOCOc1ccc2oc(B(O)O)cc2c1
Product: CCOCOc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3[N+](=O)[O-])cc2c1
Yield: 90.2 %

Procedure:
By following the same procedure as described in Example 1 (step d), was prepared using (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester (12) (100 mg, 0.30 mmol) and 5-ethoxymethoxy-benzofuran-2-boronic acid (4) (92.5 mg, 0.39 mmol). Work-up as described in example 1d, followed by purification of the crude product by flash column chromatography using 10-25% ethyl acetate in hexane. Evaporation of solvent afforded 120 mg of the desired compound (13) as yellowish solid.
Reaction SMILES: O=O.[CH2:3]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[C:14]([F:25])[CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Li+].CC([N-]C(C)C)C>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:3]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][N:19]=2)=[C:14]([F:25])[CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2ccc(C)cn2)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: O=O
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(-c2ccc(OCCCCCCCC)cc2F)nc1
Temperature: 25 °C

Procedure:
With atmospheric oxygen and moisture being excluded, 7.9 mmol of 2-(4-octyloxy-2-fluorophenyl)-5-methylpyridine dissolved in THF and, about 15 minutes later, 8.7 mmol of 1-bromooctane are added at -70° C. to a solution of 8.7 mmol LDA (prepared from BuLi and diisopropylamine) in THF in the presence of 1.04 ml of DMPU. The reaction mixture is allowed to heat up to room temperature, stirring is continued for a further hour and working up is carried out as usual.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:29]=1)[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:29]=1)[CH2:25][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cc(Cl)cc(-c2ccccn2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cc(Cl)cc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-chloro-5-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 437.09 g/mol.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:50]2[N:51]=[C:52]([NH:55]C(OC(C)(C)C)=O)[S:53][CH:54]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]3)/[C:50]3[N:51]=[C:52]([NH2:55])[S:53][CH:54]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:33])=[O:32])[N:40]=1
Reactant: CC(C)(C)OC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 25.6 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (1.98 g, 2.21 mmol), DCM (18.4 mL) and TFA (10.2 mL, 133 mmol). Half of the crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (300 mg, ca 50%) as an off-white powder. LCMS: Rt=0.29 min, m/z=530.1 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.69 (s, 1H), 7.04 (br s, 1H), 5.43 (d, J=5.5 Hz, 1H), 4.93-4.78 (m, 2H), 4.74-4.67 (m, 1H), 4.22-4.12 (m, 2H), 1.36-1.20 (m, 2H), 1.20-1.00 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[N:15]1[N:16]([CH2:20][CH2:21][OH:22])[N:17]=[CH:18][CH:19]=1.O>CN(C=O)C>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:22][CH2:21][CH2:20][N:16]2[N:17]=[CH:18][CH:19]=[N:15]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: OCCn1nccn1
Reactant: C=CCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(COCCn2nccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
207 mg (8.21 mmol) 95% Sodium hydride were given at −50° C. to a solution of 1.00 g (5.47 mmol) 1-allyloxy-4-chloromethyl-benzene and 619 mg (5.47 mmol) 2-(2H-[1,2,3]-triazol-2-yl)-ethanol in 10.0 ml DMF. The mixture was allowed to warm slowly to r.t., stirred overnight and 6 ml water added. The formed oil was collected with 10 ml dichloromethane, the aqueous phase extracted with 10 ml dichloromethane and the combined organic phases dried over Na2SO4.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][C:9]1[CH:10]=[C:11](/[CH:48]=[CH:49]/[CH2:50][CH2:51][N:52]2[CH2:55][C:54]3([CH2:60][CH2:59][CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56]3)[CH2:53]2)[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:17]([O:24][C@@H:25]2[O:42][C@H:41]([CH2:43][O:44]C(=O)C)[C@@H:36]([O:37]C(=O)C)[C@H:31]([O:32]C(=O)C)[C@H:26]2[O:27]C(=O)C)=[N:18][NH:19][C:20]=1[CH:21]([CH3:23])[CH3:22]>ClCCl>[O:24]([C:17]1[C:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11](/[CH:48]=[CH:49]/[CH2:50][CH2:51][N:52]3[CH2:53][C:54]4([CH2:60][CH2:59][CH2:58][NH:57][CH2:56]4)[CH2:55]3)=[CH:10][C:9]=2[CH3:8])=[C:20]([CH:21]([CH3:23])[CH3:22])[NH:19][N:18]=1)[C@@H:25]1[O:42][C@H:41]([CH2:43][OH:44])[C@@H:36]([OH:37])[C@H:31]([OH:32])[C@H:26]1[OH:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CC4(CCCN(C(=O)OC(C)(C)C)C4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(/C=C/CCN2CC3(CCCNC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add 4.0 M HCl/1,4-dioxane (1.5 mL, 1.5 mmol) to a solution of tert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1h-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl}-2,6-diazaspiro[3.5]nonane-6-carboxylate in dichloromethane (2 mL) and stir at rt for 4.0 h. Concentrate the mixture under the reduced pressure to a foamy solid. Treat the solid with 2.0 M ammonia in MeOH (2 mL) overnight. After 18 hours at room temperature, concentrate to remove the solvent under reduced pressure. The resulting residue is purified by preparative HPLC method: high pH, 19% B for 3 min, 19-34 B % for 5 min @85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3@pH 10, solvent B—MeCN to yield the title compound as solid (47 mg, 0.08 mmol). MS (m/z): 570.8, 571.8 (M+1), 568.7, 569.8 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>C(#N)C.O>[CH2:10]([N:14]([C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CCCCNCC
Solvent: O
Solvent: CC#N
Product: CCCCN(CC)c1cc(Cl)nc(C)n1
Yield: 99.7 %

Procedure:
A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10 mmol) in 5 ml of acetonitrile was treated with N-butyl-ethyl-amine (2.000 g, 20 mmol) and heated at reflux for 0.5 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 2.271 g (100%) of title compound as a light-brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.22-1.36 (m, 2H), 1.45-1.6 (m, 2H), 2.43 (s, 3H), 3.25-3.60 (m, 4H), 6.15 (s, 1H) ppm.
Reaction SMILES: FC(F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:36])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:16][C:15]([CH3:36])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[CH:3][N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)c(F)cc1F
Yield: 55 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (31.7 mg, 0.166 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 57 mg, 0.166 mmol), HOBT (26.9 mg,0.199) mmol, and EDC (47.8 mg, 0.249 mmol) in 4 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol in dichloromethane) gave 40 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 3.00 (m, 2H), 3.30 (m, 2H), 3.93 (m, 1H) 4.04-4.24 (m, 2H), 4.23 (s, 1H), 4.35 (m, 1H), 4.97-5.48 (m, 2H) 7.22 (m, 1H), 7.44 (m, 1H), 8.04 (m, 1H). ESI-MS 507 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13](=O)[CH2:14][C:15](=O)[CH3:16]>C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:12])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C)cc2C)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (118.7 g, 0.68 mol) in 300 ML of glacial acetic acid was added 2,4-pentanedione (68.0 g, 0.68 mol). The resulting solution was stirred at 100° C. for 18 h and then was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate, filtered through a pad of silica gel and concentrated to afford 131 g (95%) of the title compound, which was used without purification. LRMS (NH4-CI): 203.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[C:34](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[C:14]([F:15])([F:17])[F:16])[N:8]2[CH3:34])=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(C)c2cc1Cl
Temperature: 25 °C

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (1.30 g, 2.63 mmol) (Synthesis Example 8, Stage 3) and potassium carbonate were initially charged in acetonitrile (39 ml) and admixed with iodomethane (561 mg, 3.95 mmol). The reaction mixture was heated under reflux overnight. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:4]([C:18]([OH:20])=O)[CH2:3]1.C(N(CC)CC)C.ClC(OCC)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:4]([C:18]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:20])[CH2:3]1
Reactant: C1COCCN1
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2)N1CCOCC1
Reaction time: 0.5 h

Procedure:
4.5 g (0.016 mol) of 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 6 are suspended in 110 ml of acetonitrile at 0° C. 1.1 equivalents of triethylamine are added and the reaction mixture is stirred for 30 minutes, then 1.1 equivalents of ethyl chloroformate are added while maintaining the temperature between 0° and 5° C. After stirring for 30 minutes, 1.1 equivalents of morpholine are added to the filtrate. One equivalent is stirred at room temperature for 2 hours. The precipitate is separated, the filtrate is evaporated under vacuum. The residue is recrystallized.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH2:17][NH2:18])=[CH:15][N:14]=[CH:13]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClC(Cl)Cl>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH2:17][NH:18][C:20](=[O:22])[CH3:21])=[CH:15][N:14]=[CH:13]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CCc2ccccc2C1n1cncc1CN
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1cncn1C1c2ccccc2CCC1(C)C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred mixture of 5.1 parts of 1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazole-5-methanamine and 75 parts of trichloromethane was added dropwise a solution of 2.0 parts of acetic acid anhydride in 150 parts of trichloromethane. Upon complete addition, stirring was continued for 1 hour at room temperature. The reaction mixture was washed with a sodium carbonate solution 10% and water, dried, filtered and evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 3.61 parts (60.6%) of N-[[1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazol-5-yl]methyl]acetamide; mp. 166.3° C. (compound 2.47).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(Nc2cc(I)ccn2)c1
Temperature: 130 °C
Yield: 16 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (500 mg, 2.24 mmol), 3-nitroaniline (620 mg, 4.49 mmol), and Cs2CO3 (1460 mg, 4.48 mmol) in dry DMF (12.5 mL) was heated for 1 h at 130° C. in a microwave oven. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (DCM/MeOH 100:0 to 95:5) to yield the desired product A5 as a white solid (122 mg, 16%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 7.21 (d, J=5.4 Hz, 1H), 7.29 (s, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.93 (m, 2H), 8.74 (t, J=2.1 Hz, 1H), 9.62 (s, 1H). MS (ES) C11H8IN3O2 requires: 341. found: 342 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:21][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[Cl:1][C:2]1[S:21][C:5]2[NH:6][C:7](=[S:23])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[C:4]=2[CH:3]=1
Reactant: O=C1CN=C(c2ccccc2[N+](=O)[O-])c2cc(Cl)sc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1C1=NCC(=S)Nc2sc(Cl)cc21

Procedure:
1 g (0.00327 mol) of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one are heated to reflux with 0.8 g of phosphorus pentasulphide in 30 ml of absolute pyridine, nitrogen being conducted through the solution. The mixture is separated on a column (φ3 cm) filled with 50 g of Silica gel[(0.05 to 0.2 mm) (Merck)] (the product travelling on the front and the impurities travelling only slowly). After concentration of the pyridine solution under a vacuum, the residue is treated with methylene chloride and brought to crystallization. After completion of the crystallization in a refrigerator, the mixture is filtered under a vacuum and washed with a small amount of ice-cold methylene chloride. Recrystallization from absolute methanol yields 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione in the form of yellow crystals, melting point 213°-215° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:26][C:27]([F:44])([F:43])[C@H:28]([O:30][C:31](=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1)[CH3:29]>>[F:26][C:27]([F:44])([F:43])[C@H:28]([O:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([C@@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:32])[CH3:29]
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)cc1
Product: C[C@@H](OC(=O)N1CCC([C@H]2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (R)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=1.07 min; Mass spectrum (ESI+): m/z=499 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[C:14]4[C:19]([CH2:20][C:8]=3[C:7]=2[CH:6]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C@@H:9]3[C:14]4[C:19]([CH2:20][C@@H:8]3[C:7]=2[CH:6]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Reaction time: 8 h

Procedure:
A solution of 5,10-dihydro-8-tert-butylindeno[1,2-b]indole (0.57 g, 2.2 mM) in trifluoroacetic acid (5 cm3) was stirred rapidly, and triethylsilane (0.7 cm3, 2 eq ) added in one portion. The reaction was stirred overnight, poured into water (10 cm3) and neutralised by the addition of sodium hydroxide. The product was extracted into diethyl ether (2×5 cm3), and the combined extracts were washed with water, dried (Na2SO4) and evaporated to yield a pink solid. This was washed with cold petroleum ether (60°-80° C.), and then crystallised from petrol to yield a colourless solid. Yield: 0.47 g, 81% M.p. 103°-105° C.; 1H NMR (CDCl3) δ: 7.4-6.9 (6H, m), 6.58 (1H, d, J=8 Hz), 5.25 (1H, d, J=8.5 Hz), 4.15 (2H, br.m), 3.5 (1H, dd, J=16.0 and 9 Hz), 3.2 (1H, d, J=16 Hz), 1.2 (9H, s).