Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>>[O:38]1[C:42]2([CH2:47][CH2:46][N:45]([C:21]3[N:20]=[C:19]([O:18][C:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:29]=[C:30]([N:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)[CH:31]=[C:2]([F:1])[CH:3]=5)=[CH:9][CH:10]=4)[CH:24]=[CH:23][N:22]=3)[CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC4(CC3)OCCO4)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 1,4-dioxa-8-aza-spiro[4.5]decane according to conditions described in general procedure C. Mp: 115-117° C.; 1H NMR (400 MHz, CDCl3) δ 1.64 (t, J=5.0 Hz, 4 H), 3.26 (t, J=4.3 Hz, 4 H), 3.77 (s, 4 H), 3.88 (t, J=4.7 Hz, 4 H), 3.96 (s, 4 H), 5.98-5.99 (m, 1H), 6.77 (d, J=11.7 Hz, 1 H), 7.07 (d, J=7.8 Hz, 1 H), 7.32-7.34 (m, 2 H), 7.50-7.60 (m, 3 H), 7.90 (d, J=8.2 Hz, 1 H), 8.00 (d, J=8.6 Hz, 1H), 8.10 (s, 2 H), 8.15-8.17 (m, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:65])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@:39]1([C:48]([N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[O:49])[CH2:41][C@@H:40]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(=O)([O-])O.[Na+].[O:71]=[C:72]1[CH:76]=[CH:75][C:74](=[O:77])N1C(OC)=O>O1CCOCC1.O>[O:71]=[C:72]1[CH:76]=[CH:75][C:74](=[O:77])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:65])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@:39]1([C:48]([N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[O:49])[CH2:41][C@@H:40]1[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
64 mg (70 μmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 97) were taken up in 3 ml of 1:1 dioxane/water, then adjusted to pH 9 with 4 ml of saturated sodium hydrogencarbonate solution and subsequently admixed with 16.3 mg (110 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. Then another 8 mg (55 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate were added, and the reaction mixture was adjusted again to pH 9 and stirred at RT for a further hour. This was followed by concentration and purification of the remaining residue by means of preparative HPLC. At first, 31 mg of an as yet uncyclized intermediate were obtained. 27 mg of this intermediate were taken up again in 2 ml of 1:1 dioxane/water and then admixed with 250 μl of saturated sodium hydrogencarbonate solution. After stirring at RT for 2 hours, the reaction mixture was concentrated and the residue was purified by means of preparative HPLC. After lyophilization, 20 mg (29% of theory) of the title compound were obtained.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[C:25]([O:24][C:22](=[O:23])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCCN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCCN1CCNCC1
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 4-(4-tert-butoxycarbonylaminobutyl)piperazine-1-carboxylic acid benzyl ester (16) (3.26 g, 8.33 mmol), acetic acid (0.5 mL), and palladium hydroxide on carbon (60% wet, 0.98 g) in methanol (15 mL) was stirred under atmospheric hydrogen for 16 h. The catalyst was removed by suction filtration over Celite. The filtrate was concentrated in vacuo and the resulting residue was purified by Biotage silica gel column chromatography using concentrated ammonium hydroxide/methanol/dichloromethane to give 17 as a yellow oil (1.94 g, 91% yield): 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.53 (m, 4H), 2.35 (m, 6H), 2.45 (br, 1H), 2.94 (t, 4H), 3.12 (m, 2H), 5.32 (br, 1H); ESI MS m/z 258 [C13H27N3O2+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[N:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:45]([C:42]3[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=3)(=[O:47])=[O:46])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccncc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Diisopropylethylamine (0.3 mL, 1.7 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 100 mg, 0.24 mmol) in CH2Cl2 (6 mL). The solution was stirred at room temperature for 30 min and then a solution of pyridine-4-sulfonyl chloride (which may be prepared as described above; 213 mg, 1.2 mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give {6-fluoro-4-[1-(pyridine-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (45 mg, 42%) as an orange liquid. MS cald. for C23H24FN2O4S [(M+H)+]: 443, obsd. 443.4.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:38][C:39](=[O:41])[CH3:40])([CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([O:25]CC4C=CC=CC=4)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.CO.[C].[Pd]>[C:35]([O:34][CH2:33][C:6]([NH:38][C:39](=[O:41])[CH3:40])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([OH:25])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)NC(CCc1ccc(-c2cccc3c(OCc4ccccc4)cccc23)cc1)(COC(C)=O)COC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)NC(CCc1ccc(-c2cccc3c(O)cccc23)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
The compound (1.45 g) of Example (1-1) was dissolved in ethyl acetate (30 mL) and methanol (10 mL), 10% palladium carbon (500 mg) was added, and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. After celite filtration, the filtrate was concentrated, and the residue was washed with diethyl ether to give the object product (0.99 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH:4]=[CH:5][N:6]=1>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:16]([F:19])([F:17])[F:18])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Cc1nccn1-c1ccc(N)cc1C(F)(F)F

Procedure:
2-methyl-1-(4-nitro-2-trifluoromethyl-phenyl)-1H-imidazole (6.0 g, 22.1 mmol) is dissolved in ethanol (100 mL). After hydrogenation catalyzed by palladium (10 wt % on activated carbon, wet, Degussa type, 1 g) under 1 atm H2 balloon for overnight, the reaction mixture is filtered through a pad of celite and washed with ethanol. The combined filtrate and washings are concentrated to afford the title compound, which is used for next reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C:16](=O)[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)#[N:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C@H:16]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([C:20]#[N:21])=[CH:23][CH:24]=4)[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C1C[C@H]2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)N2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CN[C@H]2C[C@H]3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of formula (In), wherein R11 is 4-cyano, m is 1, W=NH, and the bonds depicted as wavy bonds define the 7aS,6S stereoisomer, was prepared as follows. To a solution of (7aS)-2-(3,5-dichloro-phenyl)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3,6-trione (0.5 g) (0.0017 mol) (Preparation 20), in 50 mL of DCM was added molecular sieves 4A, 4-cyanobenzyl amine (0.27 g) (0.002 mol), then NaBH(OAc)3 (0.54 g) (0.00255 mol.). The reaction mixture was stirred overnight at RT and then the insoluble material eliminated. After evaporating the solvent, the residue was purified by SiO2 chromatography (eluent: DCM/MeOH 98/2) to afford the titled compound and its stereoisomer. 7aS,6S stereoisomer (70 mg). NMR (CDCl3, 200 MHz): 7.45 (2H, d), 7.3 (1H, m), 7.2-7.1(4H, m), 4.25 (1H, dd), 4.05 (1H, d), 3.65 (2H, dd), 3.4(1H, m), 3.02 (1H, dd), 2.35-2.2 (1H, m), 2.0 (1H, bd).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([OH:31])[CH:22]=1.O[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:41]([O:40][C:39]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:31][C:23]1[CH:22]=[C:21]([F:20])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)NCCCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1OCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction was carried out under N2 atmosphere. Triphenyl phosphine (0.52 mol) was added to a solution of methyl 4-fluoro-2-hydroxybenzoate (0.47 mol), tert-butyl 5-hydroxypentylcarbamate (0.47 mol) and diisopropyl azodicarboxylate (DIAD; 0.94 mol) in THF (1 l) dropwise at −20° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. The resulting mixture was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([CH2:31][N+:32]#[C-])(=O)=O)=CC=1.C(O)C.CC(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>COCCOC>[C:31]([CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][C:8]2([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:20][CH2:19]1)#[N:32]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)C1(CN2CCC(=O)CC2)CCOCC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)C1(CN2CCC(C#N)CC2)CCOCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a stirred solution of tert-butyl-4-[(4-oxopiperidin-1-yl)methyl]tetra hydro-2H-pyran-4-carboxylate (8.77 g, 0.0295 mol, step 3 of Example 3) in 1,2-dimethoxyethane (250 mL) was added p-toluenesulfonylmethylisocyanide (11.51 g, 0.0590 mol), ethanol (3.96 mL, 0.0678 mol) and potassium t-butoxide (11.58 g, 0.1032 mol) at 0° C. The resulting mixture was stirred at 50° C. for 16 h. After cooling, the reaction mixture was poured into sat. NaHCO3 aq. (200 mL), and the mixture was extracted with CH2Cl2 (200 mL×3). The extracts were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (2:1) to give 5.76 g (63%) of the title compound as yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@H:35]([CH2:36][OH:37])[C@@H:38]([CH3:41])[CH2:39][CH3:40])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-((2S,3S)-1-hydroxy-3-methylpentan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C22H25FN4O3S, 444.16; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.16-8.13 (m, 1H), 8.06 (d, J=1.4, 1H), 7.86 (m, 1H), 7.67-7.62 (m, 1H), 7.58-7.53 (m, 1H), 7.39-7.28 (m, 3H), 3.46-3.35 (m, 2H), 3.13 (q, J=5.4, 1H), 1.60-1.49 (m, 1H), 1.48-1.36 (m, 1H), 1.07-0.93 (m, 1H), 0.84-0.74 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:20][N:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Br[C:33]1[S:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=1.C(N(CC)CC)C>ClCCCl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:39][CH:38]([C:35]1[N:34]=[C:33]([N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][O:24][C:21]3[CH:22]=[CH:23][C:18]([C:15]4[CH:16]=[CH:17][C:12]([S:9]([CH3:8])(=[O:10])=[O:11])=[CH:13][CH:14]=4)=[N:19][CH:20]=3)[CH2:27][CH2:28]2)[S:37][N:36]=1)[CH3:40]
Reactant: CC(C)c1nsc(Br)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nsc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Yield: 37.1 %

Procedure:
A mixture of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine trifluoroacetate (107 mg, 0.23 mmol), 5-bromo-3-(1-methylethyl)-1,2,4-thiadiazole (48 mg, 0.23 mmol), triethylamine (0.096 mL, 0.69 mol) and 1,2-dichloroethane (3 mL) was stirred and heated at reflux for 2 h, and the mixture was concentrated. The crude product was purified by reverse-phase preparative HPLC using CH3CN:H2O gradient (30:70 to 70:30) with 0.05% TFA as a modifier to give 25 mg (19%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.49 (d, 1H, J=2.6 Hz), 8.13-8.06 (m, 2H), 8.06-7.99 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 7.39 (dd, 1H, Ja=8.8 Hz, Jb=2.6 Hz), 4.06-3.94 (m, 4H), 3.27-3.17 (m, 2H), 3.12-2.99 (m, 4H), 2.23-2.08 (m, 1H), 2.05-1.95 (m, 2H), 1.65-1.50 (m, 2H), 1.31 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 473 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([NH2:14])=[NH:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH3:15].[Cl:16][C:17]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:18]=1[CH:19]=[C:20]([C:23]#[N:24])[C:21]#[N:22]>>[NH2:24][CH2:23][C:20]1[C:21]([NH2:22])=[N:13][C:12]([C:10]2[CH:9]=[C:8]3[C:4]([CH:5]=[CH:6][N:7]3[CH3:15])=[C:3]([O:2][CH3:1])[CH:11]=2)=[N:14][C:19]=1[C:18]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:17]=1[Cl:16]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COc1cc(C(=N)N)cc2c1ccn2C
Product: COc1cc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)cc2c1ccn2C

Procedure:
The title compound, MS: m/e=428.0 (M+H+), was prepared from 4-methoxy-1-methyl-1H-indole-6-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C=O)C.[CH2:12]([O:19][CH:20]1[CH2:24][O:23][CH:22]([CH2:25][CH2:26]O)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH2:12]([O:19][CH:20]1[CH2:24][O:23][CH:22]([CH2:25][CH2:26][Cl:4])[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCCC1CC(OCc2ccccc2)CO1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClCCl
Product: ClCCC1CC(OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
To an ice-cold stirred solution of oxalyl chloride (1.005 mL, 11.48 mmol) in CH2Cl2 (30 mL) was added DMF (0.914 mL, 11.80 mmol), dropwise, over 10 min. The ice bath was removed and the white slurry stirred for 30 min at room temperature. The reaction was cooled to 0° C. in an ice bath and a solution of 2-(4-(benzyloxy)tetrahydrofuran-2-yl)ethanol (2.3847 g, 10.73 mmol) in CH2Cl2 (30 mL) was rapidly added via cannula. The resulting clear yellow solution was stirred for 2 h at room temperature and 3 h at reflux. After cooling to room temperature the mixture was concentrated and the resulting yellow residue taken up in Et2O (100 mL), washed with water (3×50 mL) followed by brine (25 mL), then dried (MgSO4), filtered and concentrated to give a colorless liquid. Flash column chromatography on a silica gel column using 9:1 hexane/ethyl acetate provided 4-(benzyloxy)-2-(2-chloroethyl)tetrahydrofuran (2.47 g, 10.26 mmol, 96% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ: 7.27-7.37 (5 H, m), 4.48 (1.6 H, s), 4.41 (0.4 H, s), 4.17-4.23 (1 H, m), 3.96-4.11 (2 H, m), 3.72 (0.8 H, dd, J=10.1, 4.9 Hz), 3.59-3.70 (2.2 H, m), 2.30 (0.8 H, dt, J=13.4, 7.0 Hz), 2.09-2.25 (1.2 H, m), 1.89-2.01 (1 H, m), 1.69-1.74 (0.8 H, m), 1.57-1.64 (0.2 H, m). LCMS (M+H) calcd for C13H18ClO3: 241.1; found: 241.05.
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][C@@:15]12[C@@H:32]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[C:27](=[O:33])[CH2:26][CH2:25]4)[CH2:22][CH2:21][C:20]1=[CH:19][C:18](=[O:34])[CH:17]=[CH:16]2.[Cl-].[NH4+]>CS(C)=O>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][C@@:15]12[C@@H:32]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[C:27](=[O:33])[CH2:26][CH2:25]4)[CH2:22][CH:21]=[C:20]1[CH2:19][C:18](=[O:34])[CH:17]=[CH:16]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43COC3CCCCO3)[C@@H]1CCC2=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)C=C[C@@]43COC3CCCCO3)[C@@H]1CCC2=O

Procedure:
To a solution of potassium t-butoxide in dimethylsulfoxide at 25° C. under nitrogen is added 19-tetrahydropyranyloxy-1,4-androstadiene-3,17-dione in dimethylsulfoxide with stirring. After 15 minutes the mixture is poured onto cold aqueous solution of ammonium chloride. The solid which forms is rapidly filtered, washed well with water and dissolved in ether. The ether solution is washed with water, dried over sodium sulfate and evaporated at room temperature to yield 19-tetrahydropyranyloxy-1,5-androstadiene-3,17-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][CH:9]([O:20][C:21](=[O:31])[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH3:23])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.O>[Cl:32][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][CH:9]([O:20][C:21](=[O:31])[CH:22]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:28][CH:29]=1)[CH3:23])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)C(C)c2ccc(N)cc2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)C(C)c2ccc(NS(C)(=O)=O)cc2)cc1OC
Temperature: 0 °C
Yield: 36.1 %

Procedure:
Compound 16 (26 mg, 0.05 mmoles) is dissolved in dry CH2Cl2 (10 mL) under nitrogen atmosphere. The solution is cooled to 0° C. and triethylamine (0.009 mL, 0.066 mmoles) and methanesulphonyl chloride (0.0052 mL, 0.06 mmoles) are added. The mixture is then allowed to react at room temperature for 17 hours. The reaction mixture is then diluted with water (15 mL) and extracted with AcOEt (2×30 mL). The organic phase is dried over Na2SO4 and the solvent is evaporated. The crude is purified by preparative HPLC to yield 10 mg of the title compound as a mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[C:23]4[C:18](=[C:19]([O:24]C)[N:20]=[CH:21][CH:22]=4)[N:17]([CH3:26])[CH:16]=3)=[CH:13][C:12]([N+:27]([O-:29])=[O:28])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[C:23]4[CH:22]=[CH:21][NH:20][C:19](=[O:24])[C:18]=4[N:17]([CH3:26])[CH:16]=3)=[CH:13][C:12]([N+:27]([O-:29])=[O:28])=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])cnc3Nc3ccc(F)cc3)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc([N+](=O)[O-])cnc2Nc2ccc(F)cc2)c2cc[nH]c(=O)c21
Temperature: 90 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of Example 14b (0.5 g, 1.27 mmol) in 1,4-dioxane (7 mL) was treated with hydrogen chloride solution (4 M in 1,4-dioxane, 3.2 mL, 12.7 mmol) and stirred at 90° C. for 2 hours. The reaction mixture was concentrated and then treated again with hydrogen chloride solution (4 M in 1,4-dioxane, 3.2 mL, 12.7 mmol). The mixture was heated for 2 hours at 90° C. and then concentrated to dryness to give 0.482 g (100%) of the title compound.