Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:10]([C:22](O)=[O:23])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:21])[N:16]([OH:20])[N+:17]([O-:19])=[O:18]>>[NH:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:10]([C:22]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:21])[N:16]([OH:20])[N+:17]([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N(O)[N+](=O)[O-])C(=O)O
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N(O)[N+](=O)[O-])C(=O)NCc1ccccc1
Yield: 81 %

Procedure:
Boc-Arg(NO2)(OH)CONHBn was prepared according to Example 42 by coupling benzylamine to Boc-Arg(NO2)(OH)COOH in a 81% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CCN(Cc5ccccn5)CC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione (30 mg, 0.066 mmol) in DMF was added 2-(bromomethyl)pyridine hydrogen bromide (26.0 mg, 0103 mmol). The mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-(pyridin-2-ylmethyl)piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=544)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20](Br)=[N:19][N:18]=[C:17]2[CH3:22])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:23]>CS(C)=O.C(Cl)(Cl)Cl>[CH3:22][C:17]1[N:16]2[C:5]3[C:6]([C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:23][C:20]2=[N:19][N:18]=1)=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=3
Reactant: Cc1nnc(Br)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nnc2nc(-c3ccccc3)c3cc(Cl)ccc3n12
Temperature: 0 °C

Procedure:
In the next place, a solution of 0.5 g of the above-mentioned 5-chloro-2-(3-methyl-5-bromo-4H-1,2,4-triazol-4-yl)benzophenone in 20 ml of dimethylsulfoxide was heated, with stirring, at about 180° C for 10 hours, during which ammonia gas was continuously passed into the reaction mixture. After cooling, the reaction mixture was poured into ice-water and the resulting crystals were filtered, washed with water and dried. The crystals thus obtained was dissolved in chloroform and chromatographed on silica gel using chloroform as an eluent. The product thus separated was recrystallized from isopropyl ether to give 1-methyl-5-phenyl-7-chloro-s-triazolo[4,3-a]quinazoline, m.p. 325° - 327° C.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[C:15]2[O:16][C:17]3[C:22]([C:23]4([CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)[C:14]=2[CH:13]=[CH:12][CH:11]=1)=[CH:21][CH:20]=[C:19]([O:30][CH3:31])[CH:18]=3)C1C=CC=CC=1>C(O)C>[ClH:1].[OH:9][C:10]1[C:15]2[O:16][C:17]3[C:22]([C:23]4([CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[C:14]=2[CH:13]=[CH:12][CH:11]=1)=[CH:21][CH:20]=[C:19]([O:30][CH3:31])[CH:18]=3
Reactant: COc1ccc2c(c1)Oc1c(OCc3ccccc3)cccc1C21CCN(C)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)Oc1c(O)cccc1C21CCN(C)CC1

Procedure:
A solution of 4-benzyloxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride (1.5 g.) in ethanol (200 ml.) is hydrogenated using 5% w/w palladiun-on-carbon catalyst at 1 atmosphere and 25° C. The catalyst is filtered off and the ethanol evaporated to give a gummy residue which is crystallised from ethanol-ether to give 4-hydroxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 223°-224° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7](/[C:19](=[N:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)[CH2:8]CCC1C=CC(OC)=CC=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39](CO)=[CH:38][CH:37]=1>>[C:1]([O:5][C:6](=[O:33])[N:7](/[C:19](=[N:25]\[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])/[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)[CH2:8][C:39]1[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCCN(C(=O)OC(C)(C)C)/C(=N/C(=O)OC(C)(C)C)n2cccn2)cc1
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)/C(=N\C(=O)OC(C)(C)C)n2cccn2)cc1

Procedure:
The title compound is prepared by an analogous procedure to Intermediate E by replacing 3-(4-methoxyphenyl)-1-propanol with 4-methoxybenzylalcohol. [M+H]+ 431.
Reaction SMILES: Br[C:2]1[S:6]/[C:5](=[CH:7]\[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])/[N:4]([CH2:19][CH2:20][CH2:21][CH3:22])[C:3]=1[CH3:23].[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>C(N(CC)CC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([N:4]1[C:3]([CH3:23])=[C:2]([C:28]#[C:27][C:25]([OH:29])([CH3:26])[CH3:24])[S:6]/[C:5]/1=[CH:7]\[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:9])[CH2:20][CH2:21][CH3:22]
Reactant: C#CC(C)(C)O
Reactant: CCCCN1C(C)=C(Br)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCN1C(C)=C(C#CC(C)(C)O)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Temperature: 100 °C
Yield: 59.5 %

Procedure:
A mixture of product from Example 13 (33 mg, 0.08 mmol), 2-methylbut-3-yn-2-ol (10 mg, 0.1 mmol), CuI (2 mg, 0.01 mmol and Pd(Ph3P)4 (30 mg, 0.03 mmol) in triethylamine (10 mL) was heated at 100° C. for 1 hour. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (hexane-EtOAc 1:1) to afford 20 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.40 (sextet, J=7 Hz, 2H), 1.67 (quintet, J=7 Hz, 2H), 2.34 (s, 3H), 3.85 (s, 3H), 3.95 (t, J=7 Hz, 2H), 5.50 (s, 1H), 6.72 (s, 1H), 7.13 (d, J=9 Hz, 1H), 7.43 (dd, J=9 Hz, 3 Hz, 1H), 7.66 (d, J=3 Hz, 1H); MS (ESI) m/z 420 (M+H)+. Anal calcd for C22H26ClNO3S: C, 62.92; H, 6.24; N, 3.34. Found: C, 62.85; H, 6.28; N, 2.92.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]([NH:12][C:13]([NH2:15])=[NH:14])#N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:10]([NH:12][C:13]([NH2:15])=[NH:14])[NH:9][C:4]=2[CH:3]=1
Reactant: N#CNC(=N)N
Reactant: Nc1ccc(F)cc1N
Product: N=C(N)Nc1nc2ccc(F)cc2[nH]1
Yield: 72.9 %

Procedure:
4-Fluoro-o-phenylenediamine (10.40g) was reacted with cyanoguanidine (6.95g) in a manner analagous to that described in Example 3 to yield a brown crystaline precipitate (11.61g) which on crystalisation from water yielded 5-fluoro-2-quanidinobenzimidazole (9.17g) m.p. 217°-218°C as brown needles.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)=[CH:3][CH:2]=1.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].N1C=CC=CC=1>O>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:4]2[CH:5]=[CH:6][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:2][CH:3]=2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: OCCCCCCCCOc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CCCCCCCCOc2ccc(-c3ccccc3)cc2)cc1

Procedure:
A mixture of 33.26 g of 8-([1,1'-biphenyl]-4-yloxy)-1-octanol, 23.37 g of tosyl chloride and 200 ml of pyridine was allowed to stand in a refrigerator overnight. Then water was added, the solid collected, washed with water and dissolved in chloroform. This solution was washed with dilute hydrochloric acid then saturated aqueous sodium bicarbonate, dried and the solvent removed, giving the desired compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[H-].[Na+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCc2cc(Br)ccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C

Procedure:
5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before tert-butyl bromoacetate (92 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO3 (10 mL) was carefully added. The mixture was extracted with EtOAc, and the organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C14H16BrNO3 [M+Na]+: 348. Found: 348.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.O1CCC[CH2:28]1>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:28])[N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccc(F)cc2)ccn1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: CN1N=C(n2cc(-c3ccnc(N)c3)c(-c3ccc(F)cc3)n2)CCC1=O
Yield: 38 %

Procedure:
The reaction was carried out in the same manner as in Example 33 except for using 100 mg (0.29 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-(1,4,5,6-tetrahydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 50 in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole, and using 3 ml of N,N-dimethylformamide as a solvent in place of tetrahydrofuran to obtain 39.5 mg of the title compound as a white powder. (Yield: 38%)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)[C:5](=[O:25])[N:4]([CH3:26])[CH:3]=1.[CH3:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[NH:43][C:44]([C:46]1[S:50][C:49]2[CH2:51][CH2:52][CH2:53][CH2:54][C:48]=2[CH:47]=1)=[O:45].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:19][CH2:18][CH2:17][N:15]([CH3:16])[C:13]([C:12]1[CH:20]=[CH:21][C:9]([NH:8][C:6]2[C:5](=[O:25])[N:4]([CH3:26])[CH:3]=[C:2]([C:33]3[C:28]([CH3:27])=[C:29]([NH:43][C:44]([C:46]4[S:50][C:49]5[CH2:51][CH2:52][CH2:53][CH2:54][C:48]=5[CH:47]=4)=[O:45])[CH:30]=[CH:31][CH:32]=3)[N:7]=2)=[CH:10][C:11]=1[N+:22]([O-:24])=[O:23])=[O:14]
Reactant: CN(CCO)C(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1[N+](=O)[O-]
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N(C)CCO)c([N+](=O)[O-])c2)n1
Yield: 61.8 %

Procedure:
4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-N-(2-hydroxy-ethyl)-N-methyl-2-nitro-benzamide (4) (250 mg, 0.59 mmol, 1.0 equiv), 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (257 mg, 0.65 mmol) and tetrakis(triphenylphosphine)palladium (68 mg, 0.06 mmol) are dissolved in 1,4-dioxane (2.0 mL) and sodium carbonate (1N, 1.0 mL) and heated in a microwave glass reactor for 6 minutes at 140° C. Once completed the reaction is transferred to a seperatory funnel with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure. The resulting residue is then triturated with DCM and hexane to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid [3-(6-{4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-3-nitro-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide (5) as a light yellow solid (225 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@:11]([CH2:36][CH2:37]I)([CH2:12][CH2:13][C@@H:14]3[C:23]2=[CH:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C-:39]#[N:40].[K+]>CN(C=O)C>[Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@:11]([CH2:36][CH2:37][C:39]#[N:40])([CH2:12][CH2:13][C@@H:14]3[C:23]2=[CH:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@]2(C)C3=CC[C@]4(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]4[C@@H]3CC[C@]2(CCI)C1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@]2(C)C3=CC[C@]4(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]4[C@@H]3CC[C@]2(CCC#N)C1
Temperature: 60 °C
Reaction time: 36 h
Yield: 82.4 %

Procedure:
A suspension of 2.23 g (3.31 mmol) of 3β,17β-bis-(tert-butyldimethylsilyloxy)-5-(2-iodoethyl)-5β-androst-9(11)-ene (Example 4e) and 948 mg (15.11 mmol) of KCN in 48 ml of DMF is stirred for 36 hours at 60° C. under argon. After cooling, it is poured into ice-cold 1N NaOH solution and extracted with dichloromethane. After chromatography of the crude product on silica gel with hexane/ethyl acetate, 1.56 g (75.5% of theory) of the nitrile with a melting point of 194-195° C. (hexane), [α]D +15.0° (CHCl3, c=0.5), is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:38])([F:37])[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:24]([F:38])([F:37])[F:23])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol 17b (23.4 g, 78.7 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (54.0 g, 394.0 mmol) at room temperature. The mixture was warmed up to 90° C. and stirred for 30 min, and then 2,2,2-trifluoroethyl-p-toluensulfonate (20 g, 78.7 mmol) was added. The reaction mixture was warmed up to 140° C. and stirred for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between ethylacetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE to give the title compound 17c as a white solid (26.0 g, 87.2%, HPLC: 97.45%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.54 (d, 1H), 7.45 (m, 1H), 7.40 (d, 1H), 7.18 (d, 2H), 7.00 (d, 2H), 4.80-4.64 (m, 2H), 4.01 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH:23]([N:26](C(C)C)CC)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.CN>ClCCl>[CH3:23][NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:22])[F:21])=[N:4]2)=[CH:13][CH:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid (87 mg, 0.28 mmol) and diisopropylethylamine (0.1 ml) in dichloromethane (3 ml) was treated with 1,1′-carbonyldiimidazole (46 mg, 0.28 mmol) in one portion and stirred at room temperature for 15 minutes. Then methylamine hydrochloride (22 mg, 0.33 mmol) was added and stirring continued for 1 hour. The reaction mix was added to a 5 g pre-packed silica column and eluted with 0-50% ethyl acetate in petroleum ether to give the title compound (28 mg, 31%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:26]1[C:31]([F:32])=[CH:30][C:29]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:28][C:27]=1[F:40]>>[F:32][C:31]1[CH:30]=[C:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:27]([F:40])[C:26]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1F
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(3-fluoro-4-methoxyphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-3,5-difluorophenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.55-7.63 (m, 2H), 7.22 (t, J=8.8 Hz, 2H), 6.86-6.91 (m, 2H), 5.22 (s, 2H), 3.97 (s, 3H), 2.88 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H15F6NO4S, 490.1 (M−H). found 489.9.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[OH:27][CH2:26][C:20]1([NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1(CO)CCCCC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: O=C(NC1(CO)CCCCC1)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (1-aminocyclohexyl)methanol (CAN 4313-56-8) as starting materials and isolated (55 mg, 53%) as a white solid; MS (ESI, m/z): 373.0 (M+H+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]=O)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.[CH3:51][O:52][NH2:53]>C(O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]=[N:53][O:52][CH3:51])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CON
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 66.4 %

Procedure:
To a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-(2-oxoethoxy)benzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (200 mg, 0.365 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.147 mL, 1.82 mmol), sodium acetate (299 mg, 3.65 mmol) and O-methylhydroxylamine hydrochloride (152 mg, 1.82 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (3×25 mL). The organic layer was separated, washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.5:8.5 Acetone:Pet. Ether) to afford the title compound (140 mg, 64.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([CH:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2([CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([Cl:26])[CH:28]=3)[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 50 °C

Procedure:
A mixture of rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-azepane-1-carboxylic acid tert-butyl ester (0.3 g, 0.82 mmol) (from Example 61b supra), 3-chlorobenzyl bromide (0.20 g, 0.97 mmol) (Aldrich), potassium iodide (0.16 g, 0.98 mmol) and potassium carbonate (0.24 g, 1.77 mmol) in acetone (5 mL) was heated at 50° C. for overnight The solvent was removed. The residue was purified by chromatography to give rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-azepane-1-carboxylic acid tert-butyl ester as white solid. (Yield 50 mg, 12.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of DMAP (0.012 g, 0.096 mmol), 5-bromo-2-chloropyridin-3-amine (0.2 g, 0.96 mmol) and benzene sulfonyl chloride (0.61 ml, 4.8 mmol) in pyridine (0.16 ml, 1.92 mmol) is heated at 50° C. overnight. The reaction is cooled to room temperature and absorbed onto silica. Purification by flash chromatography (SiO2, 10-20% EtOAc in iso-hexane) yields N-(5-Bromo-2-chloro-pyridin-3-yl)-benzenesulfonamide as a white solid. [M+H]+ 347.