Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[OH:67][CH:68]1[CH2:73][CH2:72][N:71]([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:71]4[CH2:72][CH2:73][CH:68]([OH:67])[CH2:69][CH2:70]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: OC1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 26.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(4-hydroxypiperidin-1-yl)benzaldehyde (1.2 eq, 0.091 mmol, 19 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (11 mg, 26%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.41-1.49 (m, 2H, 2× piperidine CHAHB), 1.81-1.84 (m, 2H, 2× piperidine CHAHB), 2.62 (s, br, 4H, piperazine N(CH2)2), 2.97-3.02 (m, 2H, 2× piperidine CHAHB), 3.62 (s, 2H, NCH2), 3.64 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 3.66-3.70 (m, 2H, 2× piperidine CHAHB), 4.68 (d, J=4.2 Hz, 1H, CHOH), 7.04 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 7.39 (dd, J=7.6, 4.7 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.8 Hz, 1H, pyridine H-4), 7.99 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (d, br, J=4.5 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2), 13.17 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][CH3:40])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][CH2:39][CH3:40])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCCc1ccccc1O/C(=C/C(=O)OCC)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (623 mg, 0.003 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (1.98 g, 0.015 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0440 mg, 34%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:33])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH:30]([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[C:34](Cl)([Cl:36])=[O:35]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:33])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:34]([Cl:36])=[O:35])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH:30]([CH3:31])[CH3:32])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2)c(OC(C)C)c1
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:22]([NH:25][OH:26])[CH2:23][CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:25]([OH:26])[CH2:22][CH2:23][CH3:24])=[O:18])[CH:15]=[C:10]3[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1
Reactant: CCCNO
Agent: Cl
Product: CCCN(O)C(=O)c1cc2ccn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with N-propyl hydroxylamine hydrochloride in a manner similar to step 8 of example 1. 1H NMR (DMSO-d6) δ ppm 11.93 (br s, 1H), 8.88 (s, 1H), 7.99 (s, 1H), 7.88 (d, 1H, J=3.0 Hz), 7.34 (m, 2H), 7.15 (d, 2H, J=8.8 Hz), 6.69 (d, 1H, J=3.0 Hz), 5.56 (s, 2H), 3.66 (t, 2H, J=7.1 Hz), 1.64 (m, 2H), 0.83 (s, 3H). LCMS (API-ES, M+H+): 328.1. HRMS calcd for C18H19FN3O2 (M+H) 328.1456, found 328.1458. HPLC: 100% purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=[CH:10][C:9]=2[NH2:25])=[CH:4][CH2:3]1.[K+].[C:28]([C:30]1[N:31]=[C:32]([C:43]([O-])=[O:44])[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=1)#[N:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:11]=[CH:10][C:9]=2[NH:25][C:43]([C:32]2[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=[C:30]([C:28]#[N:29])[N:31]=2)=[O:44])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)N3CCOCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 60.0 mg of crude 2-(4,4-dimethyl-cyclohex-1-enyl)-4-[2-(mopholine-4-sulfonyl)-ethyl]-phenylamine (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with 53.3 mg (0.174 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 111 mg (0.238 mmol) of PyBroP to form a slurry, which was treated with 82.8 μL (0.476 mmol) of DIEA. The mixture was stirred at RT for 4 h, diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 60.3 mg (crude) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C31H41N5O5SSi, 628.3 (M+H). found 628.0.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][NH2:12])=[CH:4][C:3]=2[O:2]1.[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([N:22]=[C:23]=[O:24])=[CH:16][C:15]=2[O:14]1>C1C=CC=CC=1>[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([NH:22][C:23]([NH:12][CH2:11][CH2:10][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)=[O:24])=[CH:16][C:15]=2[O:14]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: O=C(NCCc1ccc2c(c1)OCO2)Nc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-methylenedioxyphenylethylamine (0.25 g, 1.5 mmol) and 3,4-methylenedioxy-phenyl isocyanate (0.25 g, 1.5 mmol) in benzene (25 ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0078B (0.43 g, 85%) as a pale brown solid.
Reaction SMILES: C[O:2][C:3](=[O:38])/[CH:4]=[CH:5]/[C:6]1[C:10]([C:11](=[O:30])[C:12](=[O:29])[N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:15][CH2:14]2)=[C:9]([CH3:31])[NH:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+].O>C(O)C>[CH3:31][C:9]1[NH:8][C:7]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:38])=[O:2])[C:10]=1[C:11](=[O:30])[C:12](=[O:29])[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)/C=C/c1c(-c2ccccc2)[nH]c(C)c1C(=O)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)c(/C=C/C(=O)O)c1C(=O)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
To a solution of 155 mg (0.295 mmol) (E)-3-(5-methyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-acetyl}-2-phenyl-1H-pyrrol-3-yl)-acrylic acid methyl ester in 2 ml ethanol 12 mg ((0.295 mmol) sodium hydroxide and 0.5 ml water were added. The mixture was stirred for 24 h at RT. The solvent was evaporated and the residue was treated with 1N HCl. The precipitate was filtered off and dried to give 120 mg (80%) of the title compound. MS 512.17 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][C:16]=3[CH3:30])[N:11]=2)=[CH:6][C:5]=1[CH:31]=[CH2:32])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH2:31]([C:5]1[CH:6]=[C:7]([C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:16]=3[CH3:30])[N:11]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH3:32]
Reactant: C=Cc1cc(-c2nc(-c3ccc(CCC(=O)OC(C)(C)C)cc3C)ns2)ccc1OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc(CCC(=O)O)cc3C)ns2)cc1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
A solution of tert-Butyl 3-(4-(5-(4-ethoxy-3-vinylphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)propanoate (0.01 g, 0.025 mmol) in methanol (1.5 mL) and ethyl acetate (1.5 mL) was degassed with nitrogen. 10% Palladium/Carbon (0.01 g) was added to the reaction mixture which was stirred under a balloon of hydrogen for 30 min. The reaction was filtered through a disposable frit and concentrated in vacuo. The resulting oil was dissolved in 20% solution of trifluoroacetic acid in dichloromethane (4 mL) and stirred at rt for 2 h after which the reaction was concentrated in vacuo. Silica gel chromatography eluting with 2% methanol/methylene chloride afforded 4.5 mg of the title compound: 1H NMR (500 MHZ, CDCl3) δ 7.86 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 4.20-4.30 (m, 2H), 3.00-3.08 (m, 2H), 2.70-2.79 (m, 4H), 2.65 (s, 3H), 1.48-1.52 (m, 3H), 1.23-1.32 (m, 3H), ESI-MS (m/z) 453.3; HPLC A: 4.68 min.
Reaction SMILES: NC1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[H-].[Na+].IC.[CH3:36][N:37]([CH:39]=O)[CH3:38]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:39]([N:37]([CH3:36])[CH3:38])=[C:3]([C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.050 g (0.106 mmol) of the product from Example 17 in DMF (1 mL) at 0° C. was treated with sodium hydride (0.010 g; 60% dispersion; 0.232 mmol). After the addition, the reaction mixture was stirred for 20 minutes at 0° C., and then treated with iodomethane (26 μL; 0.424 mmol). The reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 501.0 (M+1), 503.0 (N+3); Rt=5.08 min.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[O:24][C@@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:11]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:35](Cl)(Cl)(=[O:37])=[O:36].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>ClCCl.CN(C)C=O>[C:1]([O:9][C@@H:10]1[O:24][C@@H:23]([C:25](=[S:35](=[O:37])=[O:36])[O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:13]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:11]1[O:12][C:41]1[NH:40][CH:44]=[CH:43][N:42]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OC([C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](Oc2ncc[nH]2)[C@H]1OC(=O)c1ccccc1)=S(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
107.0 g (0.232 mole) of the compound (13) was dissolved in 1070 ml of dichloromethane and 214 ml of dimethylformamide, to which 62.5 g (37.2 ml, 0.463 mole) of sulfuryl chloride was added dropwise at a low temperature (−10 to −78° C.). The resulting solution was stirred at room temperature for 3 hours and then cooled in an ice-bath. The solution was stirred while 157.8 g (2.32 mole) of imidazole was added portionwise at the rate keeping the temperature of reaction mixture under 5° C. The resulting mixture was stirred at room temperature for 20 hours, after which 400 ml of ice-water was added. The aqueous layer was extracted three times with 100 ml of dichloromethane (3×100 ml). The combined organic solution was washed with 200 ml of brine and dried over MgSO4. The solvent was removed under reduced pressure and dimethylformamide was removed under high vacuum. The syrupy residue was coevaporated with 100 ml of 2-propanol under reduced pressure to obtain a white solid product (14), which was used for the next reaction without further purification.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]([NH2:17])=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([Br:30])=[C:24]([O:31][CH3:32])[CH:23]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1>[Br:30][C:25]1[C:26]([O:28][CH3:29])=[CH:27][C:22]([C:20]2[N:17]=[CH:15][S:2][CH:19]=2)=[CH:23][C:24]=1[O:31][CH3:32]
Reactant: COc1cc(C(=O)CBr)cc(OC)c1Br
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cscn2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
An oven-dried flask under argon was charged with P2S5 (0.53 g, 1.2 mmol), anhydrous dioxane (5 mL), and formamide (0.53 mL, 13.3 mmol). The reaction flask was fitted with a reflux condenser and a drying tube and refluxed for 2.25 hours. A separate oven-dried flask under argon was charged with 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.313 g, 0.93 mmol) and anhydrous dioxane (6 mL). The thioformamide mixture (above) was decanted into the reaction flask leaving solids behind. The reaction flask was fitted with a reflux condenser, put under a drying tube and refluxed for 3 hours then cooled to room temp. After stirring overnight, the mixture was made basic with the addition of an aqueous solution of 2 M Na2CO3, diluted with H2O then extracted with EtOAc three times. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The crude solid was dissolved in CH2Cl2 and adsorbed onto silica gel. Purification by chromatography (0-35% EtOAc-hexanes) gave 4-(4-bromo-3,5-dimethoxyphenyl)thiazole as a white solid (0.20 g, 73% yield).
Reaction SMILES: C(Cl)(=O)C.[Cl:5][C:6]1[N:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)=[CH:9]2>CO>[Cl:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][N:12]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
Solvent: CO
Solvent: CC(=O)Cl
Product: Clc1ccc2ncc(N3CCNCC3)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (4.3 mL, 60.5 mmol) was added to MeOH (11 mL) at 0° C., the resulting solution was stirred at 0° C. for 30 min. To this solution, tert-butyl 4-(6-chloro-1,5-naphthyridin-3-yl)piperazine-1-carboxylate (D-18) (207 mg, 0.59 mmol, 1.0 eq) was added, and the mixture was stirred at RT for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo to afford the desired product 2-chloro-7-(piperazin-1-yl)-1,5-naphthyridine (D-19), which was used for next reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ: 8.99 (d, J=2.7 Hz, 1H), 8.28 (d, J=8.7 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 3.68 (m, 4H), 3.22 (m, 4H); ESI-MS m/z: 249.06[M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[C:18]1([S:24]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:10]=3[C:2]([I:1])=[CH:3]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCCOc1ncnc2[nH]cc(I)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1ncnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
To 5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (25, 3.67 g, 11.5 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere of nitrogen, sodium hydride (506.0 mg, 12.65 mmol) is added. The reaction is stirred at room temperature for 20 minutes, then benzenesulfonyl chloride (26, 1.614 mL, 12.65 mmol) is added. The reaction is stirred at room temperature for 30 minutes, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (27, 4.50 g). MS (ESI) [M+H+]+=460.0.
Reaction SMILES: [CH3:1][C:2]([CH3:56])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:53])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:52])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:55])[CH3:54])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]>ClCCl>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:52])([CH2:21][CH2:22]3)[C@@:19]3([CH3:53])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:55])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:56])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)=[N:46][CH:47]=1.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)Nc2ccc(Cl)cn2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)Nc2ccc(Cl)cn2)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((5-chloropyridin-2-yl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (100 mg, 0.126 mmol) in dichloromethane (4 mL) stirred at rt was added TFA (2 mL, 26.0 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was evaporated to get the crude product which was purified by preparative-HPLC to give the title compound as a TFA salt (60 mg, 55.9%). 1H NMR (400 MHz, CHLOROFORM-d) δ=11.06 (br. s., 1H), 8.54 (d, J=9.0 Hz, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.83 (dd, J=2.3, 9.0 Hz, 1H), 7.10 (d, J=15.8 Hz, 1H), 6.09 (d, J=15.8 Hz, 1H), 4.52 (dd, J=4.3, 11.5 Hz, 1H), 3.30-3.12 (m, 1H), 2.82-2.52 (m, 3H), 2.38-2.08 (m, 3H), 2.04-1.75 (m, 3H), 1.75-0.60 (m, 41H); LC/MS: m/z calculated 734.4. Found 735.3 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccccc3)cc2C1
Yield: 90 %

Procedure:
2-(tert-butoxycarbonylamino)-5-hydroxyindan (100 mg, 0.40 mmol) synthesized in the above Reference Production Example 1 was dissolved in acetone (2 ml), to which potassium carbonate (58 mg, 0.45 mmol) and benzylbromide (48 μl, 0.40 mmol) were added, and the mixture was heated to reflux for 3 hours. The reaction mixture was extracted with ether and dried, and then the solvent was distilled off under reduced pressure to obtain 2-(tert-butoxycarbonylamino)-5-phenoxyindan (120 mg, 0.36 mmol) having the following physical properties:
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26].C(OCC)(=O)C>C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N)C1=O
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccsc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.66 g of t-butyl α-[6-amino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [synthesized as described in Example 42(g)] was N-alkylated using 0.86 g of butyl 2-bromo-4-phenylbutyrate by the same procedure as is described in Example 42(h). The reaction product was subjected to silica gel column chromatography using a 1:20 by volume mixture of ethyl acetate and methylene chloride, to give two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).