Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][N:10]=[C:11]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)[N:4]2[N:3]=1.[I:22]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[C:9]([I:22])[N:10]=[C:11]([C@H:12]3[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]3)[N:4]2[N:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(=O)[nH]c(N)nn32)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]c(N)nn32)CC1

Procedure:
A solution of methyl trans-4-(2-amino-4-oxo-3,4-dihydroimidazo[5,1-f] [1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.200 g, 0.000686 mol) and N-iodosuccinimide (0.278 g, 0.00124 mol) in anhydrous DMF (4.0 mL) was stirred at rt for 48 h. The reaction was concentrated in vacuo then partitioned between H2O and EtOAc. The aqueous material was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (2×), Na2S2O3 (2×) and brine (1×). The aqueous was re-extracted with CHCl3 and combined with the EtOAc fractions dried over Na2SO4, filtered and concentrated in vacuo resulting in 229 mg, (79.9% yield) of the title compound as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.65 (m, 4H), 1.88-2.06 (m, 4H), 2.33-2.45 (m, 1H), 2.91-3.01 (m, 1H), 3.61 (s, 3H), 6.17 (s, 2H) and 10.82 (br. s., 1H); MS (ES+): m/z 417.82 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8].[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH2:15])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 8 (13.3 g, 36.66 mmol) in 75 ml DCM was treated with 25 ml TFA and stirred overnight at RT. The solvents were evaporated and the residue was dissolved in DCM and evaporated again. Yield: 21 g (TFA-salt), oil, crude material
Reaction SMILES: [CH2:1]([N:6]1[C:10]([C:11]([NH:13][C:14]2[CH:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[O:20])[N:16]([CH3:32])[CH:15]=2)=[O:12])=[CH:9][C:8]([NH:33][C:34]([C:36]2[N:37]([CH3:44])[CH:38]=[C:39]([N+:41]([O-])=O)[CH:40]=2)=[O:35])=[CH:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:45]([OH:47])C>[Pd]>[CH:45]([NH:41][C:39]1[CH:40]=[C:36]([C:34]([NH:33][C:8]2[CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:20])[N:16]([CH3:32])[CH:15]=3)=[O:12])[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=2)=[O:35])[N:37]([CH3:44])[CH:38]=1)=[O:47]
Reactant: CC(C)CCn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)Nc1cc(C(=O)NCCCN2CCN(C)CC2)n(C)c1
Reactant: CCO
Agent: [Pd]
Product: CC(C)CCn1cc(NC(=O)c2cc(NC=O)cn2C)cc1C(=O)Nc1cc(C(=O)NCCCN2CCN(C)CC2)n(C)c1
Reaction time: 3 h
Yield: 53 %

Procedure:
N-[1-Isopentyl-5-({[1-methyl-5-({[3-(4-methyl-1-piperazinyl)propyl]-amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]-1-methyl-4-nitro-1H-pyrrole-2-carboxamide (120 mg, 0.197 mmol; see step (ii) above) was dissolved in ethanol (20 mL) to which Pd/C-10% (77 mg) was added at 0° C. under N2 with stirring. The reaction mixture was hydrogenated for 3 h at room temperature and atmospheric pressure. The catalyst was removed over Kieselguhr and ethyl formate (20 mL) was added to the ethanolic solution. The reaction mixture was heated under reflux for 48 h. Ethanol and excess ethyl formate were removed under reduced pressure and the crude product was purified by HPLC. The product was obtained as yellow solid with no distinct melting point (75 mg, 53% yield) after freeze-drying.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.N(OC(C)(C)C)=O.[Si]([N:22]=[N+:23]=[N-])(C)(C)C>>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:22]=[N-:23]
Reactant: Nc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of aniline (500 mgs, 5.37 mmol) in acetonitrile (10 mL, 191 mmol) was cooled down in an ice bath and treated with tert-butyl nitrite (680 mgs, 6.59 mmol) and dropwise with TMS-N3 (0.713 mL, 5.37 mmol). The ice bath was removed and the mixture was stirred overnight at r.t. under N2. Acetonitrile was carefully evaporated (NB: azidobenzene is also volatile) and the residue (750 mgs) was passed through a silica gel pad (20 g) and eluted with petroleum ether (35-55° C.). Evaporation of the solvent gave the title material as an oil (500 mgs, 4.20 mmol, 78% yield) that still contains some traces of solvent as shown by 1H NMR. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.32-7.41 (m, 2H), 7.12-7.19 (m, 1H), 7.01-7.09 (m, 2H).
Reaction SMILES: [CH2:1]([N:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:7]([C@@H:9]1[NH:21][CH2:20][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>O1CCCC1>[CH2:22]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([C@@H:9]1[N:21]([C:34](=[O:35])[NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:36])[CH:28]=2)[CH2:20][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:8])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCN(CCCCC)C(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: CCCCCN(CCCCC)C(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
0.114 g (3R)-3-(N,N-dipentylcarbamoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole is dissolved in 2 ml tetrahydrofuran and 42.7 mg of m-tolylisocyanate is added. The solution is stirred at room temperature for 1 hour, evaporated, and the residue triturated with hexane to give 0.119 g (3R)-3-(N,N-dipentylcarbamoyl)-2-(3-methylphenylcarbamoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, m.p. 154°-155° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]([OH:9])=O)[CH:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[O:3]1.[N+]([O-])(O)=O.[N+:19]([O:22][CH2:23][CH2:24][NH2:25])([O-:21])=[O:20]>>[N+:19]([O:22][CH2:23][CH2:24][NH:25][C:7]([CH:5]1[CH:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[O:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2cccs2)O1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccs2)O1
Yield: 26.9 %

Procedure:
A procedure similar to that described in Example 19 was repeated, but using 500 mg of 2-oxo-5-(2-thienyl)oxazolidine-4-carboxylic acid and 480 mg of N-(2-nitrooxyethyl)amine nitrate, to obtain 190 mg of the title compound as pale yellow plates, melting at 101°-103° C.
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:16]([CH2:19][CH2:20]Cl)[CH2:17][CH3:18])[CH3:15].C(N(CC)CC)C>CC(C)=O>[CH2:14]([N:16]([CH2:19][CH3:20])[CH:17]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18])[CH3:15]
Reactant: O=C1NCCNC1c1ccccc1
Reactant: CCN(CC)CCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Yield: 64 %

Procedure:
144 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 121 g. of diethylamino ethylchloride, 340 cc. of triethylamine, and 1600 cc. of acetone for 24 hours. The cooled solution is filtered to remove triethylamine hydrochloride and the filtrate is evaporated to dryness. The residue is dissolved in water, 40 % sodium hydroxide solution is added thereto, and the oil which forms an upper layer, is extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate, the benzene is removed by distillation, and the residue is distilled in a vacuum. A light yellow, viscous oil of the boiling point 175° C./0.05 mm. Hg is obtained. The oil is twice recrystallized from n-heptane. 145 g. of the above mentioned compound melting at 53°-56° C. are obtained.. The yield is 64 % of the theoretical yield.
Reaction SMILES: N#N.[CH:3]1[C:20]2=[C:21]3[C:10]([C:11]4[C:22]5[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=5)[CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:30]([O:33]C(CCl)CCl)CCl.Cl>O.ClC1C=CC=CC=1Cl>[CH:18]1[C:19]2=[C:22]3[C:11]([C:10]4[C:21]5[C:6](=[CH:5][CH:4]=[CH:3][C:20]2=5)[CH:7]=[CH:8][CH:9]=4)=[CH:12][CH:13]=[CH:14][C:15]3=[C:16]([CH:30]=[O:33])[CH:17]=1
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reaction time: 16 h

Procedure:
A 3 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with perylene (Aldrich Chemical Co., Milwaukee, WI, 53201, 25 g, 99 mmol) and o-dichlorobenzene (500 mL). The liquid was warmed until all the large chunks of solid dissolved (80° ) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 51.2 g, 0.897 mol, 23 mL), was added in one portion. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 14.9 g, 0.13 mol, 11.7 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40° over 2 h and further stirred for 16 h. Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., 2nd and Mallinckrodt St., St. Louis, MO, 63147, 100 g) and filtered again. The clear yellow solution was passed through a 500 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted perylene from the aldehyde and a more polar product. Fractions (5 L) containing the aldehyde were combined and the PhCH3 removed. The resulting oily solid was shaken with CH3OH (200 mL) and the orange-brown crystals which formed were collected by filtration to give after drying 23.2 g (83%) of 3-perylenecarbaldehyde mp 223°-233°, (C,H), (lit. mp 236°(darkens >230 °)), N. P. Buu-Hoi and C. T. Long, Recueil 75 1121 (1956).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[CH:35]1([CH:41]=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:41][N:17]2[CH2:18][C@@H:14]([N:12]3[N:11]=[N:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[N:13]3)[CH2:15][C@H:16]2[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])[CH2:25][CH2:26]2)=[O:20])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=CC1CCCCC1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2CC2CCCCC2)CC1
Yield: 11.7 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using cyclohexanecarbaldehyde (16 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (8.5 mg, 11.7%) as light yellow oil. MS m/e=561.3 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.O>[N:25]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[N+:26]=[N-:27]
Reactant: COC(=O)[C@H](Cc1ccc(OCCBr)cc1)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCCN=[N+]=[N-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
A mixture of 1A (1.61 g, 4.0 mmol) and sodium azide (0.78 g, 12.0 mmol) in DMF (27 mL) was stirred at room temperature for 20 h. The reaction mixture was diluted with H2O (120 mL) and extracted with EtOAc (3×60 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, step-wise gradient from 2-40% EtOAc in Hexanes) to give 2A (1.46 g, 100%) as a clear oil. 1H NMR (600 MHz, CDCl3): δ 7.05 (2H, d, J=8.4 Hz), 6.85 (2H, d, J=8.4 Hz), 4.97 (1H, d, J=7.8 Hz), 4.51-4.58 (1H, m), 4.13 (2H, t, J=5.4 Hz), 3.71 (3H, s), 3.58 (2H, t, J=5.4 Hz), 3.06 (1H, dd, J=13.8, 5.4 Hz), 3.00 (1H, dd, J=13.8, 5.4 Hz), 1.42 (9H, s); 13C NMR (150 MHz, CDCl3): δ 172.3, 157.3, 155.1, 130.4, 128.7, 114.6, 79.9, 66.9, 54.5, 52.2, 50.2, 37.5, 28.3; MS (ESI, m/z): 387 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[O:18]=[C:19]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][N:20]1[CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:39]=[C:38]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[CH2:8][CH2:9]1)[CH2:37][N:20]1[CH2:21][CH2:22][CH2:23][C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:18]
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(3-(trifluoromethyl)benzyl)piperazine (0.395 g, 1.616 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.500 g, 1.616 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.403 g, 2.101 mmol) in dichloromethane (2 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF25-40 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 35 minutes (flow=35 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.40-7.61 (m, 4H), 7.27-7.34 (m, 8H), 7.18-7.25 (m, 2H), 4.23 (s, 2H), 3.64-3.69 (m, 2H), 3.55 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 3.43-3.49 (m, 2H), 2.60-2.67 (m, 2H), 2.38-2.49 (m, 4H), 1.79-1.89 (m, 2H); MS (ESI+) m/z 536 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[NH:13][CH3:14].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[N:27]=[C:28]=S>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[NH:27][C:28]1[N:13]([CH3:14])[C:12]2[C:6]3[CH2:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=3[C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:2]=2[N:1]=1
Reactant: CNc1c(N)cc(C(=O)OC)c2c1CC(C)(C)O2
Reactant: Fc1cccc(Cl)c1N=C=S
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Yield: 56.3 %

Procedure:
The title compound was prepared following the procedure described for Step-1 of Intermediate-3 using methyl 5-amino-2,2-dimethyl-4-(methylamino)-2,3-dihydrobenzofuran-7-carboxylate (1.10 g, 4.4 mmol), 1-chloro-3-fluoro-2-isothiocyanatobenzene (Intermediate-14, 1.0 g, 5.3 mmol), N,N-di-isopropyl carbodimide (0.5 mL) and acetonitrile (3.0 mL) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 1.46 (s, 6H), 3.34 (s, 2H), 3.53 (s, 3H), 3.72 (s, 3H), 7.00 (m, 1H), 7.06 (s, 1H), 7.17 (t, J=9.3 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 10.39 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1>>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(Br)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-bromophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.22 (2H, s), 5.74 (1H, s), 7.28 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=7.6 Hz), 7.42 (1H, d, J=4.4 Hz), 7.49 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=1.2 Hz), 7.64 (1H, s), 8.05 (1H, s), 8.72 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H11BrN4O, 355. Found, 355.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:6]=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]([CH2:39][C@@H:40]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:41]C3CCCCO3)C(=O)OC(C)(C)C)=[CH:25][CH:24]=2)[CH:8]=[CH:9][C:10]=1[C:11]([NH:13][S:14]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:12])([CH3:3])[CH3:2].[ClH:54]>CO>[ClH:54].[ClH:54].[OH:41][C@H:40]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:39][NH:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][S:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])=[O:12])=[C:5]([S:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)=[CH:24][CH:25]=1
Reactant: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](OC3CCCCO3)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)c1cccnc1
Agent: Cl
Solvent: CO
Product: CC(C)Sc1cc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)ccc1C(=O)NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl [2-[3′-(isopropylthio)-4′-[[(3-pyridylsulfonyl)amino]carbonyl]-4-biphenylyl]-ethyl][(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]carbamate (411 mg) and hydrogen chloride in methanol (10%, 8.22 ml) was stirred at room temperature overnight. The mixture was evaporated and recrystallized from ethanol to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-N-(3-pyridylsulfonyl)-4-biphenylcarboxamide dihydrochloride (242 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(Cl)Cl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCNc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 50 °C

Procedure:
A solution of 1.608 g (6.7 mmol) of 4,4-dimethyl-6-bromo-1,2,3,4-tetrahydroquinoline in 1.5 ml of triethylamine in a heavy-walled tube was degassed under argon and then treated with 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was degassed again under argon, treated with 2.09 g (21.2 mmol) of trimethylsilylacetylene and the tube was sealed. The mixture was heated at 50° C. for 48 hours. After cooling to room temperature methylene chloride was added to the reaction mixture and the mixture filtered. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1cccc(Br)n1
Reactant: C#CCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCC#Cc1cccc(C=O)n1
Yield: 84.3 %

Procedure:
A solution of 6-bromopyridine-2-caboxaldehyde (15.0 g), 1-undecyne (12.9 g), triethylamine (24.5 g), bis(triphenylphosphine)palladium(II)chloride (1.1 g, 2%), and copper(I)iodide (0.15g, 1%) in dry tetrahydrofuran (60 ml) was heated under nitrogen at 55° C. for 10 hrs. The reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, and the solution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was flash chromatographed on silica gel, eluting with 0%-2%-ethyl acetate:hexane. The appropriate fractions were collected and evaporated to yield 17.5 g (84.0%) of product.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[K+].[K+].[CH2:21](Cl)[O:22][CH3:23]>CO.C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:21][O:22][CH3:23]
Reactant: COc1ccc2c(Br)c(O)ccc2c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COCOc1ccc2cc(OC)ccc2c1Br
Temperature: 20 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
To a solution of 1-bromo-6-methoxynaphthalen-2-ol (described in U.S. 61/423,799) (2.90 g, 11.5 mmol) in MeOH (20 mL) and THF (20 mL) was added K2CO3 (3.18 g, 23.0 mmol) and MOMCl (1.10 g, 13.8 mmol). The resulting mixture was stirred at 20° C. for 48 hours and stirred at 30-40° C. for 5 days. An aqueous/EtOAc workup was followed by purification by silica gel column chromatography (PE to PE/EtOAc=200/1) to give the product (1.90 g, yield 56%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH:11]([CH2:12][CH2:13]3)[CH:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.C(O)(C)C>Cl>[Cl:19][C:5]1[C:6]([NH:8][C@H:9]2[CH:14]3[CH2:15][CH:11]([CH2:12][CH2:13]3)[C@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1C2CCC(C2)C1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4C5CCC(C5)[C@H]4C(N)=O)n3)cc2CC1
Reaction time: 2.5 h

Procedure:
Into a microwave vial was placed 3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid amide (90.0 mg, 0.000299 mol) and 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (60 mg, 0.0003 mol) in isopropyl alcohol (6 mL, 0.08 mol). Several drops of 4M HCl were added to the reaction mixture and the contents subjected to microwave conditions (120° C., 20 min). Total reaction time was 150 min at 120° C. A solid had precipitated out of the reaction mixture overnight and was collected by filtration to give (2R,3S)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]heptane-2-carboxylic acid amide; hydrochloride. 1HNMR (400 MHz, DMSO-d6) δ 10.62 (broad s, 1H), 10.15 (broad s, 1H), 9.19 (broad s, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.62 (dd, 1H, J=8.6, 18.7 Hz), 7.36 (d, 1H, J=6.6 Hz), 7.29 (s, 1H), 7.17 (d, 1H, J=8.6 Hz), 4.07 (q, 1H, J=8.6 Hz), 3.74 (m, 4H), 3.36 (m, 4H), 3.31 (s, 3H), 2.93-3.09 (m, 4H), 1.87 (d, 9.8 Hz), 1.55 (m, 2H), 1.28 (m, 2H), 1.18 (d, 1H, J=9.8 Hz); MS (m/e) 485 (M+1).