Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH:16](OS(C1C=CC(C)=CC=1)(=O)=O)[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1.O>S1(=O)(=O)CCCC1>[CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH:16]([N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3
Reactant: Cc1ccc(S(=O)(=O)OC(c2ccc3ccc4c(c3c2)C(C)(C)C(=O)O4)C(F)(F)F)cc1
Reactant: c1nc[nH]n1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC1(C)C(=O)Oc2ccc3ccc(C(n4cncn4)C(F)(F)F)cc3c21

Procedure:
A solution of 1,1-dimethyl-8-(2,2,2-trifluoro-1-tosyloxyethyl)-2(1H)-naphtho[2,1-b]furanone and 1,2,4-triazole (0.5 g) in tetrahydrothiophen-1,1-dioxide (1 ml) was heated at 140° for 18 h. The mixture was treated with water (20 ml) and extracted twice with diethyl ether, and the combined ether extracts were dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using ethyl acetate: pentane, 1:1 v/v, as eluant, to give 1,1-dimethyl-8-[1-(1H-1,2,4-triazol-1-yl)-2,2,2-trifluoroethyl]-2(1H)-naphtho[2,1-b]furanone. Nmr in deuteriochloroform: δ 8.35(1H,s); 8.15(1H,d); 8.09(1H,s); 7.98(1H,d); 7.87(1H,d); 7.51(1H,dd); 7.46(1H,d); 6.14(1H,q); 1.78(3H,s); 1.75(3H,s).
Reaction SMILES: [N:1]1([C:57](OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][C@H:2]1[C:3]([NH:5][C@@H:6]([C:13]([NH:15][C@H:16]([C:24]([NH:26][C@@H:27]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:51]([NH2:53])=[O:52])[CH2:47][CH2:48][S:49][CH3:50])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[CH2:28]C1C=CC=CC=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl>C(OCC)(=O)C>[NH:1]1[CH2:57][CH2:56][CH2:55][CH2:54][C@H:2]1[C:3]([NH:5][C@@H:6]([C:13]([NH:15][C@H:16]([C:24]([NH:26][C@@H:27]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:51]([NH2:53])=[O:52])[CH2:47][CH2:48][S:49][CH3:50])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[CH2:28][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)c1ccccc1)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](NC(=O)[C@@H]1CCCCN1)c1ccccc1)C(N)=O

Procedure:
Condensation of BocPro-DPhg-PheNHNH2 (1.27 g.) and HDPhe-Leu-MetNH2 hydrochloride salt (Example 23, 1.11 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DPhg-Phe-Dphe-Leu-MetNH2 in 89% yield. De-t-butoxycarbonylation of BocPro-DPhg-Phe-DPhe-Leu-MetNH2 (1.67 g.) using hydrogen chloride in ethyl acetate gave HPro-DPhg-Phe-DPhe-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt pentahydrate in 12% yield.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:51])[CH:24]([C:26]1[CH:31]=[CH:30][C:29](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:28][CH:27]=1)C.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:29]2[CH:30]=[CH:31][C:26]([CH2:24][C:23]([O:22][CH3:21])=[O:51])=[CH:27][CH:28]=2)=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1ccc(C(=O)OC(C)C)c(CN(C)C2CC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1

Procedure:
Following General Procedure B and using 2-[(cyclopropyl-methyl-amino)-methyl]-4-ethynyl-benzoic acid isopropyl ester (Intermediate 122, 0.07 g, 0.26 mmol), methyl-2-(4-iodophenyl)-propionate (Reagent 1, 0.081 g, 0.29 mmol), triethyl amine (2 mL), copper(I)iodide (0.03 g, 0.158 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.09 g, 81%).
Reaction SMILES: [CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=[O:33])C(C)C>ClCCl>[CH:8]([C:9]([CH:14]([CH3:15])[CH3:13])=[O:33])([CH3:17])[CH3:7].[CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Cl
Agent: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)C(C)C
Reaction time: 2 h

Procedure:
To a solution of 5.5 g. of the product of Example 1 in 150 ml. of dichloromethane containing 25 ml. of triethylamine a solution of 4.2 ml. of isobutyryl chloride in approximately 25 ml. of dichloromethane is added dropwise, with constant stirring. On heating to reflux, the white precipitate originally formed redissolves. Refluxing is continued for 2 hours; the solution is cooled, washed with water and with saturated sodium bicarbonate, dried over anhydrous potassium carbonate, and stripped down to a dark gum, which is taken up in hexane, boiled and decolorized. After concentrating the clear solution tp 100 ml. and cooling, a gum separates which solidifies completely on standing. After 1 week, 1,2,3,4,8,9-hexahydropyrido[4', 3':2,3]indolo[1,7-ab][1]benzazepin isopropyl ketone, m.p. 122°-124°, is isolated.
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[CH2:4][CH2:3]1)[N:12]=[C:11]([CH3:15])[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]3=[O:24].CC([NH3+])(C)CO.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([O-:38])=[O:37])=[C:34]([F:41])[CH:33]=1.C(=O)([O-])[O-].[Ca+2].CS(C)=O>O>[F:41][C:34]1[CH:33]=[C:32]([NH:31][CH:2]2[C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][C:5]=3[CH2:4][CH2:3]2)[N:12]=[C:11]([CH3:15])[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]4=[O:24])[CH:40]=[CH:39][C:35]=1[C:36]([OH:38])=[O:37]
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Br)CC3
Reactant: Nc1ccc(C(=O)[O-])c(F)c1
Agent: CC(C)([NH3+])CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)O)c(F)c1)CC3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 6-bromo-2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (26 g), p-amino-o-fluorobenzoic acid 1,1-dimethyl-2-hydroxyethylammonium salt (42 g), calcium carbonate (21.4 g) and DMSO (200 ml) was stirred at ambient temperature for 72 hours. The mixture was poured onto a mixture of ice and water (1 liter). The precipitate was isolated, washed with water and dried under vacuum. The product was purified by column chromatography using initially a 9:1 mixture of methylene chloride and methanol and then a 9:1:0.1 mixture of methylene chloride, methanol and acetic acid as eluant. There was thus obtained o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoic acid as a gum (20 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[O:34][CH3:35])[C:18]([Cl:36])=[CH:17][N:16]=1.ClC1N=C(Cl)C(Cl)=CN=1.COC1C=C(N2CCOCC2)C=CC=1N>CO.C(Cl)Cl>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:24][C:23]=2[O:34][CH3:35])=[N:20][C:15]([NH:13][C:10]2[CH:11]=[CH:12][C:3]3[N:2]([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:9]=2)=[N:16][CH:17]=1
Reactant: CN1CCCCc2cc(N)ccc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc(N2CCOCC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCCCN3C)ncc1Cl

Procedure:
Following the procedure of Example 101b, 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (33 mgs, 0.19 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (1.2 eq) [prepared using a procedure analogous to Example 1d using 2,4,5-trichloropyrimidine and 2-Methoxy-4-morpholin-4-yl-phenylamine] were reacted except that the ISCO chromatography gradient was 0% to 5% MeOH/CH2Cl2 to give 5-Chloro-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-N*2*-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-pyrimidine-2,4-diamine (46.96 mgs) as an off-white/grey solid. MP=206-207° C. 1H-NMR (CDCl3) δ 8.27 (d, J=8.9 Hz, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.36 (s, 1H), 7.28-7.24 (m, 1H), 6.91 (d, J=9.1 Hz, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 6.50 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 3.91-3.89 (m, 4H), 3.17-3.15 (m, 4H), 2.91-2.85 (m, 4H), 2.82-2.77 (m, 4H), 1.89-1.78 (m, 2H), 1.71-1.58 (m, 2H); LC/MS (ESI+): 495.29 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][C:49]1[CH:54]=[CH:53][C:52]([N+:55]([O-])=O)=[CH:51][C:50]=1[NH2:58].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:55][C:52]1[CH:53]=[CH:54][C:49]([CH3:48])=[C:50]([NH:58][C:12]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=2)=[O:14])[CH:51]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)c1cnc2ccccc2c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl[Sn]Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 150 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (50 mg, 0.26 mmol), HBTU (99 mg, 0.26 mmol) and DIEA (138 μL, 0.79 mmol) in THF (2.6 mL) was added 2-methyl-5-nitro-phenylamine (40 mg, 0.26 mmol). The mixture was heated at 150° C. in the microwave for 20 min and the resulting solution was concentrated. The residue was dissolved in EtOH (2 mL) and SnCl2.2H2O (293 mg, 1.3 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was basified with sat. NaHCO3 solution to pH 7-8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99% CH3CN/H2O) to yield the product, N-(5-amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (94) (6 mg, 8%). HPLC ret. time 2.06 min, 10-99% CH3CN, 5 min run; ESI-MS 294.2 m/z (MH+).
Reaction SMILES: [C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[C@:7]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)([CH3:12])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].O>CC#N>[C:1]([CH:5]1[N:6]2[CH2:16][CH2:15][CH2:14][CH2:13][C:7]2([CH3:12])[C:8](=[O:11])[N:9]1[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)[C@@](C)(CCCCCl)N[C@H]1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN1C(=O)C2(C)CCCCN2C1C(C)(C)C
Temperature: 80 °C
Yield: 83.1 %

Procedure:
To a solution of (2R,5R)-2-(tert-butyl)-5-(4-chlorobutyl)-3,5-dimethylimidazolidin-4-one (D45) (310 mg, 1.18 mmol) in dry MeCN (4 ml), anhydrous Na2CO3 (63 mg, 0.6 mmol) and NaI (178 mg, 1.18 mmol) were added sequentially. The solution was heated at 80° C. for 12 hrs. The reaction was allowed to cool at RT, poured into water (10 ml) and extracted with Et2O (3×10 ml). The organic phases were collected, washed with NaCl sat sol, dried over Na2SO4 and evaporated in vacuo to afford the title compound (D46) (220 mg)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:22][CH2:23][CH3:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2].CC1(C)C2CC1CCC2NS(C1C=CC(C#CCCO)=CC=1)(=O)=O>>[CH2:1]([O:3][CH:4]([O:22][CH2:23][CH3:24])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C#CCNc2ccc(F)cc2)cc1
Agent: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Product: CCOC(OCC)c1ccc(CCCNc2ccc(F)cc2)cc1
Yield: 96 %

Procedure:
When the product of Step A was substituted for N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl)benzene sulphonamide in Example 18, Step C, the similar process afforded the title crude product (0.195 g; 96%) as creamy paste. 1H-NMR (CDCl3) 7.35 (d, 2H, J=8.01 Hz); 7.14 (d, 2H, J=8.1 Hz); 6.85 (t, 2H, J=7.54 Hz); 6.51-6.45 (m, 2H); 5.46 (s, 1H); 3.73-3.48 (m, 4H); 3.07 (t, 2H, J=6.97 Hz); 2.71 (t, 2H, 7.45 Hz); 1.96-1.85 (m, 2H); 1.22 (t, 6H, J=7.07 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7])[CH3:2].[Cl:9]([O-:13])(=[O:12])(=[O:11])=[O:10].CS[C:16]1[S:20][CH:19]=[CH:18][S+:17]=1>O1CCCC1>[Cl:9]([O-:13])(=[O:12])(=[O:11])=[O:10].[S:17]1[CH:18]=[CH:19][S:20][C:16]1=[N+:6]([CH3:7])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8]
Reactant: CSc1scc[s+]1
Reactant: CCOC(=O)CNC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C[N+](C)=c1sccs1
Temperature: 25 °C

Procedure:
To 30 ml of tetrahydrofuran, 1.4 g of N-methylglycine ethyl ester was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and recrystallized from acetone-ethyl ether, whereby 1.7 g (yield: 67%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-ethoxycarbonylmethylammonium perchlorate (Compound No. 1) was obtained as crystals having a melting point of from 104° to 105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([SH:14])=[S:13])[CH2:8][CH2:7]1.[OH-].[Na+].[CH3:25]I>CO>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([S:14][CH3:25])=[S:13])[CH2:10][CH2:11]1
Reactant: COc1ccc(CN2CCN(C(=S)S)CC2)c(OC)c1OC
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN2CCN(C(=S)SC)CC2)c(OC)c1OC
Yield: 97.9 %

Procedure:
In a nitrogen atmosphere, 2.0 g of 4-(2,3,4-trimethoxybenzyl)-1-piperazinecarbodithioic acid, 0.26 g of granular sodium hydroxide, and 3 ml of methanol were mixed, and stirred atroom temperature to yield a homogeneous reaction solution. To the solution was dropwise added under chilling with ice a solution of 0.39 ml of methyliodide in 2.4 ml of methanol. After the addition was complete, the reactionsolution was stirred for 2.5 hours at room temperature. The solvent was then distilled off under reduced pressure, and chloroform and water were added to the residue. The chloroform portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 2.0 g of the desired compound as a white powder, yield 97.9%.
Reaction SMILES: N1CCCC1.C(OC([N:16]1[CH2:20][C@H:19]([O:21][CH3:22])[CH2:18][C@H:17]1[CH2:23][C:24](=[O:31])[CH2:25][C:26](OCC)=O)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2].C(O)C.O1CCCC1>[CH3:22][O:21][C@H:19]1[CH2:20][N:16]2[C@H:17]([CH2:23][C:24](=[O:31])[CH2:25][CH2:26]2)[CH2:18]1
Reactant: CCOC(=O)CC(=O)C[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: CO[C@@H]1C[C@H]2CC(=O)CCN2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
3.79 ml (45.4 mmol) of pyrrolidine, 1.50 g of molecular sieves (MS4A) and 3.75 g of 20% palladium hydroxide on carbon were added to a solution of 15.00 g (41.3 mmol) of (2S,4R)-1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)-4-methoxypyrrolidine [prepared as described in Preparative Example 1 (ii)′ above] in 150 ml of ethyl acetate and the mixture was then stirred for 2 hours at room temperature under a hydrogen atmosphere. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 150 ml of tetrahydrofuran, and the solution thus obtained was added dropwise with stirring to an ice-cooled suspension of 4.70 g (124 mmol) of lithium aluminum hydride in 100 m] of tetrahydrofuran, and the reaction mixture was then stirred for a further 18 hours at room temperature. At the end of this time, 19 ml of a 4% aqueous solution of sodium hydroxide were added carefully to the reaction mixture at 0° C., and after the addition of 250 ml of ethanol, the resulting mixture was filtered. The filtrate thus obtained was concentrated by evaporation under reduced pressure and the residue was purified by chromatography on an alumina column using ethyl acetate as the eluant to afford 4.13 g (yield: 59%) of the title compound as a pale brown powder.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH:8]=[CH:7]1)(C)(C)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:6][CH:7]=[C:8]2[C:24]1[CH:25]=[CH:20][N:21]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:23]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: COc1cccc2ccn([Si](C)(C)C(C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-7-methoxy-1H-indole (prepared by TBDMS protection of 7-methoxy-1H-indole) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 660 mg (93%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O>[N+](C1C=CC=CC=1)([O-])=O>[F:12][C:13]1[CH:14]=[C:15]([C:16]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]3[N:8]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: O=Cc1ccc(F)c(F)c1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1cnc2[nH]c(-c3ccc(F)c(F)c3)nc2c1
Yield: 27.9 %

Procedure:
1.00 g 2,3-diamino-5-nitro-pyridine and 0.95 g 3,4-difluorobenzaldehyde were stirred in 60 ml nitrobenzene at 160 C for 26 hrs. The solvent was removed under vacuum and the residue dissolved in 40 ml pyridine at 60 C. The solution was cooled in an ice bath. Precipitated product was isolated by filtration and dried to yield 0.5 g of the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:31][C:32]1[CH:39]=[C:38](F)[CH:37]=[CH:36][C:33]=1[C:34]#[N:35].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:38]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([Cl:31])[CH:39]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(C#N)c(Cl)c2)cc1)Cc1ccccc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
Combine the compound from Example 218 step 2 (692 mg, 2.12 mmol) and K2CO3 (323 mg, 2.33 mmol) in DMF (9 mL), stir the mixture at room temperature for 30 min and then add 2-chloro-4-fluoro-benzonitrile (330 mg, 2.12 mmol), and heat at 100° C. overnight. Cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Purify by flash chromatography on silica gel (eluent: EtOAc/hexane 15/85) to obtain the title compound (940 mg, 95%). Electrospray MS M−1 ion=461, 1H-NMR (CDCl3, 400 MHz): 7.57 (d, 1H, J=7.8 Hz), 7.36-7.13 (m, 7H), 7.00-6.85 (m, 4H), 4.44-4.36 (m, 2H), 3.49-3.32 (m, 2H), 2.83-2.73 (m, 2H), 1.51-1.43 (m, 9H).
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.[H][H]>CC(C)=O.[Pd]>[C:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Yield: 73.4 %

Procedure:
A stirred solution of (R)-5-(2-benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8.5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone-85 mL-and mixed acetone/water-81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([CH3:20])[CH3:19])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].Cl[C:22]([O:24][CH3:25])=[O:23]>N1C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([CH3:20])[CH3:19])=[C:6]([CH2:7][NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[CH:16]=1
Reactant: CC(C)Oc1ccc(N)cc1CNC(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(OC(C)C)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 78.8 %

Procedure:
To 8F (24 mg, 0.09 mmol) in pyridine (15 mL) at 0° C. was added methyl chloroformate (18 μL, 0.24 mmol). After removing the ice bath and stirring at rt 7 h, the reaction was concentrated and purified via preparative HPLC (MeOH/water/TFA) to provide 8G (24 mg, 83%). LC-MS: 361.22 (M+Na)+.