Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20]1([CH2:26][CH2:27]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br-]>>[CH2:1]([N:8]([CH3:13])[CH2:9][CH2:10][N:11]([CH3:12])[CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCN(C)Cc1ccccc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Product: CN(CCc1ccccc1)CCN(C)Cc1ccccc1

Procedure:
A mixture of 0.900 gm N-benzyl-N,N'-dimethylethylenediamine, 1.10 gm powdered sodium carbonate and 0.75 ml of 2-phenylethylbromide is refluxed for 5 hours. An additional 0.25 ml of bromide is added during this time. The reaction mixture is then cooled and filtered. The filterate is concentrated in vacuo and the residue chromatographed on silica gel using an eluent of CH2Cl2 /CH3OH/NH4OH (97/3/0.3) to yield 0.875 gm of N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)ethylenediamine.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH3:47][N:48]([CH2:50][C@@H:51]1[CH2:56][CH2:55][CH2:54][N:53]([C:57](=[O:68])[C@H:58]([NH:66][CH3:67])[CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:52]1)[CH3:49].C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@@H:22]([C:23](=[O:25])[N:66]([C@H:58]([CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:57]([N:53]1[CH2:54][CH2:55][CH2:56][C@@H:51]([CH2:50][N:48]([CH3:49])[CH3:47])[CH2:52]1)=[O:68])[CH3:67])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N1CCC[C@@H](CN(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C[C@@H]1CCCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.9 %

Procedure:
At 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (379 mg, 1.98 mmol) was added to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propionic acid (651 mg, 1.98 mmol) and 1-hydroxy-7-azabenzotriazole (269 mg, 1.98 mmol) in dichloromethane (10 ml) and N,N-dimethylformamide (5 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of (2R)-1-((3S)-3-((dimethylamino)methyl)piperidin-1-yl)-2-methylamino-3-phenylpropan-1-one (600 mg, 1.98 mmol) in dichloromethane (10 ml) and ethyldiisopropylamine (0.51 ml, 2.97 mmol) were added successively. The reaction mixture was stirred for 3 days, while it was warming up to room temperature. Ethyl acetate (100 ml) was added. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml). The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.18 g of N-((1R)-1-{N-[(1R)-1-benzyl-2-((3S)-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[Cl:31])[N:17]=2)[CH2:11][C@@H:10]1[CH3:33])=O)(C)(C)C>O1CCOCC1>[Cl:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][NH:9][C@@H:10]([CH3:33])[CH2:11]2)[N:17]=1)=[O:32]
Reactant: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
Add 1 mL of conc. hydrochloric acid into a solution of 4-[6-(2-chloro-4-fluoro-benzoylamino)-pyridin-2-yloxy]-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 109, 0.678 g) in 1,4-dioxane 20 mL and heat at 100° C. After 40 min., partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column eluting with dichloromethane-2M NH3 in methanol, gradient to give the title compound (0.53 g). Mass spectrum (electric spray) m/z=364 (M+1); 1H NMR (CDCl3): 8.53 (br s, 1H), 7.84 (br d, 1H), 7.73 (dd, 1H), 7.63 (dd, 1H), 7.21 (dd, 1H), 7.10 (ddd, 1H), 6.49 (dd, 1H), 4.93 (m, 1H), 3.14 (m, 1H), 2.78 (m, 2H), 2.12 (m, 2H), 1.75 (br, 1H), 1.48 (m, 1H), 1.19 (m, 1H), 1.12 (d, 3H).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:9]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[N:34]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCCCCC>C(OCC)(=O)C>[Cl:7][C:8]1[C:9]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:10][C:11]([NH:14][S:40]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)(=[O:42])=[O:41])=[N:12][CH:13]=1
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: O=S(=O)(Cl)N1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NS(=O)(=O)N2CCCCC2)ncc1Cl
Temperature: 70 °C
Reaction time: 96 h
Yield: 46.4 %

Procedure:
A pyridine (2 ml) solution of the [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (101 mg, 0.235 mmol) obtained in Example 196 and piperidine-1-sulfonyl chloride (48 mg, 0.259 mmol) was stirred at 70° C. for 19 hours. To the reaction mixture was added piperidine-1-sulfonyl chloride (48 mg, 0.259 mmol) and the resulting mixture was stirred at 70° C. for 4 days. The reaction mixture was returned to room temperature and then, concentrated under reduced pressure. The residue thus obtained was diluted with ethyl acetate. The diluted solution was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=4:1) eluate was concentrated under reduced pressure to yield a white solid. The resulting solid was washed with hexane-ether, and collected by filtration to give the title compound (63 mg, 0.109 mmol, 47%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[C:13]=2[CH3:28])[CH2:7][CH2:6]1)=[O:4].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([C:3]([N:2]([CH3:29])[CH3:1])=[O:4])[CH2:6][CH2:7]4)=[C:13]([CH3:28])[C:14]=3[N:15]=2)=[CH:39][N:40]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1c(CN2CCN(C(=O)N(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)N(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 126. NMR (CDCl3): 2.44 (s, 3H, CH3), 2.56-2.60 (m, 4H, 2×CH2), 2.85 (s, 6H, 2×CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.83 (s, 2H, CH2), 3.88-3.91 (m, 4H, 2×CH2), 4.03-4.05 (m, 4H, 2×CH2), 5.22 (sbr, 2H, NH2), 9.35 (s, 2H, 2×ArH). MS: (ESI+): MH+=498.32
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reaction time: 8 h
Yield: 94 %

Procedure:
A 500 mL Par hydrogenation bottle was charged with ethyl 5-nitroindole-2-carboxylate (8) (5.0 g, 21.36 mmol), 10% Pd/C (0.3 g), methanol/THF (150 mL, 1:4 v/v), and was purged with hydrogen. The reaction mixture was shaken with 40 psi H2 overnight. The catalyst was removed by filtration and the solvent was evaporated to give 4.10 g (94% yield) of the title compound 18 as a brown solid. 1H NMR (CDCl3), 8.77 (s, 1H), 7.26 (s, 1H), 7.23 (t, 1H, J=0.8 Hz), 7.21 (d, 1H, J=0.7 Hz), 7.03 (dd, 1H, J=0.7, 1.5 Hz), 6.93 (dd, 1H, J=0.7, 1.6 Hz), 6.80 (dd, 1H, J=2.2, 8.6 Hz), 4.38 (dd, 2H, J=7.2, 14.3 Hz), 1.40 (t, 3H, J=7.2 Hz); 13C NMR (CDCl3) 162.02, 140.30, 138.14, 131.87, 128.45, 127.77, 117.12, 112.50, 107.36, 105.86, 60.87, 14.41. This product is unstable and therefor it was used immediately in next step.
Reaction SMILES: C(=O)(O)[O-].[Na+].C(OCC)(=O)C.Cl.[NH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[Cl:25][CH2:26][C:27](Cl)=[O:28]>O>[Cl:25][CH2:26][C:27]([NH:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: NC1CCc2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)NC1CCc2ccccc2C1=O
Reaction time: 1 h
Yield: 568 %

Procedure:
To a stirred solution of sodium bicarbonate (4.0 g) in water (50 ml) layered with ethyl acetate (200 ml) was added solid 2-amino-3,4-dihydronaphthalen-1(2H)-one hydrochloride (4.0 g, 2 mmol). After the solid had dissolved chloroacetylchloride (1.6 ml, 2 mmol) was added dropwise over 10 minutes. After stirring for 1 hr, the ethyl acetate layer was separated, washed with brine and dried over Na2SO4. Evaporation afforded 2.7 g (57%) of a dark solid; m.p. 118°-122° C. The product was purified by chromatography on silica using ethyl acetate: hexane (1:1 v/v) to elute, m.p. 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:25](OC)(OC)(OC)[O:26][CH3:27].C(O)(=O)CC>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([N:17]4[C:18]5=[N:19][CH:20]=[CH:21][CH:22]=[C:23]5[N:24]=[C:25]4[O:26][CH3:27])[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(OC)(OC)OC
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Solvent: O
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N2-(trans-3-((7-chloroquinoxalin-2-yl)amino)cyclobutyl)pyridine-2,3-diamine (118 mg, 0.346 mmol), tetramethyl orthocarbonate (922 μl, 6.92 mmol) and propionic acid (12.91 μl, 0.173 mmol) were combined under nitrogen. The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with saturated ammonium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give the crude material as a off-white solid. It was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a hexane to ethyl acetate gradient, to provide 7-chloro-N-(trans-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)quinoxalin-2-amine (85 mg, 0.223 mmol, 64.5% yield). M+1: 380.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][C:39]=1[NH:53][S:54]([CH2:57][CH3:58])(=[O:56])=[O:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:41]4[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[C:39]([NH:53][S:54]([CH2:57][CH3:58])(=[O:55])=[O:56])[CH:40]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: CCS(=O)(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCS(=O)(=O)Nc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Yield: 94.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example 14) (170 mg, 0.307 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide (intermediate 18) (125 mg, 0.368 mmol) using PdCl2(dppf) (50 mg, 0.0614 mmol) in sodium carbonate (97 mg, 0.920 mmol), DME/water (10/2 mL) to afford 200 mg of the crude titled compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)=[O:16])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Product: COc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.50 g of ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate (J. Amer. Chem. Soc., 68, 1268 (1946)) and 3.0 mL of 4-chlorobenzylamine is stirred 1 h at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.39 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[NH2:18][C:19]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH2:24]([C:19]([NH:18][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])([C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH3:27])[CH3:25]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Product: CCC(CC)(NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=394.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5](=[N:10][NH:11][C:12](=[O:34])[C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[Cl:33])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].CI.[C:37](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:4][C:2]([C:5](=[N:10][N:11]([CH3:37])[C:12](=[O:34])[C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[Cl:33])[C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:1])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)NN=C(C(C)(C)C)C(C)(C)C)c(Cl)cc2F)c1=O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN(N=C(C(C)(C)C)C(C)(C)C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 20.3 %

Procedure:
A mixed solution of 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid, 2-[1-(1,1-dimethylethyl)-2,2-dimethylpropylidene]hydrazide (0.48 g), excess of methyl iodide and potassium carbonate (0.132 g) in acetonitrile (20 ml) was heated at reflux temperature overnight. The mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and brine. The organic phase was washed with brine (×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluted with a mixed solvent of ethyl acetate and hexane (1:4 to 1:2) to give the titled compound (0.25 g) along with its, 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid, 2-[1-(1,1-dimethylethyl)-2,2-dimethylpropylidene]-1-methylhydrazide (0.1 g, Compound No. 6-8)
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][CH2:36][CH3:37])[C:31]([O:33]C)=[O:32])=[CH:23]2.O[CH2:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[NH:42][CH2:41][CH2:40][CH2:39][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][CH2:36][CH3:37])[C:31]([OH:33])=[O:32])=[CH:23]2
Reactant: CCCC(Cc1cc2cc(O)ccc2[nH]1)C(=O)OC
Reactant: OCCCNc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.12 g, 0.48 mmol) was added to the solution of methyl 2-[(5-hydroxyindolyl)methyl]pentanoate (0.03 g, 0.12 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.026 g, 0.17 mmol), as prepared in step b of Example 1, and tri-n-butylphosphine (0.09 g, 0.46 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (10%-50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.016 g, 36%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (m, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.02 (d, J=3.3 Hz, 1H), 6.88 (dd, J=8.9, 2.4 Hz, 1H), 6.53 (m, 1H), 6.40 (m, 2H), 4.32 (br s, 1H), 4.42 (m, 1H), 4.25 (m, 3H), 3.52 (m, 5H), 2.91 (m, 1H), 2.20 (m, 2H), 1.72 (m, 2H), 1.43 (m, 3H), 0.95 (t, J=7.2 Hz, 3H).
Reaction SMILES: [ClH:1].Cl.C([O:5][C:6]([C:8]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[NH:34])[NH2:33])[CH2:27][C:26]=3[CH:35]=2)[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])C>Cl>[ClH:1].[ClH:1].[C:32]([N:28]1[CH2:29][CH2:30][CH2:31][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:8]3([C:6]([OH:7])=[O:5])[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)=[CH:35][C:26]=2[CH2:27]1)(=[NH:33])[NH2:34]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=N)N)CCC3)CCN(c2ccncc2)CC1
Agent: Cl
Product: N=C(N)N1CCCc2ccc(OCC3(C(=O)O)CCN(c4ccncc4)CC3)cc2C1
Yield: 197.2 %

Procedure:
4-(2-Amidino-2,3,4,5-tetrahydro-1H-benz[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (150 mg) was dissolved in 6N-hydrochloric acid (2 ml), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, insoluble material was removed and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (140 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][C:18]([NH2:25])=[N:19][C:20]=3Cl)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CN(C)C.N1C(=[O:40])C2NC=NC=2N=C1N>O.C1COCC1>[CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:40])[NH:19][C:18]([NH2:25])=[N:17][C:16]2=3)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C1CCC(Cn2cnc3c(Cl)nc(N)nc32)O1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: CN(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)C1CCC(Cn2cnc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To [5-(2-Amino-6-chloro-purin-9-ylmethyl)-tetrahydro-furan-2-yl]-phosphonic acid diethyl ester (100 mg, 0.25 mmol) in water (7 mL) and THF (5 mL) was added trimethylamine (1.6 mL, 6.4 mmol). The reaction mixture was stirred at RT under nitrogen overnight. Conversion to guanine was confirmed by UV spectroscopy. The THF was removed in vacuo and the reaction mixture lyophilized. The sample was chromatographed eluting with 10% methanol/dichloromethane to give [5-(2-Amino-6-oxo-1,6-dihydro-purin-9-ylmethyl)-tetrahydro-furan-2-yl]-phosphonic acid diethyl ester as a white powder (40 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[C:43]([O:51][C:52]([F:55])([F:54])[F:53])[CH:42]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:47]([C:44]1[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][C:43]=1[O:51][C:52]([F:53])([F:54])[F:55])(=[O:49])=[O:48])[C:6](=[O:11])[C:5]2([N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(N2CCN(C(=O)OC(C)(C)C)CC2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3CCN(C(=O)OC(C)(C)C)CC3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 80.5 %

Procedure:
With 1.70 g of the compound obtained in Step 109-5 and 1.00 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 2.01 g of the title compound (amorphous) was obtained by a similar procedure to Example 2.
Reaction SMILES: O[CH2:2][CH:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CO>[O:45]=[C:43]1[C:42]2[C:41](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40](=[O:50])[N:44]1[CH2:2][CH:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CO)C(C)(C)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CN1C(=O)c2ccccc2C1=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methyl-2-phenylpropyl]carbamate (775 mg, 2.8 mmol), triphenylphosphine (915 mg, 3.5 mmol) and phthalimide (499 mg, 3.4 mmol) in THF (15 mL) at 25° C. was added diethyl azodicarboxylate (0.54 mL, 3.4 mmol). After stirring at RT for 1 h, MeOH was added (5 mL) and the reaction solution was adsorbed onto silica then purified via column chromatography(1% MeOH in DCM) affording the title compound (723 mg, 64%) as a white solid: LCMS (ES) m/z 409 (M+H)+.